The major histocompatibility complex and autism

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"Your destiny lies with me Skywalker". So said Darth Vader as he tried his very best to work on his father-son relationship skills (shortly after chopping off his son's hand).

I don't necessarily see it as my destiny to keep talking about the immune system in connection to autism and other conditions but there was perhaps an air of inevitability that I would eventually end up talking about the major histocompatibility complex (MHC) and autism. Indeed two quite recent papers by Needleman & McAllister* and Torres and colleagues** (full-text) bring the MHC into full view with autism in mind.

What is the MHC?

It's all about identification and communication. In effect the very flexible MHC lets the immune system know what is 'self' and what is 'other' by promoting 'self' peptides on the surface of all cells. This means that when 'other', foreign peptides from an invading pathogen are presented on some cells by the MHC, the immune system knows that these are not-self and acts accordingly. So lymphocyte recognition and the presentation of antigens represent two quite big tasks of the cell-surface molecules which make up the MHC (also called the human leukocyte antigen). When things go wrong with the MHC and 'self' gets confused with 'other' you get autoimmunity; something which has been speculatively linked to some cases of autism (see here).

"Always two there are" (well two main ones).

Two classes of MHC molecules play a big role, MHC class I and MHC class II although there are others; all genetically encoded for on various regions of chromosome 6. I don't really want to get too bogged down by structure and different chains between the two classes but if you want a good review have a look at this paper by Hewitt*** (full-text) and this paper by Wang and colleagues**** (full-text). A big difference seems to be where each class of glycoprotein is found; MHC class I are present on most cells in the body, MHC class II glycoproteins are only found on antigen-presenting cells such as T cells and B cells. That and the different types of 'antigen' being presented (endogenous vs. exogenous) and to what (cytotoxic T cells vs. helper T cells) respectively.

Involvement of the MHC with regards to health and ill-health is never more prominent than in the example of coeliac (celiac) disease (CD). There, CD is strongly associated with the the presentation of specific genetic alleles of the MHC known as the (HLA) DQ2 and DQ8 haplotypes (see here for a description of haplotypes). This page is about a good an explanation that there is showing how HLA DQ2 and DQ8 fit into CD; the watchwords are: glutamine and prolamin rich gluten peptides, binding to HLA DQ2 / DQ8 haplotypes, initiation of an inflammatory response, tissue damage, flat mucosa and so forth.

Assuming that I've understood and conveyed all that information accurately, the next step is to discuss where autism may (or may not) fit into the MHC story.

And autism?

If I said that the late Reed Warren was there pretty much at the beginning when it comes to looking at the MHC in cases of autism would you be surprised? Indeed if ever there was a loss to autism research, it was the fact that Dr Warren passed away far too soon leaving us all wondering what he might have accomplished had he still be on the scene.

I've posted previously about his work on the C4B null allele (here) and more recently on his IgA deficiency findings in cases of autism (here). His paper from 1992***** suggested, quote: "a gene related to, or included in, the extended major histocompatibility complex may be associated with autism". In later work, Warren together with another big name in the immune side of autism Vijendra Singh, even talked about a possible association between issues with the MHC in autism and elevations in levels of serotonin (here******). Indeed Singh still holds some scientific interest with his notion of 'autoimmune autistic disorder'.

So what did Warren and colleagues find? Well it all boils down to quite a few cases of autism presenting with the "extended or ancestral haplotype B44-SC30-DR4". That and similar findings being reported in first-degree relatives as per this study by Lee and colleagues******* and this study by Johnson and colleagues********. I interpret this as meaning that within the class II MHC - the one involved in presenting exogenous (outside-derived) antigens from bacteria and such like - where the HLA-DR4 haplotype features, cases of autism might show a link. Bear in mind also, that HLA-DR4 is also a risk factor for conditions such as type 1 diabetes (see here) thus extending the autoimmune side of things too. 

I assume you are perhaps wondering where all this MHC talk is going when it comes to a behaviourally defined condition like autism outside of just autoimmunity. Well, this is where the tie up between the immune system and other organs like the brain come into their own and the suggestion that MHC molecules might do much more than just offer antigens to the immune system. Wekerle********* (full-text) provides an excellent overview of the MHC with neurons in mind, reviewing the suggestion that the MHC may regulate important processes like synaptic pruning.

Indeed with plasticity and pruning in mind, Belmonte and colleagues********** (full-text) talked about the possibility that a decreased expression of class 1 MHC molecules may impair pruning in cases of autism, pertinent to the early brain 'overgrowth' noted in some cases. There is also another potential side to the MHC story in autism as per the suggestion of  "an increased proportion of MHC class II-expressing microglia" at least in a mouse model of autism; indeed a mouse model already covered on this blog. I'm not however going any further with this at this time but would refer you to a recent post on microglia and autism.

Based on all this and other research, I'd like to think that there is a case for involvement of the MHC at least in some cases of autism. I can't really offer a sound explanation as to the how and why outside of speculation on things like the autoimmunity comorbidity or possibly some contribution from maternal infection during pregnancy (on the basis of the familial MHC connection) as being involved. All I can say is that there is some degree of likelihood of MHC involvement at least for some diagnosed with autism. Perhaps another potential research avenue in need of further investigation?

To end, readers in the UK whether interested or not, will have probably heard about the departure of Chris Moyles from BBC Radio 1. I'm more of a Radio 2 man myself (particularly when Ask Elvis is on) but Chris Moyles played some good tunes on Friday to bow out to, one of which I always really enjoyed in a melancholic way ... The Streets and Dry your eyes. 

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* Needleman LA. & McAllister AK. The major histocompatibility complex and autism spectrum disorder. Developmental Neurobiology. July 2012.
DOI: 10.1002/dneu.22046

** Torres AR. et al. HLA immune function genes in autism. Autism Research & Treatment. 2012; 959073.

*** Hewitt E. The MHC class I antigen presentation pathway: strategies for viral immune evasion. Immunology. 2003; 110: 163-169.

**** Wang P. et al. A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach. PLoS Computational Biology. 2008; 4: e1000048.

***** Warren R. et al. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics. 1992; 36: 203-207.

****** Warren RP. & Singh VK. Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology. 1996; 34: 72-75.

******* Lee LC. et al. HLA-DR4 in families with autism. Pediatric Neurology. 2006; 35: 303-307.

******** Johnson WG. et al. HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Archives of Pediatrics & Adolescent Medicine. 2009; 163: 542-546.

********* Wekerle H. Planting and pruning in the brain: MHC antigens involved in synaptic plasticity? PNAS. 2005; 102: 3-4.

********** Belmonte MK. et al. Autism and abnormal development of brain connectivity. The Journal of Neuroscience. 2004; 24: 9228-9231.