Thursday, 5 July 2012

IL-17A elevated in cases of autism

"The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia". So say Max Michel and colleagues* in their recent paper reviewing the often intricate findings in this area of investigation. Personally, I have to say that I agree with their sentiments, after having read through quite a lot of the literature on this topic over the years. I hasten to add that both the genetic and environmental effects acting on the immune system, or any other system in cases of autism, is likely to be variable and not uniform across the condition. As far as we know...

Yet more evidence for a potential role for the immune system and certain cytokines in cases of autism has emerged from two very familiar names, Laila Yousef Al-Ayadhi & Gehan Ahmed Mostafa in this paper** (full-text) looking at levels of the proinflammatory cytokine IL-17A. I say that these are familiar names because this research tag-team have been pretty prolific in recent years as per their publication entries on autism (here) and various immune-related findings. I would perhaps also plug a few previous blog posts about their work (here, here and here).

Let's start with a description. I'm sure quite a few people who follow the immune system research in relation to autism will have heard about Th1 and Th2 (type 1 and 2 helper T-cells). As per their name, helper T-cells help; more specifically they are involved in the orchestra that this is the immune response and in particular, cytokines and their expression, different types of cytokines, depending on the type of helper T-cell. Balance seems to be quite an important concept when it comes to Th1 and Th2 as per this article by Berger*** (full-text).

For quite a long time, the concepts of Th1 and Th2 predominated. That is until another kind of helper T-cell came onto the scene: Th17 - T helper 17 cells. Th17 produces the IL-17 family of cytokines which play a role in host defence and inflammation. Th17 has also been tied to quite a few 'autoimmune' conditions such as psoriasis (here) and inflammatory bowel disease (here) among others. There is of course quite a lot of biochemistry behind Th17 cells and the counterbalance, Treg(s) (including an old friend, IL-6) but I have neither the will nor expertise to go too far into all that now.

After that very brief overview, let's go through what Al-Ayadhi & Mostafa did and found:

  • A sample of 45 children diagnosed with DSM-IV autism (mean age: 8.4 years) were included for study and compared with 40 age- and sex-matched 'apparently healthy' asymptomatic children. No comorbid autoimmune conditions were recorded in participants as far as the authors could tell.
  • Participants with autism were also 'graded' on the severity of their autism presentation by way of the CARS; most fell into the severe category (n=28); the others (n=17) were described as having mild to moderate autism.
  • Blood samples were drawn from all participants and serum levels of IL-17A determined by ELISA. Importantly, from an analytical perspective, all samples were run twice in independent experiments to confirm the results and rule out cross-reactivity (see here for a description).
  • Results: as a group, the children with autism presented with significant elevations in IL-17A compared to controls. Individually, almost half of the children with autism presented with elevated IL-17A levels based on results on or above the 95th percentile of serum IL-17A noted in the control group.
  • Severity of autistic symptoms seemed also to show some relationship with serum IL-17A levels in that the more severe presentation was associated with greater serum levels than those with a more moderate presentation. Age and gender did not seem to show effects.

There are a few things that can be taken from this study. IL-17 and inflammation. IL-17 and autism. Inflammation and autism. Need I say anything else? The association between Th17 and autoimmune disorders is something to bear in mind. I've talked before about autism and both features of autoimmunity seemingly present in some cases (here) or overlap with autoimmune comorbidity (here). The current results seem to suggest that there maybe something which might, at a biochemical level, relate autism and autoimmunity in at least some cases of autism; indeed quite a few cases judging by this latest paper. The question is: are IL-17A levels a core feature of autism or merely describing some hidden autoimmune comorbidity?

This is not the first time that a relationship between Th17 and autism has been suggested. Suzuki and colleagues**** (full-text) reported elevations in IL-17 and various other cytokines in their study of young adolescent boys with autism compared with control. Indeed the current authors also cited a potential role for IL-17 in other findings, specifically related to elevations in osteopontin levels previously discussed with parallel features according to things like symptom severity affecting results.

I suppose the final question should be: what can be done about elevated levels of IL-17? Reiterating my position about not giving medical advice or anything that could be construed as medical advice, the research literature contains a few options for further investigation. The therapeutic application of monoclonal antibodies against human IL-17A has already been mentioned in other areas of investigation. Leonardi and colleagues***** reported some initial success on the use of ixekizumab for a specific type of psoriasis, plaque psoriasis and improvement in clinical symptoms. Similar preliminary findings were also reported by Hueber and colleagues****** based the use of on another IL-17A human monoclonal antibody, AIN457 (secukinumab). Other compounds also seem to have the potential to affect IL-17 levels or production too. Lanzilli and colleagues******* for example, discussed the potential of resveratrol to affect IL-17 levels (at least in vitro).  Again, I reiterate the need for a lot more efficacy and safety research before these and other potential compounds go anywhere near people with autism.

There seems to be a rising tide of research coming through suggestive of links between at least some cases of autism and issues with the immune system and more precisely autoimmunity. Bearing in mind the 'correlation does not equal causation' motif, I think back to the post on Dr Kevin Becker's paper and the other work that has been done in this area and wonder whether we really should be making moves to more generalised screening for autoimmune markers and comorbidity where an autism diagnosis is given, if only to establish how deep the rabbit hole really goes?

To finish, and to coincide with the news about "detecting a particle consistent with the Higgs boson", the Galaxy song by Monty Python. Makes me feel quite insignificant really.

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* Michel M. et al. Immune system gene dysregulation in autism & schizophrenia. Developmental Neurobiology. June 2012.

** Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation. 2012; 9: 158.
DOI: 10.1186/1742-2094-9-158

*** Berger A. Th1 and Th2 responses: what are they? BMJ. 2000; 321: 424.1.

**** Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE. 2011; 6: e20470.

***** Leonardi C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. NEJM. 2012; 366: 1190-1199.

****** Heuber W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Science Translational Medicine. 2010; 2: 52ra72.

******* Lanzilli G. et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation. 2012; 35: 240-248.