passionless Droning about autism

Hello friends – The other day a pretty neat abstract hit my inbox: Increased serum levels of high mobility group box 1 protein in patients with autistic disorder  

BACKGROUND: High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics. METHODS: We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6ng/mL versus 5.6+/-2.5ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. CONCLUSIONS: These results suggest that HMGB1 levels may be affected in autistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder. 

I had not heard of “high mobility group box 1” before, but as being described as an ‘activator for inducing the immune response’, my interest was definitely piqued!  The author, Emanuele Enzo, was extremely gracious in providing me a copy of his manuscript.  Below are the juicy parts:      From the introduction:    

In recent years, many different mechanisms have been suggested to play a role in the pathophysiology of ASD, including impaired neurotransmission, genetic mutations, viral infections, gastrointestinal factors, and excitotoxicity (Levy et al., 2009; Rapin and Tuchman, 2008). Growing evidence has also suggested that inflammation (Cohly and Panja, 2005), neuroinflammation (Pardo et al., 2005), and oxidative stress (McGinnis, 2004) may be involved in the pathogenesis of ASD. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein released from inflammatory cells that functions as a signal for inducing inflammation and as an activator for inducing the immune response (Klune et al., 2008; Bianchi and Manfredi, 2007). The action of extracellular HMGB1 appears to be dependent on interaction with several cell surface receptors, including toll-like receptors 2/4 (TLRs-2/4) (Yu et al., 2006) and the receptor for advanced glycation endproducts (RAGE) (Rauvala and Rouhiainen, 2007). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that is activated by HMGB1 but also by advanced glycation end products and S100 proteins (Yan et al., 2009), all of which have been shown to be altered in autism (Boso et al., 2006; Junaid et al., 2004). In addition, HMGB1 seems to be released from neurons after glutamate excitotoxicity (Kim et al., 2006; Kim et al., 2008). [emphasis and links are mine]     

Some familiar players here , namely, neuroinflammation [Vargas, Li, Garbett], and TLR2 and TLR4 [Engstrom, Jyounouci].   I read Klune this afternoon and it is a very good review paper regarding HMGB1, which essentially illuminates on its description as ‘a signal for inducing inflammation’ involved with TLR2 and TLR4.  In it, HMGB1 is termed an ‘alarmin’, an endogenous immune adjuvant, or more plainly, a homegrown danger signal.   There is mention of synergistic effects in promoting an inflammatory response in conjunction with tnf-alpha, a presence in autoimmunity, cancer and other nasty conditions, as well as potential restorative effects.   Anyone who has been paying attention to the ‘abnormal immune response’ findings in autism is going to see a lot of crosstalk here. [Interested by the semantics, I would encourage readers to take a look at paperwork on resolvins as  potential mediators of inflammation].   The RAGE stuff is another paper when Enzo is an author that I haven’t read yet, but mean to.  From the results section:   

After allowance for age, BMI, and Raven’s Progressive Matrices scores, we found a positive independent association between HMGB1 levels and the ADI-R Social Scores (HMGB1, the worse the social interaction β=0.39, t=2.81, P < 0.01, Fig. 2); the higher the serum level of HMBG1, the worse the social interaction.   

Now, this is pretty interesting, because it is another instance where we observe a correlation between immunomodulators and autism severity; Grigorenko found that MIF, a known upregulator of the innate immune response,  was positively associated with autism severity, and Ashwood found an inverse relationship between the immune regulating cytokine, TGF-Beta1 and autism severity.  It would seem that by several measurements, a propensity towards an inflammatory state seems to be able to affect the degree of impairment.  

From the very lightweight discussion section:    

HMGB1 has been shown to function as a proinflammatory cytokine-like involved in both excitotoxicity (Kim et al., 2006) and glial activation (Pedrazzi et al., 2007) . Of note, growing evidence has suggested a pathophysiological role for excitotoxicity (Blaylock and Strunecka, 2009) and glutamatergic dysregulation (Blaylock, 09; Shinohe et al., 2006) in ASD. In addition, neuroinflammation may be an important feature in some patients with autistic disorder (Pardo et al., 2005; Vargas et al., 2005). Recently, Pedrazzi et al. (2007) have shown that HMGB1 promotes a specific proinflammatory program in primary astrocytes. Increased oxidative stress and immune dysregulation are other important feature in ASD (McGinnis, 2004; Cohly and Panja, 2005; Blaylock, 2009), and HMGB1 protein plays important roles in both processes (Bianchi and Manfredi, 2007; Klune et al., 2008). Interestingly, HMGB1 may induce a prooxidative state through interaction with its cell-surface receptor RAGE (Rauvala and Rouhiainen, 2007), a molecule previously implicated in the pathogenesis of ASD (Boso et al., 2006). An interesting observation in this study is that raised HMGB1 levels in our patient group were correlated with disturbances in social function as assessed with ADI–R, suggesting that this molecule  may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder. This finding is intriguing, but needs to be confirmed with further studies. 

You don’t see Blaylock get referenced too often, I need to read those papers, he does seem to have an online credibility problem that I can’t figure out.  Anyways, the statement that HMGB1 and astrocytes is particularly interesting, because we can see from the seminal Vargas paper, Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism that astrocytes were the primary producer of the increased cytokine IL-6 and chemokine MCP-1 in the brains of autistics.  A link to increased oxidative stress doesn’t surprise me too much, though again, I haven’t read anything about RAGE, so seeing another pathway towards increased oxidative stress is a nice touch.  There is a section on the weaknesses of the study including smaller study sizes and uncertainty towards the source of HMGB1.  As always, there is a call for additional study.  

Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1b (IL-1b), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy.