The Interconnectedness of the Brain, Behavior, and Immunology and the Difficult to Overstate Flaccidity of The Correlation Is Not Causation Argument
Posted by: passionlessdrone on: May 12, 2011
Hello friends –
I’ve gotten into a lot of discussions online about the vaccines and autism; generally with very poor, if not nonexistent, evidence of having changed any opinions, but relatively strong evidence ( p > .001) that persisting in making my arguments can get you called ‘an antivaccine loon’, ‘idiot’, someone who engages in ‘Gish Gallop’, or the worst insult I’ve received so far, ‘anti-science’. While I am really torn on the vaccine issue, I am certain that both peripheries of this debate are at least somewhat wrong in the conclusions that they’ve drawn from the available evidence. I do believe that lots of parents have witnessed a very real change in their children post vaccination, and I also don’t believe for a single second that vaccines are the cause of an epidemic of autism. It’s a mess and I’ve been poking around the Internet almost five years into journey autism and from my eyes, it hasn’t improved any in the past half decade. This is very sad.
That being said, while I do think we need to have a rational and dispassionate discussion about what our existing vaccine studies can and cannot tell us about autism, I’m really concerned about the fact that the vaccine wars seem to have inoculated otherwise intelligent people from any semblance of intellectual curiosity regarding the immunological findings in the autism realm. That’s a problem, because there are lots of things other than vaccines that can modify the immune response, various environmental agents and cultural changes that are relatively new, and ignoring immunological findings in autism because they happen to intersect with the function of vaccination is a huge, massive, supernova sized disservice to what history will view us poorly on, refusing to perform honest evaluation due to fear and the comfort of willful ignorance.
Here, in this post, I will make the case that this lack of curiosity on immunological findings in autism is either born of a lack of understanding on how much we know about the ties between the immune system and the brain, or alternatively, originates from a deep seated desire to avoid honest interactions. This isn’t to make the case that vaccines can cause autism, or even that the immunological disturbances observed in autism are causative, but rather that an obstinate refusal to consider these as possibilities is the sign of someone who cannot, or will not accept, the biological plausibility of immunologically driven behaviors despite a constellation of evidence.
One of the things that jumps out to me why the autism population might be a subgroup of the population susceptible to changes as a result of immune dysfunction (and thus, potentially adversely affected as a result of vaccination), is the sheer volume of evidence we now have available to us indicating an altered immune response, and indeed, an ongoing state of inflammation within the brain in the autism population, and most strikingly, repeated observations of a correlation between the degree of immune dysregulation as a propensity of an inflammatory state, and the severity of autism behaviors. Again and again we’ve seen that as markers indicative of an inflammatory state increase, so too, do severity of autism behaviors. Not only that, but there are instances wherein the decrease of components known to regulate the immune response decrease, autistic behaviors are more severe. Subtle shifts in either the start or the resolution of the immune response seems to affect autistic behavior severity in the same way. I know coincidences happen all the time, but that doesn’t mean that everything is a coincidence.
We also have a large number of studies that tell us that in vitro, similar levels of stimulation with a variety of agents cause exaggerated or dysregulated production of immune markers in the autism population.
A large percentage of the time that I mention these findings, usually within discussions with an origin in vaccination, someone decides to educate me on one of the most rudimentary scientific axioms:
Correlation does not equal causation.
It must be stated, the above statement is absolutely true. Unfortunately for the people for whom this accurate, but simplistic catchphrase comprises the entirety of their argument, it completely ignores a wealth of research that tells us in very unambiguous terms that there is incontrovertible evidence that crosstalk between the immune system and central nervous system can modify behavior. The research indicating a relationship between immune dysregulation and autism does not exist in a vacuum, but rather, is only a tiny fragment of evidence, mostly accumulated within the last few years, that tells us that the paradigm of the past decades, that of the brain as a immune privileged organ without communication to the immune system, is as antiquated as refrigerator moms and a one in ten thousand prevalence.
From a common sense, why didn’t I think of that standpoint, the best example of the interaction between the brain and the immune response is the old standard, just plain old getting sick. You live in the dirty world, you pick up a pathogen, you get sick, and suddenly you get lethargic and you start to run a fever. But is it the pathogen itself that is actually making you feel like staying in bed all day?
What is being learned is that it is not necessarily the microbial invader that is causing you to get tired and feel sore, but rather, that your decreased energy levels are centrally mediated through your brain, and the triggers for your brain to start a fever include molecules our bodies use for a wide range of communications, including immune based messaging, cytokines. Some of the most common cytokines in the research to follow include IL-6, IL-1B, and TNF-Alpha; so called ‘pro-inflammatory’ cytokines. Researchers have been plugging away at just how the immune response is capable of modifying behaviors, i.e., inducing, sickness behavior for a while now, at least in terms of autism research. From 1998, we have Molecular basis of sickness behavior:
Peripheral and central injections of lipopolysaccharide (LPS), a cytokine inducer, and recombinant proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) induce sickness behavior in the form of reduced food intake and decreased social activities. Mechanisms of the behavioral effects of cytokines have been the subject of much investigation during the last 3 years. At the behavioral level, the profound depressing effects of cytokines on behavior are the expression of a highly organized motivational state. At the molecular level, sickness behavior is mediated by an inducible brain cytokine compartment that is activated by peripheral cytokines via neural afferent pathways. Centrally produced cytokines act on brain cytokine receptors that are similar to those characterized on peripheral immune and nonimmune cells, as demonstrated by pharmacologic experiments using cytokine receptor antagonists, neutralizing antibodies to specific subtypes of cytokine receptors, and gene targeting techniques. Evidence exists that different components of sickness behavior are mediated by different cytokines and that the relative importance of these cytokines is not the same in the peripheral and central cytokine compartments.
The first sentence in this abstract references a practice that is extremely common in studying the immune system, intentionally invoking a robust immune response by exposing either animals, or cells in vitro, to the components that comprise the cell wall of certain types of bacteria; lipopolysaccharide, or LPS. LPS could be considered a sort of bacterial fingerprint, a pattern that our immune systems, and the immune system of almost everything, has evolved to recognize, and correspondingly initiates an immune response.
Because this is a conversation that frequently has an origin in vaccination, essentially the act of faking an infection, it is salient to remember that the animals or cell cultures aren’t really getting sick when exposed to LPS; there is no pathology associated with whatever type of bacteria might be housed within a cell membrane containing LPS. Usually, when the body is exposed to a gram negative bacteria, and the consequent LPS exposure, there are also effects of the bacteria that interact with the organism, but by only incorporating the alert signal for a bacterial invader, we can gain insight into the effect of the immune response itself; there isn’t anything else to cause any changes. This means that similarly to LPS administration, straight administration of these pro-inflammatory cytokines are similar to the result of getting sick with a pathogen, at least as far as the immune response is concerned.
In the above instance, administration of LPS, or simply cytokines, had been shown to be capable of causing reduced food intake and ‘decreased social activities’.
Later in 1998, Central administration of rat IL-6 induces HPA activation and fever but not sickness behavior in rats (full version), was published wherein the authors report that central administration (i.e., directly into the CNS), of cytokines in isolation (IL-6) or in combination (IL-6 + IL-1B) were capable of inducing altered HPA activation, fevers, and sickness behaviors. Effects of peripheral administration of recombinant human interleukin-1 beta on feeding behavior of the rat was published a few years later, and observed that peripheral administration (i.e., not the CNS) of IL-1B could affect how much a rat ate, with sucrose ingestion being consistently altered during periods of sickness.
Jumping ahead a few years, a review paper Expression and regulation of interleukin-1 receptors in the brain. Role in cytokines-induced sickness behavior reviewed how cytokines participate in sickness behavior, Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior examined the interactions of IL-6 and leptin in sickness behavior, and Behavioral and physiological effects of a single injection of rat interferon-alpha on male Sprague-Dawley rats: a long-term evaluation reported “these data suggest that a single IFN-alpha exposure may elicit long-term behavioral disruptions”.
Much more recently, Sickness-related odor communication signals as determinants of social behavior in rat: a role for inflammatory processes more elegantly found that behavior was modified by LPS exposure, and that this effect was neutralized by concurrent administration of the anti-inflammatory cytokine, IL-10. Similarly, Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases observed another distinct means by which interfering with the immune response could attenuate the effect of faux sickness, in part, concluding, “Thus behavioral changes induced by CNS lesions may result from peripheral expression of cytokines that can be targeted with drugs which do not need to cross the blood-brain barrier to be efficacious.” In other words, what is happening in the periphery, outside of the protective boundaries of the blood brain barrier, can none the less manipulate behaviors that are controlled by the brain.
There are tons, tons more studies like this, but the point should be clear by now; it is accepted that you can achieve some of the same behaviors the come alongside illness, such as fever and lethargy, without the presence of an actual bacteria or virus; all you need is for your brain to think that you are sick.
While it must be acknowledged that the behavioral disturbances observed in autism are a lot different than feeling the need to watch TV all day, these types of studies were among the first clues that the traditional view of the CNS as a separate entity within the gated community of the blood brain barrier needed revision.
Measuring how much sugar water a rat drank is great stuff, but the reality is that we have conservatively a gazillion studies telling us that disorders that manifest behaviorally have strong, strong ties to the immune system; and once we begin to understand the vast scope of these findings, the utter frailty of “correlation does not equal causation” becomes painfully clear to the intellectually honest observer.
The big problem I found myself with in crafting this posting was that the sheer volume of studies available really makes a complete illustration of the literature impossible; I started looking and pubmed nearly puked trying to return to me a listing of all of the things I wanted to summarize. So here is some of the best of the best; to keep things interesting, I thought I’d only include findings from 2007 or later as a mechanism to show just how nascent our understanding of the connections between the brain and the immune system really are.
Initially, we can start with a condition that nearly everyone agrees is diagnosed based on behavior, depression. It turns out, the number of findings establishing a link between immune system markers and depression is wide and deep.
Here’s a great one, Elevated macrophage migration inhibitory factor (MIF) is associated with depressive symptoms, blunted cortisol reactivity to acute stress, and lowered morning cortisol, which reports, that MIF can modify HPA axis function and is tied to depression; a particularly compelling finding considering well documented alterations in HPA axis metabolites in autism, and the fact that increased MIF has also been found in the autism population, and as levels increased, so too did autism severity.
Here is part of the abstract for Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression (full paper)
Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders.
Somewhere along the way, researchers discovered that some anti-depressants can exert anti-inflammatory effects, for examples of these findings we could look to Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors, or Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy, which concludes in part, “Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery”.
In Investigating the inflammatory phenotype of major depression: focus on cytokines and polyunsaturated fatty acids, the authors report that, “The findings of this study provide further support for the view that major depression is associated with a pro-inflammatory phenotype which at least partially persists when patients become normothymic.” A nice review of the evidence of immunological participation in depression can be found in The concept of depression as a dysfunction of the immune system (full paper).
Moving forward, we can look to schizophrenia, we have similar findings, including Serum levels of IL-6, IL-10 and TNF-a in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance, which observed an imbalanced baseline cytokine profile in the schizophrenic group; findings very similar in form with An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces. Similarly, the findings from Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls, (full paper) which states, in part:
Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia
Their findings include differentially increased and decreased production of chemokines and cytokines as a result of LPS stimulations in the case group. Of particular note, a similarly dysregulated immune profile of cytokine and chemokine generation has been found in the autism population in several studies.
We also have several trials of immunomodulatory drugs in the schizophrenic arena that further implicate the immune system in pathology, including Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial, a ‘gold standard’ trial which found that, “Aspirin given as adjuvant therapy to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development”. A similar clinical trial, Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial , another gold standard trial, which also had findings in the same vein, “Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores.” [Celecoxib is a cox-2 inhibitor; i.e., anti-inflammatory, i.e., immunomodulatory]
What about bi-polar disorder? More of the same, including, The activation of monocyte and T cell networks in patients with bipolar disorder, or Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder, which reports, in part, “Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1ß in bipolar disorder.”. These studies were published in April and March, 2011, respectively.
Brain tissue from persons with bi-polar disorder also showed increased levels of excitotoxicity and neuroinflammation in Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients (full version), and authors report differential cytokine profiles depending on state of mania, depression, or remission in Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder.
Another disorder based solely around behavior, Tourette syndrome, has increasingly unsurprising findings. Polymorphisms of interleukin 1 gene IL1RN are associated with Tourette syndrome reports “The odds ratio for developing Tourette syndrome in individuals with the IL1RN( *)1 allele, compared with IL1RN( *)2, was 7.65.” (!!!) , and Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases is yet another example of observations of CNS based immune participation in a disorder that is diagnosed by behavior.
There are also some reviews that perform a cross talk of sorts between disorders; i.e., The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder, or Immune system to brain signaling: Neuropsychopharmacological implications, published in May 2011, which has this abstract:
There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.
All of the conditions above, depression, schizophrenia, bi-polar, and tourettes are diagnosed behaviorally; it is only in the last few years that the medical dimension of these disorders were even understood to exist. None of the studies that I referenced above are more than five years old; the idea that behavioral disorders were so closely entangled with the immune system is very, very new. It should be noted that I intentionally left out disorders that also have reams of evidence of immune participation, but which are more degenerative in nature; i.e., Alzheimer’s, ALS, Parkinson’s. When discussing autism, I also left out studies involving aberrant presence of auto-antibodies, of which there are many.
One of the things that I have learned in trying to refine my thought processes during my time on the Internet is that rarely does a single study tell us much about a condition; but the converse also holds true, if we have many studies with different methodologies or measurement end points, but they all reach similar conclusions, then the likely-hood that the findings are accurate is much, much greater. All of the studies I have listed above tell us something similar; that the immune system is clearly, unmistakably playing a part in a lot of conditions classically considered neurological and diagnosed behaviorally. It isn’t enough to nitpick flaws in a single one of the studies in order for ‘correlation does not equal causation’ to make meaningful headway into the implications of these studies; instead, all of the studies above, and lots more, have to be wrong in the same way if we would like to return to a place where we can keep our heads in the sand, hoping for coincidences and bleating out catchphrases in the face of clinical findings. That isn’t going to happen. Given this reality, we should not and cannot ignore the growing evidence of immune abnormalities in the autism population, no matter how inconvenient following that trail of evidence might become.
-pD
65 Responses to "The Interconnectedness of the Brain, Behavior, and Immunology and the Difficult to Overstate Flaccidity of The Correlation Is Not Causation Argument"
May 27, 2011 at 5:07 pm
Wow. Just wow. I absolutely love this post. I got the link from the Mothering.com forums. It is getting bookmarked.
I think arguing over the internet, or even in “real” life about this stuff is pretty pointless. I’ve done my fair share of it, but no matter how eloquently you poke holes in a detractor’s argument about this stuff, they won’t get it.
I’m just going to continue making choices for my family based on my own research. You are very right when you make the point that our understanding of the immune system is limited. I always tell people we are basically in the dark ages about how it works and someday people are going to look back on these times the way we look back on physicians bleeding everyone with leeches.
May 27, 2011 at 5:15 pm
Oh, and also, your post brought up some ideas for me. How does food impact inflammation? A lot of people interested in alternative medicine claim some foods cause inflammation which is the root of disease. I know that if you have something like undiagnosed Celiac disease, you have chronic inflammation in the gut which can cause all kinds of problems. I’ve got autoimmune hypothyroidism and I had Hodgkin’s disease, so I am really interested in this.
I’ll have to go do some research and see what I can find about antioxidants like Vitamin C and anti-inflammatory cytokines. Any thoughts?
May 27, 2011 at 11:43 pm
Hi Bethany -
Thanks for stopping by my blog.
Regarding a link between inflammation and food, I think it’s probably pretty complicated, but with a wide brush view, I believe there is research that some foods / supplements can provide benifits in terms of reducing inflammation (i.e., cod liver oil / lower red meat consumption). Certainly on a case by case basis, some people might react to foods with an abberant immune response; celiac being a good example, or a less robust, but still real intolerance to gluten being another. I wouldn’t go so far as to say that this is the root of disease, maybe just the root of some problems, in some people.
I haven’t read anything on vitamin c; as an antioxidant it might have an effect, but I haven’t really looked at it. Unfortunately, the picture is complicated, and there is reason to believe that achieving the right balance of oxidants and/or cytokine profiles is desirable, as opposed to getting values lower, and that can be tricky.
- pD
June 13, 2011 at 4:20 am
Combining Dr Terry Wahls information in her book “Minding my mitochondria” and the information on this site http://coolinginflammation.blogspot.com/ I’d say yes.
May 30, 2011 at 6:34 am
Vitamin C is something you need to seriously research. It’s not just an anti-oxidant. Nor is vitamin C “just” a vitamin. It’s the core of life, and without it the body’s pathways all become a crock, including the glutathione pathway. So many biochemical functions are dependant on appropriate levels, not just an RDA which might be enough to prevent the end-point of the morbid condition “scurvy” but which has little relevance to the actual ability to live a healthy, meaningful life.
Professor Clemetson’s 3 volume 1998 text is no longer published or available, but he gave me them on a disc before he died, so if you want a copy, email me. Other than that, Professor Harri Hemila’s website is the place to start, then branch out via Pubmed.
In terms of neonatal immunity, and the potential impact of vaccines, this three part series may have embedded information of use:
May 30, 2011 at 7:11 pm
Hi Hillary Butler –
Thanks for stopping by my blog. I’m very hesitant to assign elixir of life qualities to any particular vitamin, anti-oxidant, or anything else in isolation. Starting with Harri Hemila doesn’t seem too promising, curiously.
Vitamin C for Preventing and Treating the Common Cold
The lack of effect of prophylactic vitamin C supplementation on the incidence of common cold in normal populations throws doubt on the utility of this wide practice. The clinical significance of the minor reduction in duration of common cold episodes experienced during prophylaxis is questionable, although the consistency of these findings points to a genuine biological effect.
Clearly maintaining a correct balance of antioxidants is important, but the more I read about a lot of areas, the more I think that we cannot deduce much from single points of information; the body has many ways to compensate for deficiencies.
Thanks for the other links; they touch on some ideas I’ve had in the past and some ideas I have poking around for some posts that I haven’t had time to get to yet. Specifically, it has occurred to me that the differential immune response in neonates might not be an abberation, but rather, the result of selection and that we over come that design strategy with unknown risks.
- pD
May 30, 2011 at 9:23 pm
I only have anecdotal evidence, but I’ve only gotten a bad cold / flu twice in the last 4.5 years and it was because I didn’t take a bunch of Vitamin C those 2 times. We really “believe” in Vitamin C in this house because we’ve seen it work. I don’t know if it a miracle treatment, but it certainly makes my life better…
May 30, 2011 at 10:25 pm
PD, first, (thinking about the starting sentences of your blog )you are thinking, which is more than your naysayers are, and you are closer to the “truth” than you know, or your naysayers have the foggiest about.
Re Harri – understand his position. He’s a professor at a med school. He will only write “proven” fact, which he will be the first to admit is hidebound by mindsets, and what has been ‘done’. He would be the first to admit (privately), that there is far more to that story than he can talk about. Being part of a system, automatically puts constraints on what you can say, and how.
Which is why Clemetson’s texts are so important, and why knowing your way around all the alleys of pubmed are crucial. Everything is actually there, if you know how to find it.
Secondly, like everything there is a genetic element to “requirements” for vitamin C. When we started using it, we used C-stix which measured urinary overspill. My husband at the time weight 72 kgs, and he “required” 3 grams over 24 hours. More than that and he’d “spill”. Me? Well, I have a primary immunodeficiency (though no-one else in the family does have…) , and the amount of vitamin C I require on a good day is 4 times that needed by my husband. On a bad day, that goes up to 20 times.
Now that C-stix are no longer manufactured, I have to go by diarrhoea, which is accurate, but a lot more hit and miss.
What we need depends on the way our biochemical “utility pathways” are working, or not working.
If VACCINES caused autism across the board, everyone would have autism. Every baby whose mother took thalidomide would have defects. But no drug reaction works that way. It’s always a select group – about whom the medical profession know little, who will come up with the reaction.
The term “Individual Biochemical Susceptibility” the title of a book by Dr Roger Williams, applies.
This also applies to your point about vitamin C and the common cold. Large scale number crunching trials actually bear little relevance to the individual unique biochemical system, which might work radically differently from that of the next door neighbour.
(I’m allergic to all antibiotics. Are you? rhetorical question)
Bethany,
Over and above the sort of diet recommended by Dr Terry Wahls in her book “Minding my mitochondria” the two key arms of the innate immune system are, vitamin C, (as you rightly say) and vitamin D.
The consequences to a developing baby being inside a mother for nine months, who is chronically deficient in those two things, who is also primarily eats a balanced meal on the knees of takeaways, Kentucky fry, McDonalds, donuts, coca-cola and barely knows fruits or vegetables are huge.
That sort of diet, so common in pregnant women I see in this country today, causes permanent epigenetic changes – including in the immune system. The proof is in their medical literature, but they keep their mouths shut.
And it’s my pick that the nutritional deficiencies my mother had laid the foundation for my immunodeficiency (since no-one else in the family has one) and resulted in her losing all her teeth at the age of 40.
Sorry about the ramble…
June 1, 2011 at 2:16 am
Hi Hillary Butler –
I certainly wouldn’t argue with the idea that on a person to person level, there will be differences in how a variety of agents are handled. I’ve got some things that I know work for certain ailments, or did work in the case of my son’s autism that can’t be validated on pubmed. I just think we need to be cautious about extrapolating too broadly.
Regarding diet, especially maternal diet and epigentic changes, I think we are in agreement on the danger of this kind of thing. I wrote a post about an animal model of obesity that found a striking number of physiological and behavioral similarities to autism, here. This is an area that is getting a lot of attention lately, my inbox has had tons of related notifications the past few months. Coincidentally, at this years IMFAR, findings were announced that indicated an obese mother, or mother with type II diabetes had an increased risk of bearing a child with autism, as well as serum values of TNF alpha during pregnancy showing an association. The proposed mechanism of action was upregulation of the innate immune system; i.e., a state of chronic inflammation during neurodevelopment.
No one seemed to care about the problems this presented for a static rate of autism.
- pD
May 31, 2011 at 10:42 pm
Hi pD
Wonderful! Thank you for your post.
I do think that the problem of autoimmunity, the breakdown of tolerance , is one of the cornerstones of the situation. There are two main aspects that , if you allow me, I would add
1- the topic of molecular mimicry, bystander activation and viral persistence
http://cmr.asm.org/cgi/content/short/19/1/80
2- the idea of the fertile field in autoimmunity. Even when the framework has been diabetes, I do think that the approach would be very valuable- and fruitful in ASD. Unfortunately, nobody is trying….
Nat Rev Microbiol. 2003 Nov;1(2):151-7.
Microorganisms and autoimmunity: making the barren field fertile?
von Herrath MG, Fujinami RS, Whitton JL.
Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the ‘one organism-one disease’ paradigm that is central to Koch’s postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.
3- how conditions as post strep autoimmunity are being studied of strong behavioral components and symptoms. There is no attempt to study post strep conditions in autism as a whole (including severe manifestations such as RF but also others more difficult and controversial to diagnose)
4- how far, even with all the knowledge that remains unsystematized, unanalized, and in the case of the Anecdotal evidence dismissed, we are from the discussion of a protocol of immune conditions in autism and this is also very sad.
Thank you for your post. What do you think?
June 2, 2011 at 1:59 am
Hi Maria -
I’ve been thinking about an interesting nugget I’ve seen in a couple of places regarding the possibility that a state of chronic inflammation could possibly lead to the development of auto-antibodies and autoimmunity. I think the idea being that if you keep an innate immune response active for long enough, sooner or later native proteins are captured, presented, and determined to be foreign. This could also have a place alongside molecular mimicry, if I understand correctly. I think that the PANDAS issue needs more attention, it will get there, but progress will be slow for those of us who think our children react differently for some time after they are ill.
- pD
June 2, 2011 at 2:44 am
Single vaccines can lead to a rise in autoantibodies in adults, http://www.beyondconformity.org.nz/_blog/Hilary's_Desk/post/The_ignorance_of_vaccinologists/ and they’ve not yet done studies to find out what happens after repeat vaccines. What might be the result in a neonate, which is programmed NOT to create inflammation of any sort, during the period when the body is programmed to learn “tolerance” to define self and non-self, and what is “safe”?
In this post http://www.beyondconformity.org.nz/BlogRetrieve.aspx?PostID=49837&A=SearchResult&SearchID=2203544&ObjectID=49837&ObjectType=55 look for Tsumiyama and Toplak if you’ve not seen them before… otherwise ignore…
There are heaps of medical articles which show that hepatitis B vaccine causes autoimmunity in recipients, as does the influenza vaccines. Yet how many doctors even know of the existence of these articles?
and who is asking the question – WHAT – in the vaccine, is triggering the autoimmunity, because like you, I don’t think that it’s just molecular mimicry.
These were what could be termed the “non-specific” effects of vaccines in the western world. Different from the ones that Aaby talks about in Africa.
Africa has Aaby; the western world has no-one.
June 4, 2011 at 10:52 am
Hi Hilary Butler –
Those are some interesting studies you’ve got there.
- pD
June 4, 2011 at 10:14 pm
The implications are huge, eh. And certainly define why the medical researchers only look at directions which “interest” them.
For instance: PMID 20415850 is fulltext free on pubmed. If you read that, and then put it alongside PMID 20964742 (which is not free, but I have it… email me if you want it…) and THEN put that alongside all the fulltexts in the three blog series I did at BC (links above) …you’d have to conclude that Biggelaar and Holt (PMID 20415850) are bonkers. I mean, in the face of everything that all the other researchers are putting out there about the developmenta phase… like this one: http://beyondconformity01.basecontrol.co.nz/_literature_86198/Neonatal_Immunity_Chelvarajan_07 how is it that Biggelaar and Holt truly believe that the ONLY epigenetic influences are “in utero”, but that the minute a baby is born, the immune system can only be influenced for “the good” and it’s absolutely essential and safe to toss in cluster bombs into babies bodies and (heads)?
See articles at http://www.beyondconformity.org.nz/_blog/Hilary's_Desk/post/How_a_baby_fights_infection_and_develops_the_immune_system/
The only possible reason they could have such an irrational blind spot in the face of all the other evidence put out by “pure” researchers, is that Holt and Biiggelaar are so pro-vaccine, and so much of their CVs are wedding to promoting vaccines, that any other stand would effectively cut themselves off at the knees, and they know it.
I simply can’t find any other explanation for their extraordinary refusal to see that the breastfeeding phase is a second term pregnancy in that the development is so fast, and tied to immuno-modulation which is orchestrated and deliberately down-regulated for inflammation, by breastmilk.
They have to know this.
Then to suggest that parallel comparative studies of babies in undeveloped and western countries could help to stem the huge escalation of allergies and chronic illnesses is extraordinary.
I want to knock their heads together and tell them to compare four groups in developed countries from ONLY healthy mothers with no medical conditions or allergic family history (in order to elminate obvious variables, and since they do this with all phase vaccine trials, http://www.clinicaltrials.gov why not do it with this idea?).
Western world only:
Formula-fed/fully vaccinated
Formula-fed/never vaccinated
Fully breastfed/vaccinated
Fully breastfed/fully vaccinated.
If they wanted, they could try that in a country like India where formula feeding is now de riguer…
Note the term “fully breastfed”. What most people fail to appreciate is that ONE bottle of formula changes a baby’s gut ph from about 8 down to 5.5 for two weeks, and as a result changes the gut flora hugely.
That’s been known for over 50 years, in the medical literature.
AND… since it’s gut flora that part-modulates so much of the neonatal immune response, and “conduction” of the innate orchestra is controlled by the breastmilk, …any baby which has regular complementary formula is to all intents and purposes in terms of the immune education…., “formula fed”. So those babies could be a fifth group but I’d just ignore them and keep the direction of the study specific…
Again, all this has been there for in decades of medical literature, but it’s only been in the last 20 years that they’ve started to really appreciate the power of breastmilk over the child’s immune system development.
Why is this never talked about?
When I STILL see medical people handing out formula samples, I really shake my head in disbelief.
The amount of information coming out about what breastmilk actually does in the baby’s developing immune system has been huge in the last 10 years… , amazing and absolutely stunning. I cannot understand why paediatricians still say that formula is an acceptable substitute… it may be in that it will keep a baby alive, but the studies clearly show that biochemically and immunologically right through life, formula fed babies are “different” and have much higher immunological risks until death, because their neonatal immune system went without the breastmilk priming….
And yes…. I’ve been called a “breastfeeding nazi” by young parents who want to formula feed from the start.
Shrug.
June 13, 2011 at 1:48 am
Hi Hilary Butler -
Not really immune related, but working on an upcoming post I ran into these papers that I bet you’d find inteteresting.
http://pediatrics.aappublications.org/content/115/5/1367.long
http://circ.ahajournals.org/cgi/content/full/111/15/1897
Nice.
- pD
June 2, 2011 at 2:45 am
P.S. I’ve not found any studies looking at any of the other vaccines re autoimmunity, but that might just mean I’ve not looked far enough.
June 3, 2011 at 1:55 pm
Everybody knows autism is caused by refrigerator mothers. (Sorry–I suffer from Snarkolepsy). There are studies to prove it.
Oh, my…biological basis makes sense to me. Good luck, hope you are riding on the crest of new thought towards autism.
I, too, had no answer to correlation/causation rule, but couldn’t face it logically…if science isn’t observation, what is it?
Madam Curie said There are sadistic scientists who hurry to hunt down errors instead of establishing the truth., and it seems that was done with autism.
Thank you for taking the time.
June 3, 2011 at 2:28 pm
Had you ever heard of this study? I don’t know if it was ever completed. It was very interesting to me at the time. I don’t know that it is related to what you are talking about.
http://www.autismspeaks.org/science/research/initiatives/environmental_factors_keil.php
There used to be a lot more talk of NK cells and autism. Then it seems like we got distracted by mercury.
June 8, 2011 at 6:34 am
Like Bethany said, Wow!! So very interesting. Thank you for taking the time to read through so many studies and summarize some key points for us. Clearly there is so much more to be learned in this area, and so much that has been learned but not publicized much.
Having spent the day watching movies on TV — very unusual for me — due to feeling totally bowled over by a cough/throat/cold virus — also very unusual for me — it was especially relevant to read about how cytokines tell our brains to slow us down. I always thought it was the effect of the germs that made us feel weak when sick, but that makes sense that our body has ways of telling us to rest so that the body’s resources can focus on fighting the illness.
I was aware of studies saying that inflammation in the brain and autoantibodies to the myelin basic protein coating nerve cells are more common among people with autism, and I had thought about how those might cause or exacerbate autism. It was interesting to read today that certain proinflammatory cytokines “induce sickness behavior in the form of reduced food intake and decreased social activities”. Perhaps this ability to induce decreased social activities evolved for two reasons: so that we would rest more when sick, and so that we would interact less with others and thereby not spread the germs as much? I wonder, what if this “sickness behavior” consisting of decreased social activities is exagerated by multiple vaccines with adjuvants, thus contributing to autism? Wouldn’t it be something if it is found that autism is not just brain damage due to the effects of inflammation, auto-immunity, and toxins on brain and nerve cells, but also sometimes due to a natural mechanism designed to reduce sociability, which can become exagerated and go awry? An interesting thought. Reduced food intake is also an issue for many people with autism.
This article was also interesting in relation to dietary intervention. I have often wondered (and heard various theories about) how simply removing certain foods from the diet has such a huge impact for some people. It makes sense that if certain foods are eliciting an exagerated response from the immune system (for whatever reasons, including due to vaccines) and if removing those foods calms down whatever parts of the immune system were over-responding, this could impact the brain and behavior in the ways you have touched on in this article.
June 13, 2011 at 3:37 am
@PD your reply to my post No 7 – can’t reply under yours, because there is no reply button.
Warning. Rant ahead. No offence meant, just blood pressure rattling in the upper reaches!
Yes, I’ve seen both those studies, and the pediatrics one rightly notes that there are too many confounders – in particular, because they can’t know that all those breastfed babies were ACTUALLY breastfed, just as I said in my post above yours.
They know that breastmilk orchestrates obesity (lack of)… and there isn’t enough space here to discuss why. If you research formulas, it’s enormous trying to sift out the garbage from what’s useful, but the more you look at formula, the more you wonder just what persuaded paediatricians to support it, and…
Here’s one reason why so much of what is in both those studies is spurious:
ONE of the reasons paediatricians argue for supplementational formula is that breastfed babies get “anaemic”. Breastfed babies do NOT get anaemic The whole concept of anaemia equating to iron deficiency is bad science. It’s another ludicrous concept that the medical profession has got wrong.
The whole method of measuring iron is spurious as well.
We are NOT designed to load up with iron, and the RDAs are far too high. Iron and glucose have an inter-relationship and it’s interesting to me that so many “diseases” are really iron overload. If you chelate out iron from diabetics, their diabetes improves.
Breastfed babies are “protected” from diabetes, from obesity. Why might that be? Might it be that breastfed babies have the “right” breastmilk sugar – iron balance for optimum growth?
Babies on formula, will suffer from subclinical iron overload, and that is ONE of the problems associated with both diabetes and obesity.
Have a look at PMID: 20876715 and PMID: 21620786, then work backwards, and you will see what I mean. Yet what mother hasn’t been told their haemoglobin is low, and they should go on iron. Where does the iron overload in babies come from? The mother, because the default position of the placenta is to divert iron to the baby, which is just fine under “normal” circumstances when the mothers intake is 1.5 mgs. What happens when 27 mgs per day, is tossed into the mix? How many overload grams of iron will a mother get over that pregancy? What is the effect of the baby to be?
Using PMID: 21620786 if you click on related articles you will see that they are blaming genes – rather than understanding that anaemia isn’t iron deficiency. They have the cart before the horse… I dont’ think we have an “expanding clinical spectrum of mitochondrial disorders”. I agree with Dr Terry Wahls, that we have an expanding clinical spectrum of nutritional disorders, which – like Pottenger’s cats – impact genes epigenetically, through the generations, incrementally compounding problem on problem, because we are interfered with by people who don’t understand the ramifications of their assumptions..
Since when does low haemoglobin levels PHYSICALLY equate to iron deficiency? Only when a doctor says it does, but it’s a load of rot. Anaemia could be called “iron loading anaemia” because when you load iron, you completely mess with other minerals and other b-vitamins, which affects other pathways, and results in “anaemia”. They have known that for decades, and had all sorts of explanations as to why Iron could also be bad,… like “Oh, you are minus the ‘intrinsic factor’.” “What’s ‘intrinsic factor,” doc?”. Reply: “Well, we have no idea, but it’s something intrinsic, which we can’t see, but think must be there, because what other explanation is there?” Iron supplements in pregnant women cause so many problems, iron overloads the baby – so how will they confound for that in the formula feeding studies?
And it’s never a surprise to me, when a pregnant woman obeys and takes iron, she starts having bacterial infection after bacterial infection! The doctor simply tells her to stay away from people with ‘BUGS’ !! Ever heard a doc say to pregnant mother, “GO OFF your prenatals, because bacteria feed on iron”. How do they know this? Because they know that the immune system kicks in and tries to remove iron during a bacterial infection.
People with diabetes have<b? too much iron…. Autistic kids have high levels of iron.
Hello? Does it ring a bell? What does iron overload DO, particularly to mitochondria?
Where did the iron come from? Thin air, or prenatal vitamins prescribed by the medical profession because they don’t know the difference between “low haemoglobin” – and pregnant blood which has extra fluid as part of the “built in ” design which results in “low haemoglobin” because the blood sample is “diluted”?
What’s the FDA recommendation of iron for pregnant women? 27 mgs a day… A ludicrously high amount..!!! These doctors fail to realise that excess iron intake is ONLY removed from the body at 1 mg a day in hair, skin turnover, and toe and fingernail growth… …and the rest is stored.
They “think” that the only excess condition is haemachromatosis. yet they talk about iron overload in babies. Come on. They are oblivious to the fact that iron is actually BAD for the human body, and that what they call iron deficiency, is actually a b-vitamin deficiency, and altered pathways unable to use what iron the body already has in abundance…
These two things must be factored into any study on both formula feeding and breastfeeding, because iron alters lots of biochemical pathways…. but they can’t confound for them, because they don’t accept, or know there is an issue with iron. They think it’s “good for you”.
Fortunately the breast regulates iron output at about 1 mg a day, a bit more than a baby’s body excretes – yet the medical profession considers that a deficiency…
On the other hand, someone with Gilbert’s syndrome, with a bone ferritin reading of 400 will be given the cure for this. Guess what it is. Elemental iron. It’s the only way to reduce the ferritin reading. Iron – ic isn’t it.
How can we possibly trust these people to work out what’s wrong with our kids, when their basics are so lacking that everything else becomes a wild goose chase…. The medical profession should be certified as a walking menace to pregnant mothers, babies and children, when it comes to defining how to keep them healthy
Rant off. Sorry about that, but just had to say it….
June 13, 2011 at 7:59 pm
Well, what if you are chronically anemic (ferritin levels) even when trying to take iron pills? I have that problem and I worry about it. Do I have b-vitamin deficiency then? Do you have any studies to back up all the stuff you wrote? I am interested.
June 14, 2011 at 1:28 am
Hi Hilary Butler –
I would recommend caution in blanket statements about the cluelessness of the medical community; when evaluated through a lense of intellectual honesty I do think that the science based approach we have being implemented is the best available option. Sure there might be problems, but considering the alternatives and from where we came, the classification of medical professionals as menaces does nothing but dilute whatever argument you might make. I don’t know enough to form an opinion on iron supplementation during pregnancy, it would not necessariy surprise me to find it has other effects up and above correcting low iron in the mother, but the second you reference two PMIDs and extol others to work backwards in order to explain why the entire medical community is wrong about the definition of anemia, you are no longer in the realm of discussion, but rather, as you note, ranting. This is a surefire way to insure that your points are not considered worthy of consideration, regardless of their underlying merits.
I definitely believe that as a species, we have underestimated the complexity of the developing systems and the subtlety of entangled systems that cannot be manipulated in isolation; and we may have embarked on potentially dangerous population wide experimentation. That being said, however, I”m not sure it helps to point out that iron metabolism is a compicated arena and simultaneously reduce the knowledge of the medical community to ‘they think its good for you.’.
The association between formula feeding and metabolic syndrome has nothing to do with increased iron intake, and lots to do with perinatal developmental programming of energy balance regulation, a concept with a dizzying array of experimental and observational evidence.
I sort of like the fire in your gut, and you have some interesting things that I need to think go give more detailed thought towards.
- pD
June 14, 2011 at 4:52 am
@Pd, you are, of course correct – in that the minute a person shows serious emotion, particularly if they are a woman, they must be somewhat neurotic 
.
The problem is that extra iron in pregnant women, often doesn’t resolve the anaemia, just as long term iron hasn’t resolved Bethany’s chronic anaemia.
Perhaps some of my passion is as a result of a friend of mine, who has just finished a year-long course of iron injections (I kid you not). At my request, she went and got printouts of her 3 monthly blood results which resulted in the doctor wanting to know why she wanted them. Her “anaemia” is worse than it was when she started the injections. Not once in the last four blood tests has the doctor said, “Oh hang on here, we’re going nowhere. Perhaps we should rethink this.” Why is that? Perhaps he doesn’t know enough to know where to start to rethink the issues.
I know where to start, because I’ve had 30 years practice on myself. If you are anaemic, and iron doesn’t work, you don’t have “time” to wait around to see what the “scientific” method is going to come up with, particularly when they’ve been “looking” at this for decades, but coming up with no answers.
I brough up the issue of iron because of the two studies you put up. In my mind, iron overload is a serious confounder in any bottle/breastfeeding study and should be taken into account.
I like the scientific method – when scientists think. When there is a resolution to this issue, I’ll know they have thought. Instead, I see them off on geese-chasing gambits looking for more genes.
Like neural tube defects and folic acid, (it’s the genes you know….) how many decades will it take for them to connect those dots and say, “Oh, it’s the folic acid!, not the gene….”
These researchers have been looking at the puzzling issues with iron, for decades, yet today, we have the same “recommendations” as we had decades ago.
Yes, I only put up 2 PMIDs, but this is your blog, not mine – to treatise on – but… I can toss plenty of full text articles your way, if you toss me an email with storage. Do you have a passionlessdrone@gmail or some generic one?
It’s not enough for these scientists to say “A gene does causes iron problems” any more than it would now be enough to say that a “gene” causes neural tube defects when we know that folic acid will PREVENT neural defects.
You say ***I”m not sure it helps to point out that iron metabolism is a compicated arena and simultaneously reduce the knowledge of the medical community to ‘they think its good for you.’. ***
It’s the reality. Look at Bethany. Her doctor thinks its good for her, yet her anaemia is chronic, and it’s doing nothing. In that regard, it should be helpful, if Bethany researches it thoroughly, and lands up at her doctor with a raft of medical articles and says, “Hey doc, we’ve gone nowhere for how many years? Can we look at this?”
With iron, are we talking about cross mineral reactions leading to altered biochemical pathways, or do excess levels of minerals, methylate genes?
Mitochondria has an interesting iron-clad coating (to use a lay term) but what effect does too much iron have on mitochondria? and how does it exert that effect? There are so many questions raised by all these issues, but why can I find no evidence of practical questions being answered?
That’s at the basis of my total frustration on this issue, because most pregnant women don’t need iron. They need a decent diet with adequate folic acid and b vitamins, and more fresh fruit because vitamin C increases absorption of iron six times.
June 13, 2011 at 8:22 pm
Hi Bethany, if you go to Google School and put in the words anaemia folic acid and B deficiency, download the pdfs there, and you will start to see that iron isn’t the answer. And sometimes, it’s the type of iron and dosage which is the answer.
In the few people who are TRULY iron deficient, low doses of ferrous bis glycinate rather than ferrous sulfate, is far better tolerated, and gives good results.
But the very fact that you are taking iron pills and they have done nothing, is enough to tell you that the problem isn’t iron.
June 14, 2011 at 9:02 am
Like neural tube defects and folic acid, (it’s the genes you know….) how many decades will it take for them to connect those dots and say, “Oh, it’s the folic acid!, not the gene….”
That should have read… “How many decades did it take for then to connect those dots….”
August 19, 2011 at 1:05 am
[...] causing these profiles, or how, precisely, they might give rise to an increased risk of autism. The interconnectedness of the brain and the immune systemwould be a good place to start looking for an answer to the last question [...]
October 12, 2011 at 6:35 pm
Just came across this outstanding blog today. Really good coverage of the relevant literature in this area.
Your topics are amazingly similar to those covered in my book that was just published by MIT Press: http://mitpress.mit.edu/catalog/item/default.asp?ttype=2&tid=12756
And your blog and my new book blog also have some key overlaps: http://infectiousbehavior.wordpress.com/
Keep up the good work!
Cheers,
PHP
October 14, 2011 at 10:40 pm
Hi Paul Patterson –
I am humbled that you would stop by my tiny corner of the internet and use such kind language. Thank you.
I’ve been meaning to give some detailed attention to some of the recent prenatal environment / maternal immune activation work regarding autism, including your own, but haven’t had the time to apply to it yet. I will say, I found “Activation of the Maternal Immune System Induces Endocrine Changes in the
Placenta via rIL-6″ to be particularly nice, especially the subtlety of looking for differences in poly:IC challenged mothers compared with those that received straigth IL-6. Very graceful.
A copy of your book arrived at my home today.
- pD
November 26, 2011 at 7:58 am
Hi pD
Any thoughts on these two 2011 studies …
Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation 2011
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098713/
Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024691
(Might have to google that one to get full paper which has been published on plosone.
Cheers
November 27, 2011 at 12:15 am
Hi
Got in contact with Paul Patterson
http://infectiousbehavior.wordpress.com/2011/10/19/empathy-and-evil/#comment-57
phpatterson says:
November 26, 2011 at 6:05 pm
Thx for those refs Blackheart. Those are indeed right up my alley. The NFKb connection with autism is potentially important because this protein is at the hub of the network that receives, computes, and outputs responses to inflammatory signals impinging on cells. Thus, changes in NFkB levels or activity can profoundly influence how a cell responds to cytokines, for instance. The second paper, on profiling autism candidate genes is somewhat speculative, but places many immune/inflammation genes at the heart of the autism gene network. This is consistent with the paper by Dan Geschwind and colleagues at UCLA that I consider to be the gold standard of gene network analysis in autism brains (http://www.ncbi.nlm.nih.gov/pubmed/21614001). In that paper, Dan found that the specially expressed genes in autism fell into two groups, one having to do with synapses and neuronal function, and the second having to do with glia and immune function. This place immune function once more at the heart of autism gene network activity.
————————
My Reply
blackheart says:
Your comment is awaiting moderation.
November 26, 2011 at 10:55 pm
Thanks for the reply ..
I’ve had an amateur look at some aspects of NFkB in autism and some of the other aspects that seem to correspond to the some ‘types’ of ASD. Allergies , Eczema , asthma , sleep disturbances , anxiety, and inflammatory bowel disease. (I can send you some of the paper links if you like)
Am I correct (and I don’t mind being wrong) that this is supplementing evidence of two phenotypes of autism (that has been yet to be published I believe but) presented at a South Pacific Autism conference by David Amaral at University of California Davis MIND Institute.
“One group of children – all boys – had enlarged brains and most had regressed into autism after 18 months of age; another group appeared to have immune systems that were not functioning properly.”
——————–
I’m not clear I have read this part properly
“Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism.
In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process.”
Is this suggesting two distinct pathways (aetiology) – one being genetically based and the other due environment ?
November 27, 2011 at 4:08 pm
Hi Blackheart –
Nice response from Mr. Patterson, I think that many autism discussions could use that type of tempered attitude towards findings.
I believe that a lot of the papers I’ve been reading lately, including the ones referenced by you and Mr. Patterson may help shed light on some of the seemingly paradoxical findings in the autism CNS. Specifically it seems likely to me that we will continue to find instances where multi functional or, technically, ‘pleiotropic’ genes or functional networks are implicated. In the examples of the papers you listed above, the NK-KappaB pathway is implicated in lots of functions of interest to us, clearly immune function, but also cellular signaling and/or migration. In this way, perhaps, there is a mechanism by which perturbation of this pathway could participate in several findings that on first glance might appear to be distinct from one another.
Regarding the MIND paper on two distinct phenotypes, I saw the headlines, but would like to read the paper, but this type of classification is going to be paramount if we want to really start looking at specific risks for causation. Grouping all of autism together and then analyzing to see if there is something tipping the developmental trajectory starts the process off with much too large a bucket, individual cases where the effect of an impact is real are going to be lost within the mass of ‘autisms’. That is a problem that is going to take a long time to overcome, but studies like that, or another by Jynouchi that I’ll try to discuss in another response, I think, are good incremental steps in the right direction.
Thanks for stopping by my blog, the real world is really interfering with my ability to craft some detailed responses / work on some blog postings I’ve got on the stove, but I do appreciate your thoughts.
- pD
November 29, 2011 at 8:27 am
http://www.pnas.org/content/early/2011/11/14/1107560108.abstract
“We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism. ”
In this paper …
Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024691
GO enrichment analysis of highly expressed Autism genes.
Apopotosis / Cell death.
Also …
“Expression of Glial Fibrillary Acid Protein (Gfap), an astrocyte-specific intermediate filament, also showed high expression in all brain regions beginning at the fourth postnatal month”
Centrally Administered Pertussis Toxin Inhibits Microglia Migration to the Spinal Cord and Prevents Dissemination of Disease in an EAE Mouse Model
“Centrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.”
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012400
Augmentation of major histocompatibility complex class I and ICAM-1 expression on glial cells following measles virus infection: Evidence for the role of type-1 interferon
http://onlinelibrary.wiley.com/doi/10.1002/eji.1830220126/abstract
Brain endothelial cell infection in children with acute fatal measles.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC185901/
Reactive microgliosis. Immunocytochemical staining of
brains from acute measles patients was performed for ferritin
and glial fibrillary acidic protein (GFAP) as an indication of
microglial or astrocytic reactivity respectively (20, 21). The
amount of GFAP staining was not different between measles
and controls (data not shown). The amount of ferritin staining
was increased in acute measles (Fig. 1 E) compared with a
normal control brain (Fig. 1 F), indicative of a reactive microgliosis.
Down-regulation of glial fibrillary acidic protein expression during acute lytic varicella-zoster virus infection of cultured human astrocytes.
http://www.ncbi.nlm.nih.gov/pubmed/7975257
Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice
http://www.nature.com/mp/journal/v7/n6/full/4001046a.html
Measles Virus-Induced Disruption of the Glial-Fibrillary-Acidic Protein Cytoskeleton in an Astrocytoma Cell Line (U-251)
http://jvi.asm.org/content/74/8/3874.short
———————————————————-
November 29, 2011 at 12:39 pm
Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, 2006.
http://www.ncbi.nlm.nih.gov/pubmed/20023608
“For the 2006 surveillance year, 2,757 (0.9%) of 308,038 [corrected] children aged 8 years residing in the 11 ADDM sites were identified as having an ASD, indicating an overall average prevalence of 9.0 per 1,000 population”
————————————————————
Association of Hospitalization for Infection
in Childhood With Diagnosis of Autism
Spectrum Disorders
The completeness of ASDs diagnoses in the Danish register
is assumed to be good; the prevalence of ASDs for 9-yearold
children is reported to be 5.1 per 1000,27 an estimate
similar to the American prevalence of 4.2 per 1000 for
8-year-old children living in metropolitan Atlanta.28
————————————————————
Prevalence of autism-spectrum conditions: UK school-based population study
http://bjp.rcpsych.org/content/194/6/500.abstract
“Recent reports estimate the prevalence of autism-spectrum conditions in the UK to be 1%.”
“Taken together, we estimate the prevalence to be 157 per 10 000, including previously undiagnosed cases.”
————————————————————
It seems that Denmark has an “Autism ” rate approx half that of that found in the USA and UK.
I’ve got to say that the difference between vaccine schedules is stark …
http://apps.who.int/immunization_monitoring/en/globalsummary/scheduleselect.cfm
————————————————————
Does this relate to the work undertaken by Peter Aaby / Bandim Health. re Vaccine schedules / mortality / infections ?
Frank Shann reviews 20 years of Bandim research here …
The Nonspecific Effects of Vaccines and the Expanded Program on Immunization
There is now clear evidence that the simplistic conventional model of immunization is invalid [1].
*We can no longer assume that a vaccine acts independently of other vaccines, or that it influences only infections caused by the target disease.
*Strong evidence from randomized trials suggests that bacillus Calmette-Guérin vaccine (BCG) reduces mortality from infections other than tuberculosis and that measles vaccine reduces mortality from infections other than measles [1–4].
*However, there is worrying evidence that whole-cell diphtheria-tetanus-pertussis vaccine (DTP) may increase mortality from infections other than diphtheria, tetanus, or pertussis in high-mortality areas [1, 3–8].
*These nonspecific effects of BCG, measles vaccine, and DTP are generally stronger in girls, appear to be maximal in the first 6 months after immunization, and are largely determined by the most recent vaccine administered”
“Even in unimmunized communities, diphtheria, tetanus, and pertussis cause far fewer deaths than pneumonia, sepsis, and diarrhea [11]; despite reducing mortality from diphtheria, tetanus, and pertussis, DTP will, therefore, increase total mortality if it causes even a small increase in mortality from pneumonia, sepsis, and diarrhea in high-mortality areas [12]. When DTP was first introduced into Guinea-Bissau, despite the absence of herd immunity, mortality was 5.1 deaths per 100 person-years among children who did not receive DTP but 11.3 deaths per 100 person-years among children who did receive DTP (risk ratio, 2.03; 95% CI, 1.17–3.52) [7]. I know of no other study of the introduction of DTP in a high-mortality area with sufficient power to test the effect on total mortality.”
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The expanding realm of heterologous immunity: friend or foe?
http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2005.00653.x/full
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Heterologous immunity between viruses.
http://www.ncbi.nlm.nih.gov/pubmed/20536568
Polarization of immune responses by vaccination may influence the outcome of future infections. Epidemiologic studies have shown that immunization with live attenuated vaccines that elicit predominantly type 1 immune responses, such as M. bovismeasles vaccine had a non-specific beneficial effect on childhood survival. In contrast, diphtheria-pertussis-toxoid (DPT) vaccine, which primarily elicits type 2 immune responses, had the opposite effect (Kristensen et al., 2000; Garly et al., 2003; Shann, 2004; Roth et al., 2005).
November 30, 2011 at 5:13 am
@ Blackheart.
Try this one: http://www.ncbi.nlm.nih.gov/pubmed/21411537
Implications are similar to Aabys…
November 27, 2011 at 2:52 am
@ Blackheart. Part of the problem is that geneticists haven’t yet got a full handle on epigenetics. They still want to “blame” genes, rather than look at “what” methylates genes. Often when they talk about certain cancers being “genetically” related and “running in families”, they can sometimes be putting the cart before the horse. Genes are often switched on, and off, by what we eat. So if a whole family has the same lousy lifestyle, the same genes will be triggered, because the same environmental factors will apply. Just like some families across generations eat good food, and some all live on takeaways.
So, take this article:
If everything we eat orchestrates and modulates our genes in some way, then the “switching on” or “switching off” of genes, is usally “environmentally” induced, in one way or another. Food, toxins, viruses whatever is capable of switching on genes.
Which came first? The chicken of the egg? Do you need the “gene” first, or might that gene have lain dormant if X had never been done or eaten?
I believe the same applies with autism and babies…a mother’s nutrition – alcohol, recreational drugs…, mercury filings put into teeth; drugs during pregnancy – and yes, antiobiotics – to hormonal or drug interference in labour; immediately cord clamping which has huge epigenetic effects…. whether or not a family CHOSES to formula feed, rather than breastfeed. Breastmilk orchestrates the neonatal immune system, so right there, formula feeding is going to epigenetically change the immune system default setting. And then, of course, there is what I call “cranial cluster bombs” – vaccines.
Why is it that these epigeneticists who agree that food alters how our genes work, are prepared to toss a whole bunch of monkey wrenches into a developing neonatal brain, (which goes “against” the default plan, as to how that brain develops)( – like – vaccine after vaccine after vaccine? If they accept that genes will be switched on with food, why then do they not accept that a vaccine, which will always trigger something in a baby’s brain, will “result” in immune system derangement, inflammation AND resultant autism?
The other problem which annoys me, is that the medical profession prefers to blame any genes that were switched on as if it’s some “act of god” which can’t be prevented…. and then they say, maybe we can “do something” to turn it back off.
Vaccines must never be fingered, because vaccines are “coincidental” to everything else in like, just like this parenting magazine lulls parents into complacency by saying http://www.parents.com/baby/care/pediatricians-medicine/well-baby-visits-for-your-baby/?page=1
QUOTE: “Why so many visits? Your baby’s body and mind are changing at a phenomenal rate, and frequent checkups can reveal deviations from what’s normal. Your doctor is on the lookout for any medical issues that may affect your baby, because detecting problems early makes them easier to correct. In addition, these visits coincide with the schedule of immunization shots your child will receive.”
…….and all these vaccines which just happen to “coincide” with the raft of “well baby” visits, are also just “coincidental” when something nasty happens after they are injected into your child!
So what we have is a medical people (in general) who happily talk about how “food” switches on genes etc, but then say that vaccines toxins etc… will NOT switch on specific inflammatory genes to create havoc in the brain. That the baby had the problem before X Y and Z happened.
November 29, 2011 at 3:31 am
Hi Hilary Butler -
Another interesting post with a lot of hyperbole. My thoughts are that we should exercise great caution, and not to use terms like ‘cranial cluster bombs’ in a vaccine discussion (or any discussion). I believe that any rational discussion regarding vaccines must acknowledge the difficult to overstate benefits to human kind from the very real ability to prevent disease. But even worse, any argument that is simple to show as bombastic and undefendable through the literature, an argument that can be held up again and again as the opposite of existing data, is a true gift to the people who argue with great elegance and frequency that our understandings of these interactions is complete. Vaccines are not ‘cranial cluster bombs’. If anything, the more I read, the more I become convinced that our ignorance remains far greater than our knowledge, in pretty much any area. This has become one of my foremost thoughts when trying to piece together the puzzle.
I do not know your personal draw to the autism discussion, or maybe just a vaccine discussion, and I think sometimes this can make a profound difference. My thoughts are that a dispassionate evaluation of the changes to our environment is necessary for us to understand if autism rates are rising, and any argument appears to have thrown out reasonable analysis is an impediment to this.
That being said, I do like the idea of many, subtle effects on development from sources previously considered nominal. Did you see this paper come out the other day on the effect of breastfeeding on the immune response?
Breastfeeding modulates neonatal innate immune responses: a prospective birth cohort study
Background: Neonatal Toll-like receptor (TLR) responses are biased toward Th2-polarizing responses at birth and rapidly mature toward more balanced responses during the first month of life. Postnatal TLR maturation may be guided by environmental exposure. Aims: To determine the environmental determinants of neonatal TLR function. Materials and Methods: A prospective birth cohort study was performed in 291 healthy term neonates. Mode of delivery, breastfeeding, birth month, siblings, pets and parental smoking were analyzed in relation to neonatal innate immune parameters at the age of 1 month. Whole blood concentrations of innate immune cells were measured by flow cytometry. In vitro TLR-mediated cytokine production was determined by ELISA. Results: Breastfeeding was the major determinant of neonatal innate immunity, associated with 5 (31%) of neonatal innate immune parameters, of which the association with TLR7-mediated IL-10 production was most significant (76 pg/ml in breastfed neonates vs. 293 pg/ml in formula-fed neonates, p = 0.001). Of innate immune variables, TLR3-mediated IL-12p70 production was highly associated with environmental exposures (pets, breastfeeding and mode of delivery), whereas TLR9-mediated cytokine responses were not associated with any environmental factor. Conclusion: Neonatal innate immune responses are differentially modulated by environmental exposure in the first month of life. The protective effect of breastfeeding against subsequent infections and atopy might be explained by its innate immune modulatory effects in the first month of life.
Nice. And Terrifying. The idea that something so simple as breastfeeding could persistently affect immune function is a new idea. And in alignment with my global theory of the magnitude of our ignorance, I’d have thought that breastfeeding would increase IL-10 production.
- pD
November 29, 2011 at 7:34 am
It’s not hyperbole. I’ve spent nearly 30 years tracking the medical literature on the neonatal immune system – what they know and what they don’t. The big black holes of “ignorance” which punctuate their “knowledge” are bigger than even I, really want to know, and it is seriously distressing. You are right, that their ignorance is more than their knowlege. And the terrifying thing is that it’s ***those*** “black holes” of ignorance…. which – once they figure them out,—- might put the so-called factual “knowledge” they thought they had sussed, in a completely different light … ever so far as to be — irrelevant.
Here is one of my (many) favourite quotes by a famous immunologist called Dr Robert Good:
: Good, R.A. 1974. “The Immunoglobulin A system”. Adv. Exp. Med. Biol, 45:
513–531. Impressions, summary and questions raised by the IgA Symposium. International Symposium on the Immunoglobulin A System, Birmingham, Alabama,
1973. Quote:
“In a personal way, I realized the impact of scholarly endeavour on the body of knowledge from my own attempt to encompass the body of knowledge in medicine when I was a medical student. I sat in the front row of every class. I took down everything the professor said, complemented this body of knowledge with the information I learned form my instructors in the laboratory, from relevant information I could glean from reading and digesting the best textbooks on each subject, and even from extracting the substance of the most relevant articles in contemporary scientific journals.
All this, I included in my notes for study in beautiful Morocco-bound notebooks. The scheme seemed to work, because it gave me very high grades in school, top scores in state and national board examinations and my choice of training spots and fellowships. I closed my notebooks however, for 10 years.
When I opened them again, and studied them 10 years after so carefully completing them, I was astonished to find that they were almost entirely filled with lies. Except for a few descriptions such as well-established anatomy, everything that seemed so orderly and beautiful with the rather comprehensive treatment I had given it for one moment in history, had changed, grown, and been reordered by the scholarship of the intervening ten years. That is why it is so important so frequently to take stock as we have done in this conference, and to consider what has been happening in the research laboratories and in our thinking on so many subjects.”
Close quote/
This applies even more, today. The evidence that vaccines can ppotentially become cranial cluster bombs in neonates is there, and growing by the day. included some full text articles on that blog, to back that up, and have have plenty more where they came from.
You also said, ” I believe that any rational discussion regarding vaccines must acknowledge the difficult to overstate benefits to human kind from the very real ability to prevent disease. ”
I am not irrational and completely disagree with this statement. If in the future, it’s finally admitted that vaccines are implicated in autism, and the figures of 1 in 67 correlate with vaccines, then that negates any “ability to prevent diseases”, particularly when complication rates are so low per 100,000 per population.
To understand that in a personal way, quite apart from scientific number crunching, you only have to look at any long term family tree with the later death certificates included. Mine goes back to around 1460, and in the latter centuries, cause of death was included.
Had vaccines been available, and assumed to have worked in the last 200 years only two deaths might have been theoretically prevented from typhoid and even that’s debatable.
What would have prevented many deaths are: Obstetricians who bothered to wash their hands and hadn’t decimated over around 55 mothers and babies from preventable puerperal fever,… and preventing a few wars happening, into which family members were conscripted, and killed. Those,.. and two sword duels and a couple of horse accidents were the stand-out causes of people not dying in old age..
On the scientific front, there are plenty of peer review articles on pubmed, which point out that the actual “contribution” of vaccine to the overall mortality is vastly overstated. The problem is, most people don’t know they exist, and the provaccine aren’t about to hand them to you on a plate. Some of those are also on my website.
Along with all my peers my first vaccine was administed at the age of three years of age.
Yes, “years”, not “months” or “weeks” or days.
Three years old…. Now, a baby of 5 months has had how many? They’ve finished the primary schedule.
Why is it, that autism is at miniscule levels in my peers and exploding out of the blocks in our grandchildren? It’s not just that we are older. We are exposed to the same environmental issues, even if babies appear to be more “dose-dependant” than we are. We don’t normally put babies in the “way” of environmental hazards, whereas often we do with ourselves – except …. in the circumstances of what the medical profession dictates.
The difference isn’t just the number of vaccines being given to babies, but the time at which they are given. And giving flu vaccines in pregnancy is the next definition of insanity in my opinion.
Has administering vaccines in the first two years of life, changed the dynamics and is a key driver of allergy, atopy and autism by acting as cluster bombs within the immune system and brain, at a time when no vaccines should be given to neonates…?. – Already, serious questions are being raised in the medical literature which should force immunologists to ask the question as to WHY they have condoned vaccinating babies – when they know their knowledge of the neonatal immune system is infinitesimally small. They know they don’t understand of the “software” of the immune system into which they are sticking all these needles – even if they can name the bits – so why do they assume that it will “do no harm”?.
Did you read the article you quoted from the abstract? http://www.ncbi.nlm.nih.gov/pubmed/22103307 I cracked up laughing. Here’s the start: ***” Born from a sterile intrauterine environment, the neonate is suddenly exposed to a world full of foreign antigens.”****
So now, the uterus is “sterile” and isn’t exposed to foreign antigens? So how it is we are to “believe” on the other hand, that exposure to the flu virus in utero increases childhood leukemia later? Were we not told that rubella in the fetus in this “sterile” uterus which doesn’t process foreign antigens, causes deformities of the worst kind? What about the list of intrauterine TORCH baddies?. You know, “Torch” which stands for intrauterine….Toxoplasmosis, other viruses, rubella, Cytomegalovirus and Herpes which can mess up an unborn fetus right royal, and yet the article you quoted from says the uterus is sterile without foreign antigen?
Later on they said they hadn’t checked the neonatal blood cord for immune function. Presumably that’s because they think it’s in a sterile environment? I gues fi you think the uterus is sterile, there’s not poin in checking the neonatal cord blood immune function. Yet…. having just said that, they went on to say that because they didn’t measure cord blood immune function, “we cannot exclude any prenatal effects of environmental factors on neonatal immunity”. Anyone home here?
While in their final summary they consider that the most important environmental influence on the immune system in the first month, is breastfeeding (we could have told them that years ago), there is this stunning little “aside” section on page 4 showing that a caesarean section resulted in an eight fold lower concentration of NK cells, a twofold decreased TLR3-mediated IL-12p70, and a twofold increased TLR4 Mediated IL-12p70 production which persisted for the one month, which is how long this study lasted.
According to another study I have, persistent immunosuppression after a caesarean section persists after a year. Seems to me that that’s pretty big news, don’t you think? Do you think the media might tell us that one day? No way, jose…
We are also told in this article, that the only two studies that look at the effects of early life environmental exposure were one on probiotics and another on smoking.
So this article beautifully exemplifies the lack of “knowledge” of the medical profession (which you agree with), as well as their constant illogical sweeping assumptions, the unfounded foundations (sterile intrauterine) which predetermine what they won’t study – and won’t learn, …. with regard to neonatal immunity. Belderbos shows you one insy part of breastmilk, but can’t tell you the practical implications of that – except it could be used to “create patterns to prevent future disease”
Is there anything new there? I have a bookcase full of 100 page clear files, with piles of articles all pointing this direction, and Dr Caterina Svanborg could have told Belderbos this, in the 1990′s, and more besides. I suspect that Belderbos will have a whole lot of other “nasty” surprises on the horizon in the future as well.
November 27, 2011 at 4:45 am
Food for thought (pun intended) a recent visit to our paediatrician concerning my son’s immune system (not his ASD) suggested the “food industry” was implicated in many of the childhood diseases he was attempting to ameliorate. (Without success unless food intake was taken into consideration)
My own personal observations that our son has a “immune based” ASD comes with the fact he has the triad of immune system function. Asthma , Eczema , Food allergies (some severe). It was also feeding that at times caused us the greatest concern when he was an infant.
The ‘ecological’ framework you describe makes perfect sense to me I’m just wondering whether science and medicine can’t make the connection because of a decidedly left leaning brain.
Is it the immunostimulatory effect of various vaccines that complicates or is problematic ?
I have seen some interesting research on maternal infections as well … thanks to Paul for that – anyway lots of differing hypotheses could be generated and certainly vaccines are still well in the mix.
November 27, 2011 at 5:53 am
Blackheart, your paediatrician has a point. The more refined the foods are, the less “complete” it is, and the more likely any food is to trip certain genes. Of that I’m sure. Here are just two examples. The first is a three step argument. I know people who are only “allergic” to grain, when they eat commercial grains. Why is that? becuase grain, in storehouses is sprayed with anti-fungals, and when growing is sprayed with a whole raft of sprays against, this, that and the other. These people however, can eat biodynamically grown grains quite happily. So long as those grains are whole. Refined grains bother them.
For me, I’m much better staying away from grains altogether, and at the age of 64 my father was “cured” or arthritis and an autoimmune condition, by removing all grains and nuts. he lived to 95, and his health at 70 was better than it had been at aged 3o. So absolutely the food industry has a lot to answer for, not that they care.
You ask, “Is it the immunostimulatory effect of various vaccines that complicates or is problematic ?”
They are highly problematic – and in some children, can be the “Sole” cause IMO, but in other children where there are already problems like serial acetaminophen, antibiotics and other drugs in pregnancy, caesarian (which of itself derails the development of the immune system) your classic thoughtless “normal delivery” with immediate clamped cord – vitamin K injection and onto formula as soon as possible… that babies already trying to fend of serial dominoes which have been tripped, so vaccines for them, can be even worse than in a healthy child which weren’t behind the eight ball to begin with….
I love pd’s blog because he’s one of the few people out there really thinking these through. And it seems churlish on his blog to do this – though I think I’ve put these URLS up here before anyway.
This is a blog which I put up after a radio interview with a doctor who willfully said that she agreed with me that “vaccines don’t cause autism”. I said, “That’s noy what I said at all, you are not listening.” So I put up this blog: http://www.beyondconformity.co.nz/_blog/Hilary's_Desk/post/Yes,_vaccines_can_CAUSE_autism!/
Read the first three blogs embedded into that blog which have full texts embedded into them. It will take a while to get through and if your have specific questions, email me.
((I don’t allow comment on my blog because the reason that septics (skeptics, but that’s how I spell it) dogpile on sites which question vaccines is more because they want to hear their mates bark along with them, than actually get educated. So I say what I think and to heck with them. The fact that in four years, I’ve have two emails from skeptics, tells me that they are only interested in defending the status quo at all costs….))
Also do a lot of research on Aluminium in vaccines. Aluminium is a tricky metal, used as an adjuvant. aluminium is “adjuvanted” with the antigen (aluminium and the antigen are opposite “charges” so they “stick” together like the north and south sides of a magnet ). When injected into babies it does several things. Becuase aluminium is toxic, the inate immune system flicks a red switch and calls in the cavalry – in the process of disentangling the aluminium and antigen, the immune system is forced to deal with an antigen which it otherwise would have sulkily ignored. Some aluminium will form a “depot” with the antigen in muscular tissue, which can lead to macrophagic fasciitis (which can ultimately lead to MS). But some aluminium floats free, and if you’re lucky, it is got rid of in the body, BUT if you’re not lucky, it can be taken into various body tissues and stay there. Some will land up in your blood, but will eventually be filtered out. But a recent paper (Marichall 11) shows that aluminium also forces a whole lot of host DNA to be released into the child’s system as well.
Maybe too, before receiving a vaccine, a child might have eaten a peanut butter sandwich as well – or be processing abnormal “food” aka… formula… … and as part of the digestive process, the peanuts or formula… were “dissembled” and various molecular structures from them land up floating around in your child’s body.
So what happens if aluminium, which has an OPPOSITE charge to various protein particles, docks (opposites attract – the principle of adjuvanting…) up against fragments from food, or host DNA? It “adjuvants” with it, just as it “adjuvanted” with the antigen in the vaccine. Whereas the body might normally sulkily ignore that, suddenly, the cavalry is called up again to deal with it…. If aluminium docks up with host DNA, in the process, the cavalry might set in motion….autoimmunity, becuase that normal DNA, just became a “threat”. If Aluminium docks up with a peanut particle, or that grass pollen that your child rolled in.. or anything else coursing through your child’s body, there is the possibility of that child being sensitized the first time, and if that happens again, throwing an allergic reaction the second time.
This isn’t rocket science, and on numerous occasions, I’ve brought this up with immunologists, who have no counter arguments to this, because they know it’s true. They just hope that so long as parents don’t “think” and apply “logic” then problem people like me, (or pd) will go away.
What they fail to realise is that people like myself, get incensed by the injustice of it all, when the answers are in their own medical literature, in front of their eyes, and in their own textbooks, and yet they continually deny it.
We aren’t going to get the answers from lamestream medicine, because they can only afford to tell the parents a truth, if it places the responsibility in the lap of the parents, not at the hand that injected something into the child.
That’s why your paediatrician will happily blame the food industry for your child’s problems, – and ignore the aluminium in the vaccines he’s lining up for your child’s next “well-child” visit.
And if you suggested to him that aluminium in his vaccines, might have docked up to “food” and created a problem….he’d be as aggrieved as the food industry would be, at him blaming them.
You, the parent, will be branded as paranoid or neurotic.
It’s all a big game called pass the buck-parcel.
November 27, 2011 at 9:29 am
Thanks Hilary I have passed by your blog before … and will revisit.
I suppose I’m ” reverse engineering” some of this … I can almost make out the pathway … I’ve got Paul’s book ordered. (I’m thinking right brain).
I’m interested in Paul’s work because it seems to associative with the work by Peter Aaby and Bandim Health Project. DTaP and HTMV.
It’s that work that to me stands out so starkly …
November 29, 2011 at 7:41 am
@ Blackheart, Yes Peter Aaby’s very stark work, actually raises horizontal question about unintended consequences in developed nations. Perhaps that’s why his peers greet his findings with mainly silence, if forced, caution, but really just hope he would vanish into the ether.
He’d be on my invite list for “who would you most want to spend an evening with, off the record, who would tell you honestly, everything you wanted to know”.
Huge implications – which most in the system, don’t want to look at….
December 11, 2011 at 4:56 am
pD
“I’ve gotten into a lot of discussions online about the vaccines and autism; generally with very poor, if not nonexistent, evidence of having changed any opinions, but relatively strong evidence ( p > .001) that persisting in making my arguments can get you called ‘an antivaccine loon’, ‘idiot’, someone who engages in ‘Gish Gallop’, or the worst insult I’ve received so far, ‘anti-science’. ”
Keep up the good work there are obviously many many scientists and researchers that are now beginning to understand and elucidate the very complex interplay in regards to immune system and ASD aetiology and pathology.
regards
ps Vaccines may or may not be one of the factors influencing ASD pathology and aetiology. I say lets do the science first without prejudice. Then we’ll talk about what to do.
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Here is some research I have recently found interesting … it may or may not gel with your own perceptions but this is not important. Rather it is information shared.
*Very Long * please delete as you choose to see fit. Some of it may not have an obvious connection at first glance because there is obviously a broader framework / ecology / knowledge that I have drawn on ie sleep disturbance and anti-depressants findings.
Wikipedia
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcriptionDNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. of
NF-κB plays a key role in regulating the immune response to infection (kappa light chains are critical components of immunoglobulins). Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
Known inducers of NF-κB activity are highly variable and include reactive oxygen species (ROS), tumor necrosis factor alpha (TNFα), interleukin 1-beta (IL-1β), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, and ionizing radiation.[18]
NF-κB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response.
NF-κB has been demonstrated to have diverse functions in the nervous system including roles in plasticity, learning, and memory.
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, among others. It is important to note that the key regulators of NF-κB are associated with elevated mortality, especially from cardiovascular diseases.[51][52] Elevated NF-κB has also been associated with schizophrenia
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NF-κB – I have tried to show how NF-κB activation has been shown in Autism and various immune system dysfunctions which is a recent phenotype of Autism elucidated by Dr Amaral at University of California Davis MIND Institute and further evidenced by Department of Neurology and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, California
http://www.abc.net.au/news/2011-09-08/am-autism-study/2876128/?site=melbourne
http://www.nature.com/nature/journal/v474/n7351/full/nature10110.html
Possible hypothesis – Measles MMR / Tetanus DTap (attenuated vaccine) or alternate environmental insult / trigger acvtivation of NF-κB in children with an underlying genetic susceptibility leads to …. neuro-inflammation and other characteristics of immune genome type autism.
Personal experience with my son’s co-morbid conditions – Asperger’s , eczema , chronic asthma , allergies , anaphylaxis to egg and nuts.
Neuro-inflammation (ala Johns Hopkins Vargas)
http://www.neuro.jhmi.edu/neuroimmunopath/autism.htm
http://www.neuro.jhmi.edu/neuroimmunopath/autism_findings.htm
http://www.neuro.jhmi.edu/neuroimmunopath/autism_faqs.htm
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Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation 2011
Adam M. H. Young,1,2 Elaine Campbell,1 Sarah Lynch,1 John Suckling,3* and Simon J. Powis1
1Bute Medical School, University of St. Andrews, Fife, Scotland, UK
2Autism Research Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK
3Department of Psychiatry, University of Cambridge, Cambridge, UK
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098713/
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue
This article describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK (ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6, controls: n = 5). The hypothesis was that concentrations of NF-κB would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification).
Conclusion
NF-κB is aberrantly expressed in the orbitofrontal cortex as indicated by measurements on post-mortem tissue from ASC patients, and particularly in highly activated microglia. This region is a locus of abnormal function in ASC that underlies the abnormal development of social and cognitive skills (Sabbagh, 2004).
This is the first discovery of its kind that identifies a potential mechanism for neuroinflammation in ASC through increased expression of this pro-inflammatory molecule and the significant involvement of resident immune cells. The connection of this result to changes in intracellular acidity indicates an investigation of pH across the entire brain parenchyma in living patients.
Whilst evidence of causal link remains to be established, the idea that the induction of inflammation via the NF-κB signaling cascade is observed in regions of the neocortex associated with behavioral and clinical symptoms of ASC gives credence and impetus to interventions focusing on this potential therapeutic target.
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Measles Virus Activates NF-κB and STAT Transcription Factors and Production of IFN-α/β and IL-6 in the Human Lung Epithelial Cell Line A549
http://www.sciencedirect.com/science/article/pii/S0042682201911742
Epithelial cells of the respiratory tract are the primary targets of measles virus (MV) infection. In this work we have studied the effect of MV infection on the activation of transcription factors nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT) and the production of cytokines in the lung epithelial A549 cell line. NF-κB and STAT activation were induced by MV in A549 cells as analyzed by electrophoretic mobility shift assay. NF-κB activation was rapid and it was not inhibited by the protein synthesis inhibitor cycloheximide, suggesting that MV directly activates NF-κB. In contrast, Stat1, Stat3, and interferon-stimulated gene factor 3 (ISGF3) DNA binding was induced by MV infection with delayed kinetics compared to NF-κB activation. MV infection also resulted in an efficient interferon (IFN)-α/β and interleukin-6 production. Cycloheximide and neutralizing anti-IFN-α/β antibodies inhibited MV-induced activation of Stat1, Stat3, and ISGF3 DNA binding in A549 cells. In conclusion, the results suggest that MV infection activates transcription factors involved in the initiation of innate immune responses in epithelial cells by two different mechanisms: directly by leading to NF-κB activation and indirectly via IFN-α/β leading to STAT activation.
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NF-kB: a crucial transcription factor for glial and neuronal cell function
Dept of Biochemistry, Trinity College Dublin, Ireland.
b Molecular Neurobiology Laboratory, Institute of Biochemistry and Molecular Biology
Transcription factors provide the link between early membrane-proximal signalling events and changes in gene expression. NF-kB is one of the best-characterized transcription factors. It is expressed ubiquitously and regulates the expression of many genes, most of which encode proteins that play an important and often determining role in the processes of immunity and inflammation. Apart from its role in these events, evidence has begun to accumulate that NF-kB is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer’s disease. NF-kB might also be important for viral replication in the CNS. An involvement of NF-kB in neuronal development is suggested from studies that demonstrate its activation in neurones in certain regions of the brain during neurogenesis. Brain-specific activators of NF-kB include glutamate (via both AMPA/KA and NMDA receptors) and neurotrophins, pointing to an involvement in synaptic plasticity. NF-kB can therefore be considered as one of the most important transcription factors characterized in brain to date and it might be as crucial for neuronal and glial cell function as it is for immune cells.
* 1. NF-kB as a signal transducer
* 2. NF-kB as a signal in the brain during inflammation, injury and viral infection
* 3. NF-kB as a signal in synaptic transmission and neuronal plasticity
* 4. NF-kB as a signal in neuronal development
* 5. NF-kB as an important signal in neurodegenerative diseases
* 6. Concluding remarks
Wiki – Neurogenesis
Neurogenesis (birth of neurons) is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of mammals: the hippocampus and the subventricular zone.
Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched environment have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus.,[43][48][49][50]Another factor is central nervous system injury since neurogenesis occurs after cerebral ischemia,[51] epileptic seizures,[52] and bacterial meningitis.[53] On the other hand, conditions such as chronic stress and aging can result in a decreased neuronal proliferation
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Measles: immune suppression and immune responses
http://www.sciencedirect.com/science/article/pii/S1357272504000263
Measles is a highly contagious viral disease that remains the leading vaccine-preventable cause of child mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. Several abnormalities of the immune system have been described, including changes in lymphocyte number and function, shifts in cytokine responses, immunomodulatory effects of interleukin-10, down regulation of interleukin-12, impaired antigen presentation, and altered interferon α/β signaling pathways. Although the current vaccine is very effective, knowledge of the molecular basis of the immune responses to measles virus could contribute to the development of a safer, more immunogenic measles vaccine. However, the safety of new measles vaccines must be carefully investigated, as two measles vaccines have resulted in unintended immunologic consequences: atypical measles following administration of the formalin-inactivated measles vaccine and increased mortality in girls following administration of high-titer measles vaccines.
*Need to have full access – Google search notes – (regulated the NF-κB p52 subunit and B cell lymphoma protein-3 (Bcl-3), suggesting modulation
of NF-κB transcription factor) like to see in context.
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Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292110/ ( Mayo Clinic / Dr Poland)
We hypothesize that genetic variations in the TLRs and their associated signaling molecules, that play an important role in measles virus recognition, could result in variable immune responses to measles vaccination.
In contrast, the attenuated strains of measles virus are known to induce the expression of TLR3 via an interferon-dependent mechanism triggered as a part of the host response
All analyses were adjusted for the potential confounding effects of age, gender, race, age at first MMR vaccination and age at 2nd measles-mumps-rubella (MMR) vaccination.
Tanabe et al [9] reported that laboratory adapted and vaccine strains of measles virus, including Edmonston, up-regulate the expression of TLR3 in human dendritic cells via enhanced IFN-β secretion. The 500bp region upstream of exon 1 is characterized as a measles virus-responsive segment in the TLR3 gene. This region contains the NF-κB and STAT (family of eukaryotic transcription factors that mediate the response to a large number of cytokines and growth factors) binding sites.
Note – See Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates
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J Virol. 2011 Apr;85(7):3162-71. Epub 2011 Jan 26.
The measles virus V protein binds to p65 (RelA) to suppress NF-kappaB activity.
Schuhmann KM, Pfaller CK, Conzelmann KK.
Source
Max von Pettenkofer Institute & Gene Center, Feodor-Lynen-Str. 25, D-81377 Munich, Germany.
Abstract
Nuclear factor κB (NF-κB) transcription factors are involved in controlling numerous cellular processes, including inflammation, innate and adaptive immunity, and cell survival. Here we show that the immunosuppressive measles virus (MV; Morbillivirus genus, Paramyxoviridae) has evolved multiple functions to interfere with canonical NF-κB signaling in epithelial cells. The MV P, V, and C proteins, also involved in preventing host cell interferon responses, were found to individually suppress NF-κB-dependent reporter gene expression in response to activation of the tumor necrosis factor (TNF) receptor, RIG-I-like receptors, or Toll-like receptors. NF-κB activity was most efficiently suppressed in the presence of V, while expression of P or C resulted in moderate inhibition. As indicated by reporter gene assays involving overexpression of the IκB kinase (IKK) complex, which phosphorylates the inhibitor of κB to liberate NF-κB, V protein targets a downstream step in the signaling cascade. Coimmunoprecipitation experiments revealed that V specifically binds to the Rel homology domain of the NF-κB subunit p65 but not of p50. Notably, the short C-terminal domain of the V protein, which is also involved in binding STAT2, IRF7, and MDA5, was sufficient for the interaction and for preventing reporter gene activity. As observed by confocal microscopy, the presence of V abolished nuclear translocation of p65 upon TNF-α stimulation. Thus, MV V appears to prevent NF-κB-dependent gene expression by retaining p65 in the cytoplasm. These findings reveal NF-κB as a key target of MV and stress the importance of the V protein as the major viral immune-modulatory factor.
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Measles virus-induced modulation of host-cell gene expression
http://jgv.sgmjournals.org/content/83/5/1157.short
The influence of measles virus (MV) infection on gene expression by human peripheral blood mononuclear cells (PBMCs) was examined with cDNA microarrays. The mRNA levels of more than 3000 cellular genes were compared between uninfected PBMCs and cells infected with either the Edmonston MV strain or a wild-type MV isolate. The MV-induced upregulation of individual genes identified by microarray analyses was confirmed by RT–PCR.
In the present study, a total of 17 genes was found to be upregulated by MV infection.
The Edmonston strain grew better in the PBMC cultures than the wild-type MV, and the Edmonston strain was a stronger inducer of the upregulated host cell genes than the wild-type virus.
The anti-apoptotic B cell lymphoma 3 (Bcl-3) protein and the transcription factor NF-κB p52 subunit were upregulated in infected PBMCs both at the mRNA and at the protein level.
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PLoS One. 2008;3(11):e3825. Epub 2008 Nov 27.
Modulation of the NF-kappaB pathway by Bordetella pertussis filamentous hemagglutinin.
Abramson T, Kedem H, Relman DA.
Source
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
Abstract
BACKGROUND:
Filamentous hemagglutinin (FHA) is a cell-associated and secreted adhesin produced by Bordetella pertussis with pro-apoptotic and pro-inflammatory activity in host cells. Given the importance of the NF-kappaB transcription factor family in these host cell responses, we examined the effect of FHA on NF-kappaB activation in macrophages and bronchial epithelial cells, both of which are relevant cell types during natural infection.
METHODOLOGY/PRINCIPAL FINDINGS:
Exposure to FHA of primary human monocytes and transformed U-937 macrophages, but not BEAS-2B epithelial cells, resulted in early activation of the NF-kappaB pathway, as manifested by the degradation of cytosolic IkappaB alpha, by NF-kappaB DNA binding, and by the subsequent secretion of NF-kappaB-regulated inflammatory cytokines. However, exposure of macrophages and human monocytes to FHA for two hours or more resulted in the accumulation of cytosolic IkappaB alpha, and the failure of TNF-alpha to activate NF-kappaB. Proteasome activity was attenuated following exposure of cells to FHA for 2 hours, as was the nuclear translocation of RelA in BEAS-2B cells.
CONCLUSIONS:
These results reveal a complex temporal dynamic, and suggest that despite short term effects to the contrary, longer exposures of host cells to this secreted adhesin may block NF-kappaB activation, and perhaps lead to a compromised immune response to this bacterial pathogen.
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Infect Immun. 2001 Apr;69(4):2650-8.
Proinflammatory and proapoptotic activities associated with Bordetella pertussis filamentous hemagglutinin.
Abramson T, Kedem H, Relman DA.
Source
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Abstract
Filamentous hemagglutinin (FHA) is a dominant cell surface-associated Bordetella pertussis adhesin. Recognition that this protein is secreted in significant amounts and that bacterial adhesins may have other activities, prompted an assessment of FHA effects on human macrophages. Incubation of human macrophage-like U937 cells with preparations of FHA resulted in dose-dependent cytotoxicity, with death of 95% of treated cells after 24 h. Based on the use of four independent methods, death of these cells could be largely attributed to apoptosis. FHA-associated apoptosis was also observed in THP-1 macrophage-like cells, fresh human peripheral blood monocyte-derived macrophages (MDM), and BEAS-2B human bronchial epithelial cells. Infection of MDM with wild-type B. pertussis resulted in apoptosis within 6 h, while infection with an FHA-deficient derivative strain was only 50% as effective. FHA-associated cytotoxicity was preceded by host cell secretion of tumor necrosis factor alpha (TNF-alpha), a potential proapoptotic factor. However, pretreatment of cells with a neutralizing anti-TNF-alpha monoclonal antibody inhibited only 16% of the FHA-associated apoptosis. On the other hand, a blocking monoclonal antibody directed against TNF-alpha receptor 1 inhibited FHA-associated apoptosis by 47.7% (P = 0.0001), suggesting that this receptor may play a role in the death pathway activated by FHA. Our in vitro data indicate that secreted and cell-associated FHA elicits proinflammatory and proapoptotic responses in human monocyte-like cells, MDM, and bronchial epithelial cells and suggest a previously unrecognized role for this prominent virulence factor in the B. pertussis-host interaction.
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Virology. 1999 Jun 20;259(1):74-84.
Involvement of a p53-dependent pathway in rubella virus-induced apoptosis.
Megyeri K, Berencsi K, Halazonetis TD, Prendergast GC, Gri G, Plotkin SA, Rovera G, Gönczöl E.
Source
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania, 19104, USA.
Abstract
In light of the important role of apoptotic cell death in the pathogenesis of several viral infections, we asked whether the cytopathogenicity evoked by rubella virus (RV) might also involve apoptotic mechanisms. The To-336 strain of RV induced apoptosis in Vero and RK-13 cells, but not in fibroblast cell lines. UV-inactivated RV virions did not elicit the apoptotic response, indicating that productive infection is required for the induction of cell death. Both p53 and p21 protein levels were highly elevated in RV-infected Vero cells. The level of p21 mRNA was increased, while expression of the p53 gene was unaffected by RV infection. A dominant-negative p53 mutant (p53(W248)) conferred partial protection from RV-induced apoptosis. These data implicate a p53-dependent apoptotic pathway in the cytopathogenicity of RV, thereby suggesting a mechanism by which RV exerts its teratogenic effects.
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The expanding realm of heterologous immunity: friend or foe?
http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2005.00653.x/full
Polarization of immune responses by vaccination may influence the outcome of future infections. Epidemiologic studies have shown that immunization with live attenuated vaccines that elicit predominantly type 1 immune responses, such as M. bovismeasles vaccine had a non-specific beneficial effect on childhood survival. In contrast, diphtheria-pertussis-toxoid (DPT) vaccine, which primarily elicits type 2 immune responses, had the opposite effect (Kristensen et al., 2000; Garly et al., 2003; Shann, 2004; Roth et al., 2005). BCG and
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Microb Pathog. 2002 Sep;33(3):115-25.
Bordetella pertussis infection of human respiratory epithelial cells up-regulates intercellular adhesion molecule-1 expression: role of filamentous hemagglutinin and pertussis toxin.
Ishibashi Y, Nishikawa A.
Source
Department of Immunobiology, Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, Japan. yishibas@my-pharm.ac.jp
Abstract
Adhesion molecules on respiratory epithelial cells play a critical role in inflammatory cell recruitment and accumulation at sites of inflammation. Bordetella pertussis colonizes the human respiratory tract by infecting epithelial cells, leading to an inflammatory response. In this study, the role of bacterial factors in the expression of intercellular adhesion molecule-1 (ICAM-1) on human respiratory epithelial cells was investigated in response to B. pertussis. Flow cytometry and real time RT-PCR analysis showed that BEAS-2B human bronchial epithelial cells expressed increased levels of ICAM-1 mRNA and surface protein in response to B. pertussis infection. Filamentous hemagglutinin (FHA) played a role in this response because of the impaired capability of a FHA-deficient isogenic strain. A mutant strain in which an Arg-Gly-Asp (RGD) site of FHA had been changed to Arg-Ala-Asp had diminished ability to up-regulate ICAM-1 expression. RGD sequence-associated up-regulation of ICAM-1 expression was also observed in primary normal human bronchial epithelial cells. Pretreatment of cells with integrin antagonists such as RGD-containing peptide and antibody against very late antigen-5 (VLA-5) inhibited the up-regulation of ICAM-1 expression, suggesting the participation of VLA-5 integrin in this response. Pertussis toxin (PT) prevented the up-regulation of ICAM-1 expression because a PT-deficient mutant strain induced higher levels of ICAM-1 mRNA and surface protein than the parental strain. Consistent with this, purified PT suppressed the up-regulation of epithelial ICAM-1 expression. These findings demonstrate that B. pertussis FHA up-regulates ICAM-1 expression on respiratory epithelial cells through interaction of its RGD site with host cell VLA-5 integrin, and that PT impairs this response.
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Heterologous immunity between viruses.
http://www.ncbi.nlm.nih.gov/pubmed/20536568
Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as heterologous immunity. This response can lead to enhanced or diminished protective immunity and altered immunopathology.
Here, we discuss the nature of T-cell cross-reactivity and describe matrices of epitopes from different viruses eliciting cross-reactive CD8(+) T-cell responses. We examine the parameters of heterologous immunity mediated by these cross-reactive T cells during viral infections in mice and humans. We show that heterologous immunity can disrupt T-cell memory pools, alter the complexity of the T-cell repertoire, change patterns of T-cell immunodominance, lead to the selection of viral epitope-escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T-cell repertoires within individuals, contribute to dramatic variations in viral disease.
We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines.
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Altered T cell responses in children with autism.
http://www.ncbi.nlm.nih.gov/pubmed/20833247
Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.
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Measles Virus-Induced Immunosuppression
Immunosuppression is the major cause of infant death associated with acute measles and therefore of substantial clinical importance. Major hallmarks of this generalized modulation of immune functions are (1) lymphopenia, (2) a prolonged cytokine imbalance consistent with suppression of cellular immunity to secondary infections …
Moreover, MV proteins expressed by these cells actively silence T cells by interfering with signaling pathways essential for T cell activation.
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The Xs and Y of immune responses to viral vaccines
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health
http://www.sciencedirect.com/science/article/pii/S1473309910700499
The biological differences associated with the sex of an individual are a major source of variation, affecting immune responses to vaccination. Compelling clinical data illustrate that men and women differ in their innate, humoral, and cell-mediated responses to viral vaccines. Sex affects the frequency and severity of adverse effects of vaccination, including fever, pain, and inflammation. Pregnancy can also substantially alter immune responses to vaccines. Data from clinical trials and animal models of vaccine efficacy lay the groundwork for future studies aimed at identifying the biological mechanisms that underlie sex-specific responses to vaccines, including genetic and hormonal factors. An understanding and appreciation of the effect of sex and pregnancy on immune responses might change the strategies used by public health officials to start efficient vaccination programmes (optimising the timing and dose of the vaccine so that the maximum number of people are immunised), ensure sufficient levels of immune responses, minimise adverse effects, and allow for more efficient protection of populations that are high priority (eg, pregnant women and individuals with comorbid conditions).
Interestingly females have a higher mortality in measles outbreaks. So perhaps it is another virus or the combination or the schedule (Aaby Bandim Health project)
A selection of Bandim Health Project – Research published in a variety of eminent scientific journals.
http://www .sciencedi rect.com/s cience/art icle/pii/S 0264410X06 01111X
http://www .ncbi.nlm. nih.gov/pu bmed/21093 496
http://www .ncbi.nlm. nih.gov/pu bmed/17484 223
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Sex Differences in Susceptibility to Viral Infection.
Males and Females differ in their susceptibility to a variety of viral pathogens. ….. Females often exhibit reduced susceptibility to viral infections because they typically mount stronger immune responses than males.
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NF-κB and Inflammatory Bowel Diseases
Pathogenesis of inflammatory bowel disease
http://www.ncbi.nlm.nih.gov/pubmed/17023960
Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
In spite of expanding knowledge of cellular and molecular mechanisms of intestinal inflammation, the etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. The link between the environment and IBD is still circumstantial, but definite progress is occurring in defining genetic susceptibility loci for Crohn’s disease (CD) and ulcerative colitis (UC).
The importance of the mucosal immune system to IBD is established, and evidence is accumulating that nonimmune components, such as epithelial, mesenchymal, and endothelial cells, also contribute to gut inflammation. The effect of cytokines in intestinal immunity is being elucidated by studies on their molecular mechanism, particularly the activation of nuclear factor (NF)-κB.
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Epithelial Cells and Asthma (see First study Epithelial cells of the respiratory tract are the primary targets of measles virus (MV) infection.)
http://www.raystrand.com/recommendations_open.asp?eid=1000&n_recommendation_id=218
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Pulmonary.html
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Targeting Asthma
Kristen L. Mueller
Asthma is a major public health problem. There are a variety of causes of asthma, and the pathogenesis of the disease is quite heterogeneous. Despite this, most patients are treated with broadly immunosuppressive glucocorticoids, which do not always control disease. Thus, there is substantial interest in developing more targeted therapies that may be used to treat specific clinical subtypes of patients.
Interleukin-13 (IL-13) is a cytokine that is associated with the T helper 2 type responses seen in many asthma patients and in a subset of patients remains elevated even in the face of glucocorticoid treatment. In a placebo-controlled phase II clinical trial, Corren et al. now show that treatment of adult asthma patients on glucocorticoid therapy with a monoclonal antibody against IL-13 significantly improved lung function. Patients with higher IL-13 levels showed the greatest effect. Although the trend toward reduced disease exacerbations in treated patients did not reach statistical significance, this study does suggest that a targeted approach to asthma therapy is worth pursuing.
N. Engl. J. Med. 365, 1088 (2011).
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NF-κB and Eczema
Nuclear factor kappaB activity is increased in peripheral blood mononuclear cells of children affected by atopic and non-atopic eczema.
http://www.ncbi.nlm.nih.gov/pubmed/17346428 2007
Atopic and non-atopic eczema is an inflammatory cutaneous disease which is common in childhood and is associated with a dysregulation of the immune system. Many genes encoding immune receptors, cytokines, chemokines, chemokine receptors, and adhesion molecules involved in the development of the disease are under the control of transcription factors belonging to the nuclear factor (NF)-kappaB family. To investigate the role of NF-kappaB in the development of eczema, 20 children, affected by relapsing chronic eczema, were enrolled in this study. Eleven of the 20 children showed IgE immunoreactivity and had a positive prick test. The DNA binding activity of NF-kappaB in nuclear extracts of the patients’ peripheral blood mononuclear cells (PBMC) was examined by electrophoretic mobility shift assay. We found that basal NF-kappaB-DNA binding activity in PBMC was significantly higher in the eczema patient group in comparison with the same parameter in the healthy age-matched control group. Moreover, we observed a significant correlation between NF-kappaB-DNA binding activity and patients clinical score (SCORAD). Based on these observations we speculate that NF-kappaB can play an important role in the immunopathogenesis of eczema and therefore could be considered as a potential therapeutic target.
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New insights into atopic dermatitis
http://www.jci.org/articles/view/21060
Atopic dermatitis is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental triggers and is often the first step in the atopic march that results in asthma and allergic rhinitis.
AD usually presents during early infancy and childhood, but it can persist into or start in adulthood (2). The lifetime prevalence of AD is 10–20% in children and 1–3% in adults. Its prevalence has increased two- to threefold during the past three decades in industrialized countries but remains much lower in countries with predominantly rural or agricultural areas
Wide variations in prevalence have been observed within countries inhabited by groups with similar genetic backgrounds, suggesting that environmental factors play a critical role in determining expression of AD.
The evolution of AD skin lesions is orchestrated by the local tissue expression of proinflammatory cytokines and chemokines. Cytokines such as TNF-α and IL-1 from resident cells (keratinocytes, mast cells, and DCs) bind to receptors on vascular endothelium, activating cellular signaling including the NF-κB pathway and inducing expression of vascular endothelial cell adhesion molecules. These events initiate the process of tethering, activation, and adhesion to the endothelium followed by extravasation of inflammatory cells. Once the inflammatory cells have infiltrated into the tissue, they respond to chemotactic gradients established by chemoattractant cytokines and chemokines, which emanate from sites of injury or infection (9). These molecules play a central role in defining the nature of the inflammatory infiltrate in AD
Recently, a polymorphism (G2722C) that results in functional impairment of caspase recruitment domain–containing protein 15, an intracellular receptor for LPS involved in NF-κB activation, has been associated with a twofold increased risk for development of AD
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NF-κB and Rheumattoid Arthritis
Increased nuclear factor-kappaB activation in peripheral blood monocytes of patients with rheumatoid arthritis is mediated primarily by tumor necrosis factor-alpha.
CONCLUSION:
Our results indicate a role for NF-kappaB activation and TNF-alpha in the activation of monocytes of patients with RA, and suggest an important role of circulating monocytes in RA pathogenesis.
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Inhibition of NF-κB Signaling as a Strategy in Disease Therapy
http://www.springerlink.com/content/u01487xrj6034825/
As described extensively in this issue, NF-κB transcription factors regulate a number of important physiological processes, including inflammation and immune responses, cell growth and survival, and the expression of certain viral genes. Moreover, NF-κB activity is elevated in and contributes to the pathology of several human diseases, including many cancers and chronic inflammatory diseases.
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Psychiatric disorders: The dark side of depression
http://www.nature.com/nrn/journal/v12/n8/full/nrn3072.html?WT.ec_id=NRN-201108
Leonie Welberg
Depression is associated with disruptions in circadian rhythms, including altered sleep–wake patterns, and with immune system activation, as indicated by increased levels of pro-inflammatory cytokines. Monje et al.
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Neurons and Brains etc
Nuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway
http://www.jneurosci.org/content/31/32/11697.short
These data suggest the relevance of future studies on the role of Notch/NF-κB cross talk in regulating cortex structural plasticity in physiological and pathological conditions.
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Neuronal migration
Role of nitric oxide produced by iNOS through NF-κB pathway in migration of cerebellar granule neurons induced by Lipopolysaccharide
http://www.sciencedirect.com/science/article/pii/S0898656810003049
The role of NF-κB was showed by using the inhibitor JSH-23, which decreased NO•– production and neuronal migration in LPS activated cultures. These results suggest that neuronal migration during development is susceptible to be modified by pro-inflammatory stimulus such as LPS through intracellular pathways associated with their receptors.
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Nna1 Mediates Purkinje Cell Dendritic Development via Lysyl Oxidase Propeptide and NF-κB Signaling
http://www.sciencedirect.com/science/article/pii/S0896627310006239
We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1′s role in neuronal development and why its absence renders Purkinje cells more vulnerable.
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Purkinje Cells in Autism
Density of cerebellar basket and stellate cells in autism: Evidence for a late developmental loss of Purkinje cells
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22056/full
Alterations in the cerebellum have been described as a neuropathological feature of autism.The preservation of BCs and SCs, in the presence of the reduced PC numbers as found in at least two, and possibly three, of these six autistic cases (Whitney et al., 2008) suggests that PCs were generated, migrated to their proper location in the PC layer, and subsequently died in the autistic cases that showed a reduction in PCs.*
Note – see GO: 0006915 Apoptosis (cell death) , GO: 0012501 Programmed cell death (Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates below )
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Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism
http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2009.07073.x/full
Recent studies have indicated that cerebellar pathology may play a causal role in the generation of repetitive and hyperactive behaviors. In this study, we examined the relationship between cerebellar pathology and these behaviors in a mouse model of Purkinje cell loss.
the significant relationships between Purkinje cell number and repetitive lever-pressing behavior as well as open-field activity measures provide support for a role of cerebellar pathology in generating repetitive behavior and increased activity in chimeric mice.
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The Developmental Neuropathology of Autism
http://www.springerlink.com/content/q1625n71742q8170/
The cellular neuropathology of autism is well described and illustrated in several reports. This chapter focuses on the timing and mechanism of these pathological changes, an aspect of the pathology of the autistic brain not covered in detail in the prior reports.Particular attention is paid to the changes in the brain stem, the cerebellum, and the cerebral cortex. Although the molecular (genetic) mechanism of these diverse neuropathologies is unknown, it can be seen that there is broad diversity of these changes, with perturbations of several different developmental processes, rather than reliance on a single mechanism. The vast majority of these pathologies can be dated to the prenatal period. The final section explores the relationship of these prenatally derived pathologies, and perturbation of other postnatal developmental processes, to the well-documented abnormal postnatal brain growth. I conclude that, based on the available data, that none of these mechanisms seem likely to account for the abnormal postnatal brain growth.
Note – see below Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates
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Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates
Central Immune Signaling Pathways
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024691
The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive.
(Note – Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. University California 2011
Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.
To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.
A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).
Gene Expression Values
Notably, expression values at the 6 mo time point were considerably lower for almost all genes and brain regions. This may be a function of lowered CNS transcriptional activity at this age, however a systematic error in sequencing is also likely. Since we were interested in highly expressed genes, we were not concerned this would introduce false-positive results into our subsequent analysis.
By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia—in addition to neurons—deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.
Note – Table 1. GO enrichment analysis of the 11 genes shared by Autism, Schizophrenia, and Epilepsy.
GO: 0032103 Positive regulation of response to external stimulus – Anxiety
(Any process that activates, maintains or increases the rate of a response to an external stimulus).
GO: 0031622 Positive regulation of fever – (Any process that activates or increases the frequency, rate, or extent of fever generation.)
GO : 0031620 Regulation of fever generation
GO: 0031650 Regulation of heat generation
GO: 0031652 Positive Regulation of heat generation
Shown at Table 3 Gene ontology enrichment of the 32 highly expressed Autism genes revealed four new GO categories representing two significant processes—immune system regulation and apoptosis
GO: 0002682 Regulation of Immune System Process
GO: 0006915 Apoptosis (cell death)
GO: 0012501 Programmed cell death
GO: 0031347 Regulation of defense response – (Any process that modulates the frequency, rate or extent of a defense response.)
Table 5. Canonical Pathways implicated in ASD when considering all genes versus highly expressed genes.
Of note -
Serotonin receptor signaling
Virus entry via endocytic pathways (Endocytosis is a process by which cells absorb molecules (such as proteins) by engulfing them. )
Figure 1. Summary of all genes analyzed from AutDB, CarpeDB and SZGene. Autism, Schizophrenia, and Epilepsy.
Autism shares 69 genes with schizophrenia / 43 epilepsy and 11 between all three.
Figure 4. and 5 Network 1 derived from the ASD highly expressed gene set.
(Note – NFκB hub and the complex interactions in figures)
In the first central network (Figure 4), NFκB, Jnk, and Mapk are hubs. Network 2 from the highly enriched set also contains NFκB as a hub, in addition to Tnf, TgfB1 and Myc (Figure 5). Taken together, these enriched networks, which are the most inter-connected of all ASD-derived networks, have at their core fundamental cytokine signaling molecules not previously implicated as ASD susceptibility loci. These may serve as potential final common pathways through which the heterogeneous ASD-implicated genes ultimately converge. Moreover, this represents a third, independent level of analysis whereby the highly expressed ASD genes implicate immune signaling pathways that are not apparent when the full set of ASD-associated genes is considered.
( Table 9). This underscores the importance of our findings on ASD-implicated genes, as both our approach and whole-transcriptomics studies implicate immune signaling pathways, even though most ASD-implicated genes we profiled are not dysregulated in ASD brain tissue.
Closer inspection of these networks revealed NFκB, Jnk, MapK, TNF, TGF-B, and Myc as central hubs. These central networks were supported by evidence at two other levels of our analysis (Gene ontology and canonical pathways). Taken together, our findings integrate a large set of genes implicated in ASD and suggest that they may converge onto classical cytokine signaling pathways.
While other transcriptomics studies on ASD tissue have implicated immune system signaling in ASD pathogenesis, our findings suggest that the ASD-implicated genes themselves may also be related to these functions. Interestingly, there is also mounting evidence at the cellular and tissue levels that more in depth investigation of an immune component is warranted in ASD [46]. For instance, multiple studies have demonstrated altered cytokine profiles in ASD patients [47], [48], and altered TGF-B concentration in serum and CSF correlates with disease severity [49].
This considerable attention to the immune response in previous ASD research has resulted in two prevailing theories:
1. one suggests exogenous factor(s) stimulate neuro-inflammation during development,
2. while the other postulates autoimmune activation causes ASD pathology [56], [57].
3. However, it is equally possible—as our results support—that the mutations described in ASD result in aberrant signaling regulation of immune cells during neurodevelopment.
signaling through the NFkB pathway has been shown to be important in synaptic plasticity independent of an inflammatory mechanism
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Cytokines – Pieces of the Autism Puzzle
http://www.rndsystems.com/cb_detail_objectname_SP02_Cytokines.aspx
Cytokines (Greek cyto-, cell; and -kinos, movement) are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication.
A subacute, chronic tetanus infection in the intestinal tract can promote the symptoms of autism as well.9 Tetanus toxins may be transported to the brain through the vagus nerve disrupting the release of neurotransmitters. In addition, maternal/fetal immune interactions may result in autism. Some mothers of autistic children express antibodies that are reactive to both lymphocytes from their autistic children as well as lymphocytes from their husbands.10
In light of the many potential causes, immune system abnormalities and cytokines are repeatedly implicated in ASD (see reference 12 for a review). Detection of elevated IL-2 serum levels in autistic subjects suggests that activation of a T cell subpopulation may be important in autism.
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Autism and Clostridium tetani. (Tetanus)
http://www.ncbi.nlm.nih.gov/pubmed/9881820
Clostridium tetani is an ubiquitous anaerobic bacillus that produces a potent neurotoxin. Intestinal colonization by C. tetani, and subsequent neurotoxin release, have been demonstrated in laboratory animals which were fed vegetative cells. The vagus nerve is capable of transporting tetanus neurotoxin (TeNT) and provides a route of ascent from the intestinal tract to the CNS. This route bypasses TeNT’s normal preferential binding sites in the spinal cord, and therefore the symptoms of a typical tetanus infection are not evident.
Once in the brain, TeNT disrupts the release of neurotransmitters by the proteolytic cleavage of synaptobrevin, a synaptic vesicle membrane protein. This inhibition of neurotransmitter release would explain a wide variety of behavioral deficits apparent in autism. Lab animals injected in the brain with TeNT have exhibited many of these behaviors. Some children with autism have also shown a significant reduction in stereotyped behaviors when treated with antimicrobials effective against intestinal clostridia. When viewed as sequelae to a subacute, chronic tetanus infection, many of the puzzling abnormalities of autism have a logical basis. A review of atypical tetanus cases, and strategies to test the validity of this paper’s hypothesis, are included.
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Sleep Disturbances
Evidence for activation of nuclear factor kappaB in obstructive sleep apnea
Obstructive sleep apnea (OSA) is a risk factor for atherosclerosis, and atherosclerosis evolves from activation of the inflammatory cascade. We propose that activation of the nuclear factor kappaB (NF-kappaB), a key transcription factor in the inflammatory cascade, occurs in OSA.
NF-kappaB activation occurs with sleep-disordered breathing. Such activation of NF-kappaB may contribute to the pathogenesis of atherosclerosis in OSA patients.
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Autism. 2011 Apr 8. [Epub ahead of print]
Sleep Problems in Children With Autism Spectrum Problems: A Longitudinal Population-Based Study.
Sivertsen B, Posserud MB, Gillberg C, Lundervold AJ, Hysing M.
Source
Norwegian Institute of Public Health, Norway and University of Bergen, Norway and Helse Fonna HF, Norway.
Abstract
This study examined the prevalence and chronicity of sleep problems in children who manifest problems believed to be typical of Autism Spectrum Disorders (ASD). Using data from a longitudinal total population study, symptoms of ASD, insomnia and potential explanatory factors were assessed at ages 7-9 and 11-13. Children were included in a group defined as having Autism Spectrum Problems (ASP) if they scored above a strict threshold on the Autism Spectrum Screening Questionnaire (ASSQ). Twenty-eight (0.8%) of 3700 children fulfilled the selected criteria for ASP at both waves, and the prevalence of chronic insomnia was more than ten times higher in these children compared to the controls. Children with ASP developed more sleep problems over time, with an incidence rate at wave 2 of 37.5% compared to 8.6% in the controls. The sleep problems were more persistent over time, with a remission rate of 8.3% compared to 52.4% in the controls. ASP was a strong predictor of sleep problems at wave 2 (OR = 12.44), and while emotional and behavioural problems explained a large proportion of this association, the effect of ASP on insomnia remained significant in the fully adjusted model (OR = 3.25). These findings call for increased awareness of sleep problems in children with ASP.
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Rett Syndrome (Pervasive Developmental Disorder – Females)
Genomic and transcriptomic analyses distinguish classic Rett and Rett-like syndrome and reveals shared altered pathways
Transcriptional profiling revealed blood gene signatures that clearly distinguish classic RTT and RTT-like patients, as well as shared altered pathways in interleukin-4 and NF-κB signaling pathways in both subtypes of the syndrome. To our knowledge, this is the first report on investigating common regulatory mechanisms/signaling pathways that may be relevant to the pathobiology of the “common RTT” phenotype.
http://www.sciencedirect.com/science/article/pii/S0888754310001990
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NF-κB and Autism
A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism
We have noted significant increase in NF-κB DNA binding activity in peripheral blood samples of children with autism. When the fold increase of NF-κB in cases (n = 67) was compared with that of controls (n = 29), there was a significant difference (3.14 vs. 1.40, respectively; p<0.02).
Conclusion
This finding has immense value in understanding many of the known biochemical changes reported in autism. As NF-κB is a response to stressors of several kinds and a master switch for many genes, autism may then arise at least in part from an NF-κB pathway gone awry.
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Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation 2011
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098713/
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal cortex tissue
NF-κB is aberrantly expressed in the orbitofrontal cortex as indicated by measurements on post-mortem tissue from ASC patients, and particularly in highly activated microglia. This region is a locus of abnormal function in ASC that underlies the abnormal development of social and cognitive skills (Sabbagh, 2004).
This is the first discovery of its kind that identifies a potential mechanism for neuroinflammation in ASC through increased expression of this pro-inflammatory molecule and the significant involvement of resident immune cells. The connection of this result to changes in intracellular acidity indicates an investigation of pH across the entire brain parenchyma in living patients.
Whilst evidence of causal link remains to be established, the idea that the induction of inflammation via the NF-κB signaling cascade is observed in regions of the neocortex associated with behavioral and clinical symptoms of ASC gives credence and impetus to interventions focusing on this potential therapeutic target.
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NF-kappaB activation is associated with homocysteine-induced injury in Neuro2a cells
Nadia Ferlazzo Salvatore Condello Monica Currò Giulia Parisi Riccardo Ientile and Daniela Caccamo
Department of Biochemical, Physiological and Nutritional Sciences, University of Messina – Messina, Italy
BMC Neuroscience 2008, 9:62doi:10.1186/1471-2202-9-62
http://www.biomedcentral.com/1471-2202/9/62
Published: 7 July 2008
Perinatal exposure to hyperhomocysteinemia might disturb neurogenesis during brain development and growth. Also, high levels of homocysteine trigger neurodegeneration in several experimental models. However, the putative mechanisms of homocysteine-induced toxicity in the developing nervous system have poorly been elucidated.
This study was aimed to investigate homocysteine effects in undifferentiated neuroblastoma cells, Neuro2a.
Conclusion
These observations suggest an involvement of redox state alterations and activated NF-κB in apoptosis onset triggered by homocysteine in neuroblastoma cells Neuro2a. However, further investigations are needed to characterize molecular events involved in the NF-κB activation induced by homocysteine.
Homocysteine (Hcy) is a non-proteic sulfur-containing amino acid product of methionine metabolism. Hyperhomocysteinemia is determined by genetic factors, such as deficiency in enzyme activities involved in homocysteine remethylation and transulphuration pathways, and/or reduced dietary intake of folate, vitamin B6 and vitamin B12
Deficiencies of the vitamins folic acid (B9), pyridoxine (B6), or B12 (cobalamin) can lead to high homocysteine levels.[5]12 or trimethylglycine (betaine) reduces the concentration of homocysteine in Supplementation with pyridoxine, folic acid, B
the bloodstream.[6][7] Increased levels of homocysteine are linked to high concentrations of endothelial asymmetric dimethylarginine. Recent research suggests that intense, long duration exercise raises plasma homocysteine levels, perhaps by increasing the load on methionine metabolism.[8] Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.[9][10]
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Tetrandrine attenuates spatial memory impairment and hippocampal neuroinflammation via inhibiting NF-κB activation in a rat model of Alzheimer's disease induced by amyloid-β(1-42).
He FQ, Qiu BY, Zhang XH, Li TK, Xie Q, Cui DJ, Huang XL, Gan HT.
Source
Department of Geriatrics Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Brain Res. 2011 Apr 12;1384:89-96. Epub 2011 Feb 4.
Abstract
BACKGROUND:
The neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to play a critical role in the pathogenesis of Alzheimer's disease (AD). Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese herb radix Stephania tetrandra, has been demonstrated to decrease the expression of proinflammatory mediators by inhibition of nuclear factor-κB (NF-κB) activation. The purpose of the study was to investigate effects of tetrandrine on experimental model of AD.
MATERIALS AND METHODS:
Tetrandrine was administered in a rat model of AD induced by amyloid-β (Aβ)(1-42). The learning and memory impairment was examined using Morris water maze; the extent of histological injury in hippocampus was determined by Nissl staining; NF-κB DNA binding activity was assessed by electrophoretic mobility shift assay; the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β was measured by enzyme-linked immunosorbent assay.
RESULTS:
A significant improvement was observed in learning and memory impairment in rats with tetrandrine, and the increase in NF-κB DNA binding activity, the over-expression in IL-1β and TNF-α as well as the increased histological injury in hippocampus in rats induced by Aβ(1-42) were significantly reduced following administration of tetrandrine.
CONCLUSION:
Tetrandrine could significantly ameliorate Aβ(1-42)-induced spatial learning and memory impairment, and the beneficial effect of tetrandrine treatment could be linked, at least in part, to the inhibition of NF-κB activity and the downregulation of expression of IL-1β and TNF-α, suggesting that administration of tetrandrine may provide a therapeutic approach for AD.
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Autism and SSRI (antidpressants)
Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders
Lisa A. Croen, PhD ; Judith K. Grether, PhD ; Cathleen K. Yoshida, MS ; Roxana Odouli, MSPH ; Victoria Hendrick, MD
Arch Gen Psychiatry. Published online July 4, 2011. doi:10.1001/archgenpsychiatry.2011.73
Co
December 11, 2011 at 5:02 am
Autism and SSRI (antidpressants)
Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders
Lisa A. Croen, PhD ; Judith K. Grether, PhD ; Cathleen K. Yoshida, MS ; Roxana Odouli, MSPH ; Victoria Hendrick, MD
Arch Gen Psychiatry. Published online July 4, 2011. doi:10.1001/archgenpsychiatry.2011.73
Context The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD.
Results Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.
Conclusion Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.
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Differential induction of NF-κB activity and neural cell death by antidepressants in vitro
1. Anke Post,
2. Christophe Crochemore,
3. Manfred Uhr,
4. Florian Holsboer,
5. Christian Behl
Article first published online: 18 JUL 2008
DOI: 10.1046/j.0953-816X.2000.01352.x
European Journal of Neuroscience
Volume 12, Issue 12, pages 4331–4337, December 2000
Abstract
Tricyclic antidepressants and selective serotonin reuptake inhibitors are here shown to induce cell death in a neural cell line. The exposure to these drugs led to increased generation of reactive oxygen species and a concomitant reduction of intracellular glutathione levels. Furthermore, these antidepressants induced DNA fragmentation and increased the transcriptional and DNA-binding activity of NF-κB. In contrast, treatment with type A and B monoamine oxidase inhibitors did not induce changes in NF-κB activity and did not exert a detrimental influence on cell viability. These results indicate that some antidepressant drugs may cause both oxidative stress and changes in cellular antioxidative capacity, resulting in altered NF-κB activity and, ultimately, cell death.
Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism
Hallmayer et al.
Arch Gen Psychiatry.2011; 0: 2011761-7.
http://www.ncbi.nlm.nih.gov/pubmed/21727249
Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N.
Source
Stanford University School of Medicine, Stanford (Drs Hallmayer, Lotspeich, and Phillips and Mss Cleveland and Torres), Autism Genetic Resource Exchange, Autism Speaks, Los Angeles (Mss Cohen, Torigoe, and Fedele and Drs Miller and Lajonchere), Environmental Health Investigations Branch, California Department of Public Health, Richmond (Mr Collins, Ms Smith, and Dr Grether), Division of Research, Kaiser Permanente Northern California, Oakland (Drs Croen and Risch), University of California, Davis, MIND Institute, Sacramento (Dr Ozonoff), and Institute for Human Genetics and Department of Epidemiology and Biostatistics, University of California, San Francisco (Dr Risch).
Arch Gen Psychiatry.2011; 0: 2011761-7.
Arch Gen Psychiatry. 2011 Jul 4. [Epub ahead of print]
CONTEXT:
Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins.
OBJECTIVE:
To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.
RESULTS:
For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD
.CONCLUSION:
Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.
Nature. 1999 Sep 2;401(6748):82-5.
NF-kappaB activation by tumour necrosis factor requiresAkt serine-threonine kinase.
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB.
Source
Department of Microbiology and Immunology, Indiana University School of Medicine, the Walther Oncology Center, Indianapolis 46202, USA.
Abstract
Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB by tumour necrosis factor (TNF). TNF activates phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K or kinase-dead Akt inhibits TNF-mediated NF-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children.
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M.
Source
Department of Neurology, Rosalind Franklin University, and the Chicago Medical School, North Chicago, IL, USA. chezm2@sutterhealth.org
Abstract
Recent reports implicating elevated cytokines in the central nervous system in a small number of patients studied with autismautism had clinical evaluation of their serum and spinal fluid for inflammatory changes and possible metabolic disease as part of their neurological evaluation. Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher (mean = 104.10 pg/mL) than concurrent serum levels (mean = 2.78 pg/mL) in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1. This ratio is significantly higher than the elevations reported for other pathological states for which cerebrospinal fluid and serum tumor necrosis factor-alpha levels have been simultaneously measured. This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker. More controlled study of this potentially important observation may prove valuable. have reported clinical regression. These studies have not focused on tumor necrosis factor-alpha as a possible marker for inflammatory damage. A series of 10 children with
An Open-Label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects with Prior Loss of Response or Intolerance to Infliximab for Crohn’s Disease
William J. Sandborn, M.D.; Stephen Hanauer, M.D.; Edward V. Loftus Jr., M.D.; William J. Tremaine, M.D.; Sunanda Kane, M.D.; Russell Cohen; Karen Hanson, R.N., C.N.P.; Therese Johnson, R.N.; Debra Schmitt, R.N.; Resa Jeche, A.S.
Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; University of Chicago, Chicago, Illinois
We assessed the tolerability and clinical benefit of adalimumab, a human antibody to tumor necrosis factor (TNF), in patients with Crohn’s disease who had previously received and responded to the chimeric anti-TNF antibody infliximab, but who no longer had a sustained response and/or tolerance to infliximab.
Conclusions: Adalimumab is well tolerated and appears to be a clinically beneficial option for patients with Crohn’s disease who have previously lost their response to, or cannot tolerate infliximab.
Pediatr Neurol. 2005 Sep;33(3):195-201.
Cerebrospinal fluid and serum markers of inflammation in autism.
Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, Heyes MP.
Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore Maryland 21205, USA.
Abstract
Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.
J Biomed Sci. 2011 Jul 4;18(1):48.
Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL.
Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH.
Source
Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, Korea.
Abstract
BACKGROUND:
At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis.Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs.
METHODS:
Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay.
RESULTS:
In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL.
CONCLUSION:
To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IκBα and the activation of NF-κB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.
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NF-κB prevents β cell death and autoimmune diabetes in NOD mice
http://www.pnas.org/content/104/6/1913
These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-κB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-κB in IL-1β-stimulated β cells.
December 11, 2011 at 9:12 pm
Hi Blackheart -
That’s quite a list! It’s tough to know where to start, for sure; especially as I come from a background without substantial schooling in physiology. Unfortunately, the real world has kept me from thinking on this type of thing too much as of late. I got pretty bored with the exchange @ RI and remembered pretty clearly why I’d given up on them. In any case, thanks for the links. Here are a few, very quick thoughts I have.
Known inducers of NF-κB activity are highly variable and include reactive oxygen species (ROS), tumor necrosis factor alpha (TNFα), interleukin 1-beta (IL-1β), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, and ionizing radiation.
The potential interplay between oxidative stress (i.e., ROS), inflammation, (and, mitochondrial function, IMO) is going to be an important topic for the autism community, however I can’t think of a way to overstate the difficulty in this path.
Another thing that has really bothered me for a long time regarding the findings of immune activation in the CNS is autism is the distinct lack of a hallmark feature of what you usually think of when you think, neuroinflammation, namely, a degenerative state. Clearly there is something fundamentally different between the states of inflammation in disorders like Alzheimer’s and Parkinson’s, which involve a steady decline, and other neurologically based conditions with findings of neuroinflammation, like autism, depression, or even schizophrenia. I think this is important, somehow, but haven’t been able to put my finger on the right way to approach the problem.
The real world calls. I’ll try to think about some of this later, and let you know my thoughts.
- pD
December 11, 2011 at 11:38 pm
PD you say, “Another thing that has really bothered me for a long time regarding the findings of immune activation in the CNS is autism is the distinct lack of a hallmark feature of what you usually think of when you think, neuroinflammation, namely, a degenerative state”
I don’t know why you say this. There is a ton of evidence from medical literature showing immune activation in the CNS with plenty of hallmark features of neuroinflammation. Not sure what “namely, a degenerative state”, means, either. Neuroinflammation is an on-going state, which can be reversed.
Put “evidence of neuroinflammation in CNS in Autism” into Google Scholar, or Google and you will have more than enough proof.
Try here for starters: http://onlinelibrary.wiley.com/doi/10.1002/ana.20315/full
Plenty of colour slides in that medical paper for you.
and here: http://www.namialabama.org/clientimages/44494/documents/uabpsyschiatrygrandrounds2010.pdf
December 14, 2011 at 1:41 am
Hi Hilary -
Sorry it took me a while to respond. The real world is really tearing it up.
I think you misunderstood me. Clearly there is evidence on neuroinflammation in autism. But what we don’t see in autism, in general, is behavioral deterioration over the long term. While a lot of people report behavioral regression, and loss of skills in infancy, but generally there is a plateau, as opposed to a continuing deterioration of skills over time. In fact, most people report that their child gains skills over time. I don’t know of any cases, much less a pattern, of high functioning autism in a child degrading to low functioning autism as an adult.
A lot of the disorders that have classically been associated with neuroinflammation, conditions like alzheimers, or parkinsons, follow a different pattern; a steady, and uncompromising decline in abilities. If you get a diagnosis of alzheimers, there is only one direction that the developmental trajectory will follow. That is the difference.
Of course, the cause of many of these disorders is unknown. Just saying it is the inflammatory state looks like an over simplification; but clearly it is playing a part. That is the puzzle that has me vexed, what distinguishes the inflammatory state of some disorders that are degenerative versus those disorders that are not degenerative?
- pD
December 14, 2011 at 2:21 am
Okay, I get what you mean. I also agree. Real life can be a real nuisance. There aren’t enough hours in the day.
But I think a clue to that is in that study which showed that many autistic children “improve” during a fever, and “regress” after the fever goes. A fever requires a ramp up of the inate immune system, which causes a down-regulation of other immune system activity.
Autistic children don’t have a normal functioning, balanced immune system.
Alzheimers and Parkinson’s don’t show that same sort of immune imbalance.
May 12 1999, Dr Bonnie Dunbar said this to a USA select committee:
“I would challenge any colleague, clinician or research scientist to claim that we have a basic understanding of the human newborn immune system. It is well established in studies in animal models that the newborn immune system is very distinct from the adolescent or adult. In fact, the immune system of newborns in animal models can easily be perturbed to ensure that it cannot respond properly later in life.”
IMO. that is what the relentless vaccine programme does, at a time in immunological natural programming when you should not be constantly provoking the immune system.
What this does is create “original antigen sin” in a different form to that normally understood by that definition. OAS is normally referred to as meaning, the way the immune system first reacts to a virus etc, is the way it responds to subsequent challenge.
You mess up that neonatal programming, and that “messing up” can last a very long time, even if all your efforts are directly at dampening down inflammation.
I have an immunodeficiency, so know what I have to do just to stay “normal”. And I’m allergic to all antibiotics. To stay “normal” is doable. But it requires serious nutrition, a few supplements, and knowing how to deal with infections in a way that the medical profession has no understanding of.
I know many families who have children who didn’t have any risk factors in pregnancy, or use acetaminophen or antibiotics, but whose children became autistic after vaccines. Most of them have “dampened” down their children’s inflammation aspects – most of the time.
Their children, are much more “normal” but still not normal.
But something like exposure to agricultural sprays can flick the switch, and with a snap of fingers, their children are back into clasical autism within 30 minutes. The rapidity of change backwards, is astonishing. It takes massive doses of vitamin C (and some find pycnogenol is needed ) as well as other glutathione-type support. It takes at least 12 hours to see improvement.
Anything at all that messes with the development of the immune system in utero, and in the first three years is “incriminated” including (odd as it may seem) anti-acids in pregnancy; antibiotics in pregnancy; any drugs/toxins which mess with the immune system, and infections. But those factors dont’ usually affect 100% of mothers.
There are five things which puts potential immunological monkey wrenches into babies:
Caesarians – the indisputably worst way to automatically suppress a babies immune system for at least a year, and no-one is looking at why.
NOT breastfeeding. This is dumb, dumb and dumber. And what’s worse is that most developed countries have no commitment to it, in the form of breastmilk banks. Even NZ – absolutely no commitment at all, particularly as Fontera and dairy industries are the backbone of the economy. Besides which most human mothers consider formula much more ‘acceptable” than breastmilk from another mother. There is this irrational EEuuwwwww factor as if a donor mother might have AIDS or be dirty or something. And even if developed countries did have commitments to a breast milk bank, I’m sure the medical system would ruin it with all the “requirements” on donor mothers, and then they would go and “past yer ize” it which would nuke all the bits that are most valuable, all in the name of “sterility”.
Acetaminophen products which downgrade the inate immune system, and… I’m sick of seeing mothers use it nightly to put their kids to sleep. (some of that is dealt with here: http://www.beyondconformity.co.nz/_blog/Hilary's_Desk/post/Paracetamol_should_not_be_used_for_infectious_fevers_-_revisited/ )
Antibiotics which utterly mess with the immune system something awful
And vaccines. And of those three, vaccines are the one thing which potentially affect 100% of all children. And it’s vaccines which I believe are behind the huge increase in allergies and autism. Just my opinion.
December 14, 2011 at 5:32 pm
Hi Hilary –
But I think a clue to that is in that study which showed that many autistic children “improve” during a fever, and “regress” after the fever goes. A fever requires a ramp up of the inate immune system, which causes a down-regulation of other immune system activity.
I’d love to see those findings replicated and with some biomarkers. It is a neat finding, but as far as I know, there is only one study with these findings. That being said, some of the immune programming stuff I’ve looked at in the past suggest a highly speculative possibility line of thought towards this.
Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways
Is a cool, but pretty dense paper. As we know that very early life (i.e., in utero) immune challenge is associated with autism diagnosis, there does seem to be room to peek around. Essentially the authors report that animals challenged early in life with LPS showed different peripheral and neural immune responses to challenges later in life. So, could what was observed in the fever paper be a function of an altered ‘neural anti-inflammatory pathway’? I don’t know, it does seem to fit within a model of dysregulation, as opposed to strict ‘hardwiring’, but mostly what I’ve done there is drawn a line between two points, (maybe three). Still, it is an interesting set of data to consider. (to me)
Autistic children don’t have a normal functioning, balanced immune system.
True, and a lot of things point towards a tendency towards an inflammatory state, but some other papers aren’t quite as clear on the issue. The more I read, the less I feel like we know.
Alzheimers and Parkinson’s don’t show that same sort of immune imbalance.
Well, I guess we’d need more on the definition of imbalance from your perspective, but we do seem to have tons of data implicating some of the same immunological biomarkers in alzheimers as we see in autism, i.e.,
Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer’s disease.
or
A meta-analysis of cytokines in Alzheimer’s disease.
These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β, IL-12 and IL-18 and higher CSF concentrations of TGF-β.
That looks a lot like some of the data from autism, specifically IL-6, TNF-alpha, IL-1B, and (in some places), TGF-B in the CNS. Murky! There’s a ton more studies.
You mess up that neonatal programming, and that “messing up” can last a very long time, even if all your efforts are directly at dampening down inflammation.
If there is an adverse effect associated with vaccination, something I am not sure of by any stretch, I do believe that the mechanism will be a programming effect. I have also read a little bit about the innocent bystander and/or molecular mimicry effects, but not as detailed as I would have liked.
My current thought set is that lots of small nudges are what we see in autism, get a few, you get a quirky child, get a bunch, and you get a child strongly affected. For that reason, I share a lot of your concerns regarding c-sections (associated with autoimmune disorders like asthma and altered microbiota), breastfeeding (again, immune programming effects have been noted, as well as (I think) microbiota changes), products that interfere with the immune response, which could be just as perplexing to the programming model as initiation. Clearly antibiotics and the effect on the microbiota with associated immune tinkering is problematic. Vaccines do reach nearly every child, so if there is an effect, in some instances, that we haven’t detected yet, the problem is that it touches nearly every infant.
- pD
December 14, 2011 at 5:48 pm
Indeed, postnatal vaccinations would fit neatly into the scenario of immune disturbance in autism and its effect on behavior – if only the epidemiology supported a link, which it does not.
December 14, 2011 at 7:00 pm
Hi Paul Patterson -
Respectfully, I do not believe our existing epidemiology studies are adequately designed to detect such an effect. The entirety of our vaccination research in the autism realm consists of either the presence or absence of thimerosal, which does not measure the effect of vaccination per se, or MMR studies, which ignore the vast majority of the vaccination schedule, including all shots given shortly after birth, at two, four, or six months of age. Considering the significant time dependent effects of many of the studies in animal studies, I do not think we can or should allow measurements taken at 12 (or 18) months to be sufficient guides to what happens much, much earlier in life. While all of the research I’ve read that you have authored involve maternal immune challenges, many others involve animals of much older ages. For example, the neural programming paper I referenced above challenged animals at postnatal day 14.
I’d be the first to admit the jump from animal to human is fraught with complexity and necessary caution, but I also believe we must balance this with the relative strength of our analysis regarding vaccines, which is frail.
Here is an example of what I mean. Some of your earliest research that I read involved il-6, and indeed, at the time, the idea that an innate immune response alone, without pathogenic effects from organisms, could affect change, was relatively novel. If you were to go to pubmed and look for studies that tell you what the il-6 response to pediatric vaccines is, the measurements simply have not been performed. The notion that such an increase in inflammatory cytokines, sans the effect of the actual pathogen, could affect change was a black swan when the vaccine schedule was developed. There are hundreds, or thousands of studies on the adaptive immune response in this population, but nothing, and I mean nothing, on the innate immune response. While this is quite different than the generally accepted narrative, it is the reality.
I would further suggest this paying attention to this is particularly salient considering how little we understand about the neonatal and infant innate immune response. There is some evidence that it is “designed” to inhibit a robust inflammatory response, something that may be a function of evolutionary selection, as opposed to something serving simply as an incredible danger to the infant.
For some idea of how little we understand the innate immune response of the infant, you might be interested in “Ontogeny of toll like receptor mediated cytokines responses of human blood mononuclear cells” , published in 2010 as the largest longtitudinal study of the infant immune system to date, with 35 participants. (note increases in il-10 production at birth, indicating increased ability to regulate the immune response). Neonate responses reported in “Innate immunity of the human newborn: distinct cytokines responses to LPS and other toll like receptor agonists” showed significant reductions in some inflammatory cytokines in newborns.
Unfortunately, against this background of a position of relative ignorance of the infant immune response, and an increasing suite of animal studies that indicate subtle effects of early life immune challenge are biologically plausible, we have precioys little available on the effect of the effect of vaccination itself.
-pD
December 14, 2011 at 7:17 pm
From my book:
Contrary to some activists’ claims, the medical community heard these
pleas, took notice of the Wakefield publicity, and conducted a variety of
studies to explore the potential connection. As of 2009, 13 epidemiologic
studies, generated in a number of different countries, have been published on the subject of autism and vaccination (summarized by Gerber and Offit; see the reading list). Some studies compared the increasing rate of autism diagnosis with the rate of vaccination. Other studies compared the rates of diagnosis of the “new” form of autism proposed by Wakefield—regression with GI symptoms—with the rate of MMR vaccination. Still other studies compared the rates of autism in vaccinated versus unvaccinated children. Another study evaluated the timing of the autism diagnosis in comparison to the MMR vaccination. A different study compared the age at vaccination and the rate of autism. Summarizing these findings, it is fair to say that epidemiologists have been unable to find a connection between MMR vaccination and autism, either the standard type or the proposed “new” type. There is also no effect on the rate of autism and the timing of the vaccination. Moreover, there is no genuine, statistical connection between the timing of the diagnosis and the timing of the vaccination.
December 14, 2011 at 7:53 pm
Hi Paul Patterson –
Unfortunately, the references provided by Gerber and Offit in
Vaccines and Autism: A Tale of Shifting Hypotheses
Do nothing but prove my point. Here are the thirteen articles from their reference set in Table 1, in the order provided by Table 1 from that paper.
1. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. — This is a study on the MMR.
2. . Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a causal association. — Another MMR study.
3. Kaye JA, del Mar Melero-Montes M, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. An MMR study.
4. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in Another MMR study.
5. Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations This is a study on thimerosal dosages, not vaccination.
6. Fombonne E, Chakrabarti S. No evidence for a new variant of measles-mumps-rubella–induced autism Another MMR study.
7. Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study – another MMR study.
8. DeWilde S, Carey IM, Richards N, Hilton SR, Cook DG. Do children who become autistic consult more often after MMR vaccination? – another MMR study
9. Makela A, Nuorti JP, Peltola H. Neurologic disorders after measles-mumps-rubella vaccination. A MMR study.
10. Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism – MMR
11. DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in metropolitan Atlanta. – MMR study.
12. . Peltola H, Patja A, Leinikki P, Valle M, Davidkin I, Paunio M. No evidence for measles, mumps, and rubella vaccine–associated inflammatory bowel disease or autism in a 14-year prospective study. – MMR study.
13. Patja A, Davidkin I, Kurki T, Kallio MJ, Valle M, Peltola H. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up — MMR study.
Does any one of these studies, any of them, take into consideration HEP-B, or DTAP, or Hib, or pneumoccocal, or polio vaccinations?
The conclusions of this paper admit this, albeit underhandedly:
Twenty epidemiologic studies have shown that neither thimerosal nor MMR vaccine causes autism. These studies have been performed in several countries by many different investigators who have employed a multitude of epidemiologic and statistical methods. The large size of the studied populations has afforded a level of statistical power sufficient to detect even rare associations. These studies, in concert with the biological implausibility that vaccines overwhelm a child’s immune system, have effectively dismissed the notion that vaccines cause autism.
See how neatly he tied together thimerosal and MMR , without empirical support to suddenly mean “vaccines” all together. How can studying something that happens at twelve months tell us anything about a different set of insults at two, or four, or six months? That isn’t the application of the scientific method, it is smoke and mirrors and wordsmithing.
There are other thimerosal studies, but contrary to the claims by Mr. Offit, or your book, none of the studies in question evaluated ‘vaccinated and unvaccinated’ children, unless you consider not getting the MMR “unvaccinated”. I take no pleasure from finding that the leading media spokesman for the vaccine / autism discussion is so adept at manipulation, in fact, it scares the hell out of me, but there it is. The reality is the reality.
Here is something you might want to consider before taking the written word of Mr. Offit as use for citations in the future. From the same article that you referenced, this rather difficult to believe statement is made:
Autism is not an immune-mediated disease. Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism [38].
Note that this paper by Mr. Offit was published in 2009! Someone with access to pubmed in 2009 could easily have found any of the following articles, if they were interested in either looking, or telling the real story:
Neuroglial activation and neuroinflammation in the brain of patients with autism published in 2005, which showed extensive evidence of activated microglia in parts of the brain.
We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.
In 2007, Chez reported increased TNF alpha levels in the CNS of autism in Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children
A series of 10 children with autism had clinical evaluation of their serum and spinal fluid for inflammatory changes and possible metabolic disease as part of their neurological evaluation. Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher (mean = 104.10 pg/mL) than concurrent serum levels (mean = 2.78 pg/mL) in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1. This ratio is significantly higher than the elevations reported for other pathological states for which cerebrospinal fluid and serum tumor necrosis factor-alpha levels have been simultaneously measured.
In 2007, Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects was published.
Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism. Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes.
In 2008, Immune transcriptome alterations in the temporal cortex of subjects with autism
Expression profiling of the superior temporal gyrus of six autistic subjects and matched controls revealed increased transcript levels of many immune system-related genes
All of these studies were easily available to Mr. Offit when he made the wild claim that ” there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism”. The only options available to us is that Mr. Offit was incompetent to find the papers I referenced above, didn’t understand them, or knew they existed, and purposefully declined to include them in his analysis. Of particular humor, the reference he does provide in this respect, reference 38, is:
Immunization Safety Review: Vaccines and Autism which was published in 2004, a long time in the autism literature world, and a full five years before the published his “shifting hypothesis” paper. Here is a snipet from the IOM report that failed to make it into Mr. Offit’s less than nuanced report:
Neuropathological studies of autism have revealed no evidence of cerebral inflammatory lesions or microglial activation, which is a common feature in immune-mediated encephalitis (Bauman and Kemper, 1997). However, there are very few autopsy studies of brains from people with autism and this has not been fully investigated. Analysis of CSF from young children with autism, including screening for sensitive inflammatory markers such as quinolinic acid and neopterin, has also found no evidence of inflammation (Comi et al., 1999). The sample size in these studies is small, however.
This isn’t just smoke and mirrors, it is the intentional repackaging of a nuanced, and cautious statement into one that claims authority, even in the face of repeated observations to the opposite. You’ll have to decide for yourself in Mr. Offit is incompetent or engaged in deception.
The reality is that the papers referenced by Mr. Offit, and then by yourself, simply don’t address vaccination, no matter how much we might like them to. If you have other studies that do measure the effects of vaccines other than the MMR and autism endpoints, they’d be useful to discuss. Unfortunately, they don’t exist.
Welcome to the monkey house.
- pD
- pD
December 14, 2011 at 8:53 pm
@ PH patterson. I never breathed a word about Wakefield, mercury or MMR. I’ve also never written about either except to explain why I’ve never written about them. I started to see autism after vaccines, long before the world knew about Kirby or Wakefield and long before “Jenny” became a household name, or supported a ludicrous concept called “green the vaccines”.
There are vasty more broader reasons , and had those people pushing specific barrows, actually done their homework properly, the debate would look very different today.
People don’t look for something, if they don’t know there is an “issue”, and if they don’t know where to start to research something. A doctor with brains once told me, “Hilary, beware the arrogance of ignorance”. A problem for both sides of the issue, and one which I believe you also suffer from. For some of us, the understanding that we are ignorant, has provided the foundation for finding what we know, knowing that there is always more we don’t know.
It’s hard enough for parents to research – particularly because unlike you, getting full text articles isn’t free, and can be a real mission.
You’ve read these two trials I presume? PMID: 2871241. PMID 2896826.In neither of these studies, is the word “placebo” even legitimate, as one of your colleagues has stated recently PMID: 22041301 albeit restricted to Al whereas both these studies used multiple non-inert substances in their so-called “placebos”.
The day I read these two trials, 20+ years ago, was the day I started to understand that it can be difficult to trust a medical system which indulges in selective deafness, and selective definition, to investigate anything. Of course, those were the days…. when the medical system never dreamed that parents would read what they wrote.
When “experts” start quoting “epidemiology” to squash any suggestion of vaccine culpability issues, their definitions are always something that bothers me. The definition of the word “unvaccinated” is usually as valid as the definition of the world “placebo” in the two studies above.
One study the medical system has never done, and will never do, is to do a trial looking at autistic children, and comparing them with children who NOT ONLY were never ever vaccinated, but were also breastfed, birthed without intervention, and whose mothers ate superbly when pregnant, and compared them with the “average” acceptable child, who has had all vaccines.
You may say, that’s comparing apples and pears.
Parents like myself have long since learned that if we want healthy children, the people to be most circumspect of, are the medical profession. If a pregnany mother takes the advice of the average doctor today the mother is on a downward spiral of anti-acids, antibiotics, constant scans, and needless tests – with minimal useful advice. I know, because I’ve done a huge amount of doula work, and had to sit and listen to “professional” advice consisting of the likes of: (serious morning sickness)… “Just use 5-up, cola and potato crisps,” (ultrasound scans) “we need to do them so that we can intervene if we think it’s necessary” – don’t you love the “we” bit…. (breech baby) “That’s okay, we’ll schedule a caesarian” (cracked nipples) “just supplement with formula until the cracks heal” (baby eczema) “Here use this cream” (steroids) and …. the list is endless.
And that is true about so much that the medical profession gives as an “answer”. Yes, I’ve received your book. And when I’ve finished it, I will decide whether or not I have the time to point out everything you have selectively chosen to ignore. So far, that would fill about two books.
So… you’ve quoted yourself here…, because you consider yourself a worthy “authority”.
I’ve also learned that if parents dig deep enough into the medical literarature and know where to look, they will find the real answers, not “pretend” answers.
That is where I get my answers from
Here is a little bit from the medical literature, back to you, – a skeleton within these three blogs:
http://www.beyondconformity.co.nz/_blog/Hilary's_Desk/post/Vaccines_and_neonatal_immune_development/
To save readers time, many of the full texts publicly available are uploaded into the blogs.
One you’ve read all those articles, and put flesh on the skeletons and breathed life into the core knowledge… (or lack of) , perhaps THEN you can tell us why vaccines are such a good thing to put into a neonatal immune system which …. is set by default on “anti-inflammatory” setting, in order that the baby will be able to cope with the real world properly.
The answers are all there in your own medical literature. Never in my wildest imaginations would I have ever thought that the medical profession could have ignored such basic fundamentals as the how’s and why’s of the neonatal immune system.
December 18, 2011 at 3:37 am
Hi Paul, Pd and Hilary
hmmm … I keep going back to the Aaby work on non specific effects of vaccines.
The epidemiology (bad as it is ie a + b = c ) does suggest that there may not be a link specifically between MMR and Autism , but Hornig did find an 88% regression and a clear association with GI symptoms. Thus suggesting MMR was having some sort of effect on the autism developmental continuum.
So one open ended question might be – Do ASD children have a ‘risk’ in receiving vaccines ?
There’s a couple of interesting studies (One possible pathway which might explain some of the findings)
1. Mast cell activation and autism.
Theoharides
Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine
“Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients.
2. Neuro-Inflammation, Blood-Brain Barrier, Seizures and Autism
Theoharis C Theoharides and Bodi Zhang
Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine Boston
Many children with Autism Spectrum Diseases (ASD) present with seizure activity, but the pathogenesis is not understood.
Recent evidence indicates that neuro-inflammation could contribute to seizures.
We hypothesize that and mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures.
Treating neuro-inflammation may be useful when anti-seizure medications are ineffective.
Surely there are no medical professionals that would argue against the treatment and care of severely disabled children ?
Perhaps its only 10% of ASD infants that are implicated through phenotype physiology and allergy.(perhaps it’s more). But that would still represent in the UK 700 children per annum in each birth cohort.
3. Back to Aaby and this very interesting non specific effects which is extraordinarily complex to decipher … (but which might be another hypothetical pathway) this time MMR might be ‘less protective ” than previous measles vaccine ? Which might fall in line with Paul’s research on maternal antibodies / infections (perhaps)
“A number of case-control studies from high-income countriessuggest that smallpox vaccination protect againstdiverse chronic conditions and cancers.
In a European study of people with malignant melanoma,
smallpox vaccination reduced the risk of developing malignant melanoma and smallpox vaccination improved survival among malignant melanoma patients who had been smallpox-vaccinated several years prior to diagnosis.
Considering these observations and our findings
from Guinea-Bissau, we wanted to study whether smallpox vaccine and BCG also had non-specific effects in a European setting.
Atopy, allergic rhinitis and asthma From an ecological perspective, the termination of smallpox vaccination in high-income countries coincided with an increased incidence of asthma.
We examined the occurrence of atopy, allergic rhinitis, and asthma among Danish women within a national birth cohort study.
Among the 1960 women for whom sera were available, 552 (28%) were classified as atopic; among the 1927 women with information on allergic rhinitis and asthma, 263 (14%) had allergic rhinitis, and 165 (9%) were cases of asthma.
Overall, smallpox vaccination was not associated with risk of atopy or allergic rhinitis compared to unvaccinated women.
However, smallpox vaccination was associated with an OR of asthma of 0.55 (0.30 to 1.00) adjusting for birth cohort, sibship size, age of the women’s mother at birth, and social class.
Hence, women who had received smallpox vaccination
were less likely to have asthma, an association previously not described (9).”
Now that was interesting.
Infectious disease hospitalisations
Through linking of the CSHRR to the Danish registry of hospitalisations we were able to determine infectious disease hospitalisation (N=765) for the 2039 individuals for whom we had determined vaccination status.
Preliminary analysis shows that BCG is associated with a lower risk of all-cause infectious disease hospitalization among women and a tendency towards smallpox-vaccinated subjects having a lower risk of all-cause infectious disease hospitalisation than subjects not vaccinated with these vaccines.
Smallpox-vaccinated subjects were less likely to have skin infections and BCG vaccinated subjects less likely to be hospitalised for sexually transmitted infections (STI) than unvaccinated individuals.
These observations are being pursued with studies of specific STIs including HIV-1.
The preliminary indications are that BCG protects women against HIV-1 infection (hazard ratio (HR) 0.30 (0.12-0.77)) whereas the effect for smallpox vaccine was smaller (HR=0.81 (0.24-2.73)).
…and so was that. Vaccines so many enigmatic results who’d have thought.
So another thought is – How do you design suffciently robust epidemiology to cover all the latest research found on vaccine non specific effects / gender differences / schedules and ASD phenotypes ?
December 18, 2011 at 6:23 pm
Hi Blackheart –
So one open ended question might be – Do ASD children have a ‘risk’ in receiving vaccines ?
Indeed. A lot of the time this message gets framed as ‘vaccine damage’ or ‘injury’, which I don’t think is appropriate, and in fact, can give a lot of ammunition to people who would paint the discussion as one being held by people who understand the scientific method, and those that do not.
That being said, the repeated observations of children with autism responding more vigorously in terms of the innate immune response is what makes this question so troublesome to me. One study in particular really drives this possibility home to me is Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats, which is available in full online and pretty cool. Essentially the authors report that an immune response, and an immune response alone, was capable of persistently modifying seizure susceptibility into adulthood, if the insult occurred during specific developmental timeframes. Of particular salience is that the authors found that a particular cytokine involved with the innate immune response, TNF-alpha, was sufficient to cause the effect; the researchers reported that ablating the effect of tnf-alpha with anitbodies was sufficient to remove the effect, and that increases of straight tnf-alpha (i.e., without even using LPS), was capable of causing the effect.
The most exciting finding of the present study is that a mild inflammatory response evoked by LPS during a critical period of development causes a long-lasting increase in hippocampal excitability in vitro, and enhanced seizure susceptibility to the convulsants LI-PILO, KA, and PTZ in vivo. The latter effect was observed over a range of mildly inflammatory doses of LPS and was only evident if administered during the second postnatal week (P7 and P14), and not before (P1) or after (P20) this time. Importantly, inactivation of the proinflammatory cytokine TNFα with an intracerebroventricular TNFα antibody blocked the long-term changes to seizure susceptibility induced by LPS, whereas intracerebroventricular administration of rrTNFα alone mimicked the effect of LPS on seizure susceptibility. These novel results indicate that a single transient inflammatory episode during development can modify the brain through a TNFα-dependant mechanism, making it more susceptible to generate seizures in adulthood.
That’s bang up stuff. Note that the timeframe, postnatal days 7 – 14 are generally considered to be in the postnatal day for humans as well, certainly PD14.
It just so happens, we have several studies that tell us that blood taken from children with autism and challenged, create exaggerated tnf-alpha compared with blood taken from children without this diagnosis. For example, Differential monocyte responses to TLR ligands in children with autism spectrum disorders
After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1β, IL-6 and TNFα responses following TLR2, and IL-1β response following TLR4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR9 stimulation there was a decrease in IL-1β, IL-6, GM-CSF and TNFα responses in monocyte cell cultures from children with ASD compared with controls (p<0.05).
Other studies, like Macrophage migration inhibitory factor and autism spectrum disorders. MIF is a known promoter of toll like receptors, and increased levels are associated with autoimmune conditions, and the authors found that genetic alleles and circulating levels of MIF were associated with ASD, and as MIF levels increased, so too, did autism severity.
Overall, the polymorphisms and plasma results provide suggestive evidence for neuroglial and innate immune activation in brain tissue and cerebrospinal fluid17 and increased expression of proinflammatory cytokines in the CNS or blood of patients with ASD. Persistent elevation of cytokines in the CNS may reflect an ongoing inflammatory process, microglial activation, or developmental arrest, because some cytokine levels increase during phases of neurodevelopment. Because MIF regulates the expression of innate cytokines,we hypothesize that a genetic predisposition at the MIF locus may lead to an inappropriate level of MIF production during a neurodevelopmentally sensitive period, contributing to the pathogenesis of ASD.
There are several more studies with similar findings (i.e., exaggerated innate immune response in the autism group).
That’s what really makes this an angle of research that needs to be evaluated dispassionately. If our animal models of immune programming and consequent behavioral modifications have relevance towards human infants, children with autism appear to be a susceptible subgroup to such changes because, for one reason or another, they seem to be predisposed to an increased innate immune response. There are probably many ways to arrive at a place where increased immune responses occur, maybe including a ‘double hit’ involving prenatal challenges.
One thing that you’ll often see in discussions like this is the idea that there could be common pathways being affected that cause autism, and the immune irregularities observed. This is certainly a valid point, as a lot of the same immune messenger molecules appear to have multiple roles in the body. BUT. That doesn’t mean that we can necessarily tweak the system without having an effect, even if the underlying cause lies beneath the onion layers still. The animal studies tell us unambiguously that immune system disturbances in early life can percolate up into behavioral changes; the fact that maybe there are other things that can cause behavioral and immune disturbances at the same time doesn’t modify any of these findings.
Those are some of my thoughts anyway.
- pD
December 19, 2011 at 11:56 pm
pD
Thanks for the reply we seem to share common thoughts on this issue. To my mind there is a simple growing body of evidence that an environmental trigger/s which range from bacterial infection / viruses / maternal antibodies / allergens have a very real role in autism pathology that is surrounded by an ecological framework.
“The animal studies tell us unambiguously that immune system disturbances in early life can percolate up into behavioral changes”
These types of findings are being reflected in the neurosciences as well … particular times of vulnerability where ‘stress’ can change the developmental continuum of the brains developement leading to ‘permanent’ change.
http://www.fi.edu/learn/brain/stress.html
http://news.wustl.edu/news/Pages/22770.aspx
New research shows that exposure to stress in the neonatal intensive care unit (NICU) is associated with alterations in the brain structure and function of very preterm infants.
There’s lot of other research …
Question : If an infant suffers a long term environmental stress would this lead to autism ?
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Paul has this recent post …
http://infectiousbehavior.wordpress.com/2011/12/03/gi-bacteria-and-multiple-sclerosis/#comments
“An environmental stimulus to cause multiple sclerosis (MS) has been debated for years – usually viruses or bacteria. However, a new paper by Kerstin Berer and colleagues at the Max Planck Institute of Neurobiology in Martinsreid in Germany points to the commensal bacteria in the GI tract. Using the EAE mouse model of MS, they show that gut bacteria are essential for triggering the auto-immune attack on the central nervous system. ”
I added this …
https://sfari.org/news-and-opinion/news/2011/studies-implicate-gut-bacteria-in-autism
“Autism, with its constellation of behavioral and cognitive symptoms, might seem to be all in the brain. But intriguing new studies suggest that some aspects of the disorder might originate in the gut.
For decades, doctors have heard anecdotal reports that children with autism have frequent gastrointestinal problems, suffering from bloating, abdominal pain, constipation, diarrhea and more.
The latest research, conducted over the past several years, probes the controversial possibility that whatever is amiss in the gut is not just a symptom of autism, but one of the causes. The work is an offshoot of mounting scientific interest in the human microbiome, the stew of bacteria that make their homes in our gastrointestinal tracts.
A new study, published 31 January in the Proceedings of the National Academy of Sciences, suggests that these microbial residents may direct brain development, ultimately shaping behavior1.”
December 20, 2011 at 3:15 am
Hi Blackheart -
Regarding the neonatal / ICU studies, I’ve seen some of them, but my initial thought is that just landing in the ICU is likely a giant confounder.
Question : If an infant suffers a long term environmental stress would this lead to autism ?
Not to self promote, but I did a post on environmental enrichment, The Beautiful, Dispassionate, and Humbling Complexity of Environmental Enrichment, Butterfly Wings, and How the Granularity of Our Filters Control What We Think We Know that speaks towards this possibility. In particular, the case of orphans raised in some totally destitute conditions in Romanian orphanages is in there, wherein many of the children were found to be diagnosable with ASD.
Regarding GI and autism, the most exciting thing I’ve seen lately is: Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances which I’ve been meaning to write a post about, but haven’t gotten around to. The big thing is that it tells us that the microbiota in chidldren with autism AND gi complaints is qualitatively different. The narrative has always gone like this: ‘some kids with autism have GI problems, just like some kids without autism’. This is evidence of the opposite, that children with autism and GI disturbances have very different metabolic profiles and correlations to alterations of gut bugs. Of course, those of us who have lived with an autism kid with gut issues already knew this, it is nice to see the science. Due to the nature of the expression of proteins involved with carbohydrate digestion, it was speculated by the authors that genetics were unlikely to be the underyling cause of the disturbance.
A complimentary paper by the same group will be published sometime (?) that will indicate other qualitative differences in the GI mileau in the autism population; specifically a distinct profile of inflammation.
- pD
December 20, 2011 at 5:34 am
“Qualitatively” different hits the nail right on the head … it is the same with the physiology in other areas.
That’s the kind of findings that eminent paediatric gastroenterologist John Walker-Smith et al was trying to express and that has been very much maligned. I can’t but help feel that if this was taken ‘seriously’ 13 years ago we might well be on a completely different pathway in the science of autism disease pathology.
*Note many of the authors of the study listed above were also concerned with …
Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003140
One piece in the puzzle that seems to have been ignored was …
48% of Autism children received MMR before GI onset
23% of control children received MMR before GI onset
Timothy Buie, MD was lead author of
http://pediatrics.aappublications.org/content/125/Supplement_1/S1.full
Statement 2
Gastrointestinal conditions that are reported to be common in individuals without ASDs are also encountered in individuals with ASDs. (but are qualitatively different)
That’s more (quantitatively and qualitatively) … on the face of it , it seems a vaccine in this case MMR triggered an immune response in autistic children. Which may have changed the developmental path of their ‘autism’.
Which may lead to ‘regression’ in autism … once again Hornig et al finds …
“Cases had a high rate of CPEA-defined behavioral regression (loss of language and/or other skills following acquisition), 88%, compared to published rates of 20–40% for the general ASD population”
Which is so important as indicated by the consensus statement …
“Problem behaviors are recurrent behaviors that interfere with an individual’s functioning; their occurrence often affects family and community members as well. Problem behaviors are the single most important factor in determining quality of life for individuals with ASDs and their caretakers.”
One part then is not about whether vaccines cause autism … but whether vaccines carries “risk” … in this case the risk of development of a serious GI dysfunction with serious aberrant behaviours.
That seems to have been answered….in part.
December 20, 2011 at 12:21 am
Of course this will stir up controversy because in 1998 … John Walker Smith et al…
“…we have noted important behavioural responses in several of the children when their intestinal pathology is treated. Plain radiography confirms severe constipation with acquired megarectum in almost all affected children, despite many receiving treatment for constipation. Most parents note a honeymoon period of behavioural improvement after the bowel preparation for colonoscopy and this is maintained if recurrent constipation can be prevented. Further cognitive improvement has occurred in response to aminosalicylates, provided that constipation is prevented.
Thus, we believe the report to be aimed at those involved in the care of autistic children, as a further indication that the intestine is involved; this is not apparent unless hunted for specifically by investigation, as simple as plain abdominal radiography or as invasive as colonoscopy. We re-emphasise the fact that there is a consistent pattern of gut inflammation in a high proportion of children within the broad autistic spectrum. Understanding the link between the bowel and the brain in autism may allow new insights into this devastating illness.”
December 21, 2011 at 5:11 am
Hi pD
Something you will probably be most interested in …
http://www.ncbi.nlm.nih.gov/pubmed/22175527
“The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy.
Methods. AF samples of 331 ASD cases and 698 controls were analyzed for inflammatory cytokines using Luminex xMAP technology utilizing a historic birth cohort. Clinical data were retrieved from nationwide registers, and case-control differences in AF cytokine levels were assessed using chi-square tests, logistic and tobit regression models.
Results.
1. Overall, individuals with ASD had significantly elevated AF levels of TNF-α and TNF-β compared to controls.
2. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-α and TNF-β in ASD patients.
3. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-α and TNF-β compared to controls with no psychiatric comorbidities.
4. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities.
Conclusions.
AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required.”
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I think this pretty well finishes the evidence of immune system dysfunction in ASD. What was really interesting was the elevated levels found in other childhood psychiatric disorders.
That’s got some pretty big implications to my mind.
Three plausible theories were presented in “Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates
Central Immune Signaling Pathways”
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024691
“This considerable attention to the immune response in previous ASD research has resulted in two prevailing theories:
1. one suggests exogenous factor(s) stimulate neuro-inflammation during development,
2. while the other postulates autoimmune activation causes ASD pathology.
3. However, it is equally possible—as our results support—that the mutations described in ASD result in aberrant signaling regulation of immune cells during neurodevelopment.”
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Thoughts ?
December 22, 2011 at 1:03 pm
Hi Blackheart –
I wrote a little bit about this study in my post The Fairytale of a Static Rate of Autism Part 4: Troubling Realities Acknowledged, The Incredible Shrinking Gods of the Gaps, and Otherwise Rational People Using ‘Small’ As An Empirical Measure To Answer A Critical Question, but at the time, it was only an IMFAR poster that hadn’t yet been published. I think that this finding, alongside some others implicating similar cytokine profiles has potentially very big implications for the notion of a static rate of autism.
- pD
December 21, 2011 at 5:29 am
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001190
Should the Human Microbiome Be Considered When Developing Vaccines?
Perhaps it should read – Should the human micrbiome be considered when administering vaccines ?
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http://www.epivax.com/blog/of-bugs-and-men-the-human-microbiome-immunome/
Of Bugs and Men: the Human Microbiome Immunome?
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I thought this article was quite good …
http://www.nature.com/nature/journal/v474/n7351/full/nature10213.html
Human nutrition, the gut microbiome and the immune system
“We are learning how our gut microbial communities and immune systems co-evolve during our lifespans, and how components of the microbiota affect the immune system. We are also obtaining more information about how our overall metabolic phenotypes (metabotypes) reflect myriad functions encoded in our human genomes and gut microbiomes. These observations raise the question of how the metabolism of foods we consume by the gut microbial community affects our immune systems.”
December 26, 2011 at 1:35 am
[...] The conclusion is a good layman level wrap up that speaks toward the Interconnectedness of the brain and the immune system: [...]
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- The Dangers Of Using Simplistic Rules To Understand Complicated Processes Or ‘The Poison Is In The Dose’ Versus Reality
- Extremely Long Overdue Clinical Findings “Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances”, and The Swan Song Of A Tragically Overused Autism Canard
- Adventures in Expected Findings Part II - Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism
- Developmental Programming, or If ( ( (genetics + environment) > threshold ) and timeframe == ‘critical’ ) then { infant.setPhenotype(Constants.AUTISM); }
- The Fairytale of a Static Rate of Autism Part III – Prevalence Hookups or What if They Threw An Autism Epidemic And Nobody Cared?
- passionlessdrone: Hi Blackheart - Unfortunately, I haven't had time to read this one yet (or even get a copy). But the take home message to me is largely similar; GI
- Blackheart: Paul Patterson has a commentary on a new GI paper perhaps you could give us some of your thoughts pD ... http://infectiousbehavior.wordpress.com/20
- passionlessdrone: Thanks, Blackheart! That does look pretty neat. I really hate the move by Nature to give you a teaser of an editorial though. Jerks. Here
May 12, 2011 at 5:21 pm
pD,
I just wanted to mention that I greatly enjoy your perspective on autism. If you don’t mind, I’d like to add a link to your page on my blog.
May 13, 2011 at 1:39 am
Hi Craig Willoughby –
Thanks for the kind words and stopping by my blog. I have no problems at all with you linking to my blog.
- pD