Archive for the ‘Antigens’ Category
Considering the Scaffolds of Interconnectedness, “Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus” and How Seeing The Obvious Can Still Be A Pleasant Surprise
Posted March 9, 2012on:
I’ve been thinking a lot lately about the beauty and trials of the tightly coupled systems, the interconnected pathways that keep popping up when pubmed tells me something that might be of interest on journey autism. One theme bubbling to the top of my thoughts is that there is a large set of inputs capable of tweaking the areas we see altered in autism; broken isn’t necessarily appropriate, but the research increasingly tells us that a delicately balanced set of connected processes is readily changed, and the way that the physics work out, there is no way to change just one thing when you have a polygamous marriage of chemical systems.
Imagine a orchestra where all of the musicians were physically bound to one or more of their counterparts, a system of wires, pulleys, springs and levers such that the musicians are actually participating in the playing of each other, not soccer players doing synchronized flips so much as a set of violin-em-cello-em robots, connected to play their instruments in unison, wind them up and create a symphony. Different orchestras might have a tighter wire from one member to another, or an older spring, but when they worked together, you could tell what composition they were playing. In this analogy, you cannot have the drummers start beating harder and faster without also changing how hard the French horn players blow. The situation only gets more complicated if some of our musicians were connected to several other musicians simultaneously. There would still be music if the cellist couldn’t keep a steady rhythm, but it would be different music, not just a different cello.
The communication between a lot of our “systems”, immune, endocrine, stress response and central nervous systems are a lot like musicians in the orchestra, interdependent and intimately connected.
The funny thing is, this same message is being blared to me, and to you, all the time, damn near every time you turn on the TV, but it is hidden in plain sight by legislatively mandated doublespeak. Consider how many advertisements each of us have seen for pharmaceutical drugs where the number of complications and contra-indicated conditions far, far exceed the number of desired effects?
Here is a list of common side effects of Viagra:
Diarrhea, dizziness, flushing, headache, heartburn, stuffy nose, upset stomach
So right off the bat, besides what we are looking for, we can see it is common to expect Viagra to also affect your GI system, immune system, and/ or brain function. These are the types of things that are “common”. (One wonders how Viagra would sell if it always caused headaches and diarrhea, and sometimes transiently ameliorated erectile dysfunction? ) A list of ‘severe’ side effects includes memory loss and a sudden decrease in hearing or vision. Even after decades of work by a lot of exceptionally smart people and hundreds of billions of dollars, the interlocked complexity of our bodies are continuing to prove very difficult to adjust in only the way we’d like, and seemingly minor perturbations in one area can pop up in very unpredictable fashion in other functions.
Trying to put my mind around the implications of this in regards to autism often leaves me with a sense of being profoundly humbled and woefully underprepared, not unlike a lot of my experiences with autism in the real world. Secondarily, again with great similarity to personal experience, I (eventually) come to the (re-)realization that we should rejoice in opportunities to be challenged and learning more about something makes us richer in ways more important than dollars.
A superb example of all of this and more landed in my inbox the other day, Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus (Williamson et all). [Also on this paper, blog favorite, Staci Bilbo]
Williamson reported that animals given a so called ‘enriched environment’ exhibited significantly decreased immune responses in certain portions of the brain following immune challenge, with reduced levels of several chemokines and cytokines in the hippocampus in the treatment group. (A previous discussion about environmental enrichment on this blog can be found here) In this instance, the treatment group got to spend twelve hours a day in a different area, a housing unit with “a running wheel, a PVC tube and various small objects and toys”, while the control group of animals stayed in their drab, Soviet era proletariat cages all day and all night long. Here is the abstract:
Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Environmental enrichment (EE) in rodents increases neurogenesis, enhances cognition, and promotes recovery from injury. However, little is known about the effects of EE on glia (astrocytes and microglia). Given their importance in neural repair, we predicted that EE would modulate glial phenotype and/or function within the hippocampus. Adult male rats were housed either 12h/day in an enriched environment or in a standard home cage. Rats were injected with BrdU at 1week, and after 7weeks, half of the rats from each housing group were injected with lipopolysaccharide (LPS), and cytokine and chemokine expression was assessed within the periphery, hippocampus and cortex. Enriched rats had a markedly blunted pro-inflammatory response to LPS within the hippocampus. Specifically, expression of the chemokines Ccl2, Ccl3 and Cxcl2, several members of the tumor necrosis factor (TNF) family, and the pro-inflammatory cytokine IL-1ß were all significantly decreased following LPS administration in EE rats compared to controls. EE did not impact the inflammatory response to LPS in the cortex. Moreover, EE significantly increased both astrocyte (GFAP+) and microglia (Iba1+) antigen expression within the DG, but not in the CA1, CA3, or cortex. Measures of neurogenesis were not impacted by EE (BrdU and DCX staining), although hippocampal BDNF mRNA was significantly increased by EE. This study demonstrates the importance of environmental factors on the function of the immune system specifically within the brain, which can have profound effects on neural function.
Total interconnectedness kick ass!
Considering the wide ranging and predominantly ‘rather-not-have-than-have’ properties of ‘extra’ TNF-alpha and IL-1beta in the CNS, this is a pretty interesting finding. Not only that, animals ‘protected’ through environmental enrichment also showed increased levels of growth factors known to be altered in autism, again in the hippocampus. In a very real and measurable sense, it was possible to shuffle the neuroimmune cocktail of the brain by changing things like the availability of quality leisure time. As we have seen in other areas, altering the chemical milieu of immunomodulatory factors in the brain isn’t trivial, and is increasingly associated with a variety of conditions classically diagnosed through the study of behaviors.
It should be noted that there were unexpected, and generally negative findings from this study, namely, a relative lack of biomarkers indicative of increased neurogenesis in the environmental enrichment group; something that I think took the authors by a bit of surprise.
There is a short discussion on the possibilities on why the findings of differential neuroimmune responses were found only in the hippocampus, with reference being made to previous studies indicating that this area of the brain has been found to be more susceptible to a variety of insults.
There were some other findings that struck me as particularly intriguing; something that has been hinted at previously in other studies (or transcripts), but not yet well described, likely due to the fact that the area is still largely unknown to us. Specifically, the authors reported a state of glial activation, somewhat the opposite of what they expected.
The data instead suggest that EE changes the phenotype of glia, altering their activation and attenuating their pro-inflammatory response to peripheral LPS, although this remains to be directly tested. Interestingly, the blunted neuroinflammatory response within the DG of EE rats occurring concomitant with the increase in classical glial ‘‘activation’’ markers runs counter to our initial prediction. However, we believe these data simply highlight the fact that little is known about the function of these markers. Moreover, there is a growing literature that distinguishes classical versus alternative activation states in microglia, the latter of which is associated more strongly with repair (Colton, 2009; Colton and Wilcock, 2010).
Thus, it is possible that EE shifts microglia into an alternatively activated phenotype, an intriguing possibility that we are currently exploring.
The authors discuss the fact that their findings were highly spatially specific within the brain, involved a subset of cytokines and chemokines, and environmental enrichment did not seem to affect immune response in the periphery.
The immune response within the hippocampi of EE rats was markedly attenuated for a subset of cytokines and chemokines measured in our study. Importantly, not all measured immune molecules were blunted in the hippocampi of EE rats. Furthermore, the immune response was similar for each housing group in the parietal cortex as well as in the periphery. Within the hippocampus, however, EE rats had an attenuated response of interleukin-1b (IL-1b), the TNF family of genes, and several chemokines involved in the recruitment of leukocytes and monocytes. These families of genes indicate an altered hippocampal milieu in EE rats that may be less pro-inflammatory, more neuroprotective and less permeable to peripheral infiltrating immune cells.
There is a short discussion on the existing knowledge concerning IL-B and TNF-alpha in normal and pathological conditions, and how these findings are consistent with other findings involving environmental enrichment and cognition.
Tumor necrosis factor alpha (TNFa) is well characterized for its roles in inflammation and host defense, sepsis and, most intriguing for this study, apoptosis cascades (for review, see Hehlgans and Pfeffer, 2005). The observed attenuation after an immune challenge of TNFa and several associated genes in EE rats compared to HC controls indicates a potential enduring change in the hippocampal microenvironment of enriched rats, such that one mechanism by which EE may increase neuroprotection following insults to the CNS (Briones et al., 2011; Goldberg et al., 2011; Young et al., 1999) is via altered TNF tone and function, increasing the likelihood of cell survival by reducing apoptotic signaling. In addition to attenuated IL-1b and TNF responses, EE rats showed blunted responses for several chemokines known to influence the recruitment of circulating monocytes and leukocytes to the CNS.
Finally, the authors conclude how their findings add to the literature on environmental enrichment and brain function.
In summary, environmental enrichment is a relatively simple manipulation that results in robust beneficial outcomes for the brain. While previous studies have shown a role in post-insult rehabilitation for EE, our study provides evidence that enrichment need not follow the insult in order to be beneficial. Indeed, neuroinflammatory disease states might be attenuated or delayed in their onset in the face of ongoing EE. The translational reach of this manipulation remains to be explored, but in animal models of neuroinflammation, EE may provide a simple preventative measure for negative outcomes.
The bottom line is that a fuller rat life experience resulted in different neuroimmune profiles, findings with some consistency with previous observations that an enriched rat house resulted in improved behavioral manifestations of cognitive performance. The qualities of these different neuroimmune profiles are also consistent with chemical profiles associated with positive outcomes in several conditions.
There is a deceivingly startling realization hidden in these finding, startling because it reveals the malleable nature of the seemingly different, but basic systems interacting and deceptive because it is so obvious. How many of us have known someone who deteriorated upon entering a nursing home, or even retiring from working? How many of us have kept their children inside for a week due to weather and watched their children go crazy after the already inferior indoor entertainment options are long exhausted? Those changes in emotion, in behaviors and function, just like the findings from this study, are founded by chemistry.
But seeing evidence that relatively simple environmental modifications can rejigger the molecular atmosphere of the brain is still more than a little awe inspiring. Knowing there is machinery underneath the hood is a little different than observing the cogs of cognition swell , shrink, or slow down; nothing less than a deeper understanding of the chemical basis of thought. And that is pretty cool.
Posted April 14, 2010on:
I hate to write another vaccination related post, but I keep on running into the same, tired argument, and thought it might be nice to have a single place to list and link the reasons that one of the most commonly used defenses of why we don’t need to study the vaccination schedule can be dismantled. The scary part, the really fucking scary part, is how easy it is to deconstruct the metrics being provided by experts as to why questioning the process of vaccination need not be thoroughly evaluated, and how people that ought to know better keep regurgitating the antigen gambit despite its obvious shortcomings when held to the most primitive logical tests.
For some background, lets start with basic immunology and the hows and whys of how vaccines actually work. But even before that, lets be clear: Vaccines work. I have absolutely no doubt that the purpose of vaccines, providing protection against microbial invaders is successful, and saves millions of lives every year. What I’m not so sure of, is whether or not this is the only thing our increasingly aggressive vaccination schedule has been accomplishing.
The functional success of vaccination is that we have crafted a technique that allows us to train our immune system to recognize some very nasty, dangerous, and deadly bacterial and viral pathogens. How is this done? Well, it turns out that at a very detailed molecular level, many bacteria and viruses have very specific patterns on their exterior, for our purposes, an immunological fingerprint that identifies, for example, the tetanus bacteria from the diphtheria bacteria. These fingerprints are known as antigens, and our immune systems use them to store a memory of particular pathogens we have been exposed to, so the next time such a pattern is encountered, a robust immune response can be mounted rapidly, before the pathogen gets a chance to reproduce and get us sick. The memorization of these molecular patterns, the fingerprints of specific bacteria and viruses, is the foundational premise of vaccination; by presenting these antigens to our immune system in a hopefully(?) harmless way, we train our immune system to respond to these invaders without actually having to endure the virulence of the actual bacteria or virus. Making things a bit more complicated, some pathogens have more than one molecular face to present, and as such, more than one fingerprint is necessary for our immune system to recognize. Some others, such as flu, regularly shift their molecular fingerprint; this is why there are seasonal flu shots, each year scientists must make educated guesses as to which particular influenza fingerprints will be most prevalent; when they guess correctly, the vaccine mostly works, because we have trained our immune system to see that particular antigen pattern. Other pathogens, like HIV, undergo such rapid transformation of their outward facing molecular structure that tailoring a molecular portrait of them has proven exceedingly difficult.
So, again at a very high level, vaccines work because they present antigens, immune fingerprints, from viruses or bacteria to our bodies, without the associated virulence of the organisms. The hows of creating the antigens without the problems of actual infection aren’t necessary for this discussion; lets just assume that for our purposes, you can have bacterial or viral fingerprints introduced in a vaccine without having to worry about the traditional ramifications of the actual bacteria or virus they came from. Great!
Given that, lets imagine you are a skeptic and are a bit bothered by the fact that our existing vaccine and autism research seems to be wholly comprised of studies involving either thimerosal, or the MMR. It seems a bit confusing that these two types of studies are sufficient for us to have certainty that the act of vaccination itself, or other vaccines administered at very different ages might be contributing to our apparent observations of increases in autism (or other behavioral or autoimmune disorders). If you raise a question involving this glaring blind spot in our research, a lot of the time you’ll see a response like some of these:
The only thing that makes biological sense in the discussion really is antigens and excipients and if you look at that, today’s kids get FAR fewer than say, my generation.
What is relevant is the number of antigens, and not the number of vaccines, that matters. Antigens are the active part of the vaccine which stimulates the immune response.
Another point directed to those who think that multiple vaccines overload the immune system. In actual fact, even though we are vaccinating against more diseases than in the past, we are actually using fewer antigens (the part of the vaccine which stimulates the immune response) in these vaccines than was previously the case.
You get the picture; the only measurement of interest is the number of antigens in vaccines. To be completely fair to some people that use the antigen gambit, it is in response to its equally simplistic counterpart, the ‘Vaccines Overload The Immune System’ gambit. That’s no excuse, at the end of the day, the people using crank arguments are supposed to be the cranks. What worries me is the people using the antigen gambit, are in many cases, the experts, and in the rest of the cases, folks that have listened to the experts, and parrot something that sounds sciency. It is a frightening day when you realize that if infectious disease experts had a reason, a real reason, we shouldn’t study the entire vaccination schedule, they’d provide one better than the antigen gambit.
The tour de force take down of the Vaccines Overload the Immune System gambit is “Addressing Parents’ Concerns: Do Multiple Vaccines Overwhelm or Weaken the Infant’s Immune System?“, by Paul Offit and others. It’s my guess that this document, published in the highly read Pediatrics journal, plays a big part in people believing that the only important thing about the vaccine schedule is the number of antigens involved. Here is the abstract:
Recent surveys found that an increasing number of parents are concerned that infants receive too many vaccines. Implicit in this concern is that the infant’s immune system is inadequately developed to handle vaccines safely or that multiple vaccines may overwhelm the immune system. In this review, we will examine the following: 1) the ontogeny of the active immune response and the ability of neonates and young infants to respond to vaccines; 2) the theoretic capacity of an infant’s immune system; 3) data that demonstrate that mild or moderate illness does not interfere with an infant’s ability to generate protective immune responses to vaccines; 4) how infants respond to vaccines given in combination compared with the same vaccines given separately; 5) data showing that vaccinated children are not more likely to develop infections with other pathogens than unvaccinated children; and 6) the fact that infants actually encounter fewer antigens in vaccines today than they did 40 or 100 years ago.
The biggest problem here is that the acknowledged, ‘implicit’ concern is that multiple vaccines may overwhelm the immune system. The concern we should be more concerned with is, can vaccines modify the immune system in ways that we cannot predict? This is a question that is not addressed here, but if your premise starts with the wrong question, or in this case, a bad question your conclusions shouldn’t be worth much.
All of the bullet points provided suffer from one or more maladies, including a foundational structure of gross over simplifications, insulting the intelligence of the reader, or in one case, wildly optimistic claims of a study conclusions; the same kind of thing what would get you a special article by the Chicago Tribune if you recommended children with autism try not to eat wheat for a few weeks and see what happens.
For this post, we’ll just focus on the last bullet point, and the text that supports it:
6) the fact that infants actually encounter fewer antigens in vaccines today than they did 40 or 100 years ago
This is the lead in for this question:
Parents who are worried about the increasing number of recommended vaccines may take comfort in knowing that children are exposed to fewer antigens (proteins and polysaccharides) in vaccines today than in the past.
To prove this comforting point, the authors provide this fancy table:
(Bigger view on the link to full paper – they don’t have this table exploded as its own supplement link). The good news is in green here, as noted in the text, the only reduction count in the vaccine schedule after 1960 was the change from DTP to DTAP.
The bad news is that, if counting antigens were a meaningful metric, of well, anything, the chicken pox vaccine, Varicella, now contains more antigens than the rest of the shot schedule combined.
This puts us in somewhat of a conundrum. If the ‘number of antigens’ in vaccines is what is relevant, does this mean that the Varicella vaccine puts nine times more stress on the immune system than the Pneumococcus vaccine? Does the Varicella vaccine initiate an immune response sixty nine times more strenuous than the diphtheria component of the DTAP vaccine? [Good luck finding a study to measure the innate immune response to any of those vaccines in a pediatric population.]
The DTAP was licensed in the 1980s, but Varicella didn’t get licensed until 1990; so this means that children who got DTAP, but didn’t get Varicella, got far fewer antigens, half as many, than children born just a few years later. Is this meaningful?
Here is an interesting way to view the question. Imagine the CDC was addressing a set of parents whose children was born in 1985 who were concerned about those vaccinations overloading the immune system of their children, and this was the response:
Parents who are worried about the increasing number of recommended vaccines may take comfort in knowing that your children were exposed to fewer antigens (proteins and polysaccharides) than in vaccines today.
Does this sound like a good argument?
We might also take a look at how frequently children experience mild side effects from vaccination, according to the CDC web site. Fever is an indicator of innate immune activation, though you will occasionally see arguments made that it is insufficiently characterized to draw conclusions from, but if we are trying to understand if addition of antigens is a useful measurement or not, it would seem the rates of side effects are valid goalposts. Here are some quotes; there isn’t a fancy table of this information yet.
- Varicella: Fever (1 person out of 10, or less) [69 antigens]
- Pneumococcal: Up to about 1 out of 3 had a fever of over 100.4 degrees Fahrenheit, and up to about 1 in 50 had a higher fever (over 102.2 degrees Fahrenheit). [8 antigens]
- MMR Fever (up to 1 person out of 6) [24 antigens]
- DTAP: Fever (up to about 1 child in 4) [4 – 7 antigens]
Now that is curious. According to the CDC, the vaccine with the most antigens causes fever far less frequently than vaccines with many times fewer antigens in them. If we can use addition to gain comfort from the fact that the current vaccine schedule includes fewer antigens than it used to, how do we incorporate in this information?
But if we can’t use addition for our purposes? What if, in fact, the system we are interacting with is much, much too complicated to be usefully outlined with simple addition? What if antigens aren’t the only relevant measuring point in evaluating vaccine impact on the immune system? In this case, why use the reduction in antigens in vaccines as an argument to ‘address parents concerns’? Why has such a gross over simplification achieved ubiquity in the blogosphere and indeed, why was it promulgated by the most frequently interviewed physician when the subject is autism and vaccination?
Ponder the above at your own risk.