Immune reactivity to gluten in autism

When I first saw the paper from Nga Lau and colleagues* (open-access) looking for markers of gluten sensitivity and/or coeliac (celiac) disease in children with autism I have to admit to raising a smile. I smiled because in a previous post on this blog I talked about a 'wish-list' for autism research specifically focused on the gluten and casein-free dietary intervention**. Part of that wish list was some further inquiry into why, biochemically, some people on the autism spectrum might benefit from dietary intervention. My prayers it seems have started to be answered.

Smiler @ Wikipedia  

When it comes to the area of dietary intervention for conditions like schizophrenia (no really), there seemed to be a lot more enthusiasm for looking at why some cases of schizophrenia might overlap with dietary issues over investigations into autism. I can't pretend to know why schizophrenia research took the lead; maybe something to do with Dohan and his original discussions on diet and schizophrenia or that schizophrenia research has some very talented people like Emily Severance and colleagues (see here and here and here) taking an interest. One might also speculate that some of the politics of autism - diet, gastrointestinal (GI) issues = (see here) - might also creep into this lack of autism research interest too? Who knows.

No mind, Lau et al did look at immune reactivity to gluten (or rather a fraction of gluten called gliadin) in a group of children with autism (n=37) compared with their asymptomatic siblings (n=27) and typically developing controls (n=76). They looked for anti-gliadin antibodies (IgA and IgG). They looked for antibodies to deamidated gliadin (that is where gliadin has already been subjected to some kind of enzymatic modification). They looked at antibodies to tissue transglutaminase (tTG). They even examined HLA genotype for the DQ2 and DQ8 haplotypes (linked to the genetics of coeliac disease). All in all, the primary bases were covered.

Results: well, the serum samples all came from AGRE - the Autism Genetic Resource Exchange - so no quibbling about the diagnosis of autism. They also subdivided the autism group up into those with GI symptoms and those without and remarked on those who were following a gluten-free diet too.

The authors report that levels of IgG anti-gliadin antibody were elevated in the autism group compared to siblings and controls. This differences lasted even when certain confounders such as age, gender and race were taken into account and the calculated odds ratio of an having an elevated IgG antibody levels to gliadin was not to be sniffed at either (OR 4.97; CI 1.39 - 17.8). That being said, there was cross-over between the relatively small participant groups and levels of IgA antibody to gliadin were not significantly different between the groups. Very interestingly, the presence of comorbid GI symptoms appearing alongside autism seemed to be linked to that elevated IgG antibody response to gliadin compared with no comorbid GI symptoms.

Just short of 50% of the children with autism were "positive for HLA-DQ2 and/or -DQ8 (6 DQ2, 12 DQ8)". I probably didn't explain this well, but a significant proportion of people with coeliac disease carry these haplotypes which all relates back to the almighty MHC and antigen presentation (see here for explanation).

Insofar as the other parameters on antibodies to deamidated gliadin and tTG, there was little difference to write home about. Although not wholly relevant, I'll refer you back to some interesting work down on tTG with autism in mind from a while back (see here).

A few choice quotes from the authors: "The findings indicate that the observed anti-gliadin immune response in patients with autism is likely to involve a mechanism that is distinct from celiac disease, without the requirement for TG2 activity or antigen presentation through DQ2/DQ8 MHC molecules". Well, we know that coeliac disease, when it is tested for in cases of autism, is probably not greatly over-represented in ASD despite some interesting evidence (see here). The Lau study kinda confirms that fact. But.... with all the talk about non-coeliac gluten sensitivity which has surfaced over the past few years (see here and here) one has to wonder whether for some on the autism spectrum, a similar mode of action might pertain outside of the more classical coeliac serology and markers?

It's interesting also that the authors talk about issues like the potential cross-reactivity of gluten as one implication of their findings. I'm taken back to the work of Ari Vojdani and colleagues*** on this matter. Oh and those Emily Severance findings about critters like T.gondii mixing it up with gluten reactivity (see here). I'm not necessarily saying that everyone with autism who presents with gluten antibodies has been in contact with the gondii but merely that the infection connection is an interesting one as per all that autoimmunity chatter with autism in mind.

It's interesting too that the authors also make mention of intestinal permeability as potentially being a factor to be looked at further. I know some people still look on things like 'leaky gut' as being the stuff of tree-huggers, but the evidence is growing for some effect in cases of autism (see here) with the promise of more investigations to come (see here for the Paul Patterson mouse work and here for a video from everyone's favourite autism - gut specialist researcher, Alessio Fasano).

Whilst I am pretty buoyed by seeing that this area is starting to get some research interest, I'm containing my excitement for now. It's still a long haul from gluten antibodies to suggesting that gluten may 'cause' or 'exacerbate' a complex set of conditions like the autisms even with all that gut-brain chatter which I'm certainly guilty of elevating. But due credit where it is deserved, at least Lau and colleagues have started asking some questions about this interesting area of autism research and the potential links with diet....

To finish, how about a song about Alejandro? (something for everyone in that video...)

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* Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS ONE 8(6): e66155. doi:10.1371/journal.pone.0066155

** Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013; 6: 344.

*** Vojdani A. et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.

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Lau, N., Green, P., Taylor, A., Hellberg, D., Ajamian, M., Tan, C., Kosofsky, B., Higgins, J., Rajadhyaksha, A., & Alaedini, A. (2013). Markers of Celiac Disease and Gluten Sensitivity in Children with Autism PLoS ONE, 8 (6) DOI: 10.1371/journal.pone.0066155