Wednesday, 10 July 2013

Maternal autoantibody-related (MAR) autism?

Yes you heard me right: maternal autoantibody-related autism or 'MAR autism' for short.

The term comes from some of the latest investigations published by researchers at the MIND Institute continuing an important strand of their various studies looking at the autism spectrum disorders (ASDs).
Rhesus, me? @ JM Garg / Wikipedia 

The papers in question are this one from Melissa Bauman and colleagues* (open-access) and this one from Dan Braunschweig and colleagues** (open-access) suggesting that maternal autoantibodies reactive to offspring foetal tissue might very well be an important part of quite a few cases of autism (see here for some background). An article in The Scientist covers the recent papers well so if you don't want my take, just click here and many thanks for dropping by.

You're still here. OK, thanks.

Those who actively follow this region of the autism research landscape will no doubt have already heard of similar results in transplanting purified IgG brain reactive antibodies (IgG-ASD) from mums of children with autism into pregnant mice and watching what happens to the mice offspring (see here) in terms of things like behaviour. In the Bauman study, mice were replaced with rhesus monkeys (cute picture alert) as per another occasion*** and again the development and behaviour of offspring and mother monkeys (n=8) were observed and recorded. This time around however analysis was following the application of a specific IgG mix (37 and 73kDa foetal brain autoantibodies) compared to control monkeys who received an IgG control mix from mums with no children diagnosed with autism.

Some very interesting things were observed in both mother and infants' behaviour over the 2 year period of investigation covering the main developmental periods (weaning, post-weaning, juveniles). Mums treated with IgG-ASD antibodies showed a heightened protectiveness towards their similarly exposed offspring potentially indicative of them picking up cues about their offsprings' unusual behaviour. Offspring were also more frequently taken to approaching other monkeys that were unfamiliar to them, which the authors again translated as being evidence for either not understanding the social etiquette of who and who not to approach or failing to recognise danger. Just before you sigh and click away, yes it was another study of inferring animal behaviour and superimposing it on a complex condition like autism (see here).

Allowing also for the small number of monkey participants, offspring were also tracked using neuroimaging to see whether there were any changes to brain structure or neuropathology. The authors reported that males in the IgG-ASD antibodies group seemed to show "a higher rate of brain growth" when compared to study controls added to an external control set (n=7). This alongside various other observations of the brain (see here). The net conclusion: "These outcomes are supportive of our hypothesis that the antibodies are pathogenic for one form of autism". But do bear in mind that again this was all about interpreting animal behaviour and the absolute number of 'animal participants' was small.

The second paper by Braunschweig and colleagues extended the interest in MAR by actually looking to identify the specific - exclusive - antigen(s) which were the target of the IgG antibodies. Based on an analysis of blood samples from some 250 mothers of children with autism and just shy of 150 control group mothers (with no offspring autism), researchers were able to isolate several combinations of antigens which were more reactive to the blood of mums of autistic children compared with controls. On a personal level it was nice to see mention of words like proteomics and MALDI-ToF mass spectrometry in amongst the methods.

The identified antigens were: "lactate dehydrogenase A and B, cypin (guanine deaminase), stress-induced phosphoprotein 1, collapsing response mediator proteins 1 and 2, and Y-box binding protein". They found that 23% of samples from mums with a child with autism presented with reactivity to certain combinations of these antigens compared with only 1% of control mothers. Ergo statements like "MAR autism cases could represent as much as 23 percent of all autism cases" and the subsequent chatter on developing a biomarker screen for MAR autism (of which this is the first step). Oh, and that certain antigens seemed also to correlate with specific core featues associated with autism such as stereotypic behaviours is also noteworthy.

I can't readily comment too much on the antigens linked to MAR autism. Lactate dehydrogenase (LDH) which it seems was one of the more important antigens, is for example involved in energy metabolism (see here). The authors seem to focus on its links to responding to viral infections (influenza?) or toxic exposures. I'd be interested to hear more about this as time goes by.

These are intriguing findings, of that there is no doubt and judging by some of the feedback I'm reading about the studies, this could be another important step forward in autism research (think folic acid, valproate and the elephant in the room that is glutathione). It's heartening to see that a certain Prof. Paul Patterson and his team who have also championed a role for the maternal immune system in relation to at least some offspring autism (see here) are also really interested in these findings and the potential implications of them. Indeed on the basis of the latest Patterson lab findings which I assume are going through peer-review as we speak(?), one might also start asking some wider questions about the hows and whys of maternal immune activation in relation to autism.

And finally, just in case you'd forgotten, autoantibodies outside of the maternal variety have previously been talked about with autism in mind as per the insightful work from Dr Frye (see here) who gave a great presentation at the US IACC very recently (see here).

2013 it seems is shaping up to be quite a year for autism research.

To close, Peter and Kate with some inspiring words.


* Bauman MD. et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Translational Psychiatry. 2013. 3: e278; doi:10.1038/tp.2013.47

** Braunschweig D. et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Translational Psychiatry. 2013 3: e277; doi:10.1038/tp.2013.50

*** Martin LA. et al. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun. 2008 Aug;22(6):806-16. doi: 10.1016/j.bbi.2007.12.007.

---------- M D Bauman (2013). Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey Translational Psychiatry DOI: 10.1038/tp.2013.47 D Braunschweig (2013). Autism-specific maternal autoantibodies recognize critical proteins in developing brain Translational Psychiatry DOI: 10.1038/tp.2013.47