MIND the maternal autoantibodies in autism

It's been a few weeks since I posted on research coming out of the MIND Institute. Regular readers will probably already know that I'm quite interesting in the various investigations on autism from UC Davis, and in particular how they are very usefully starting to think about subgroups and endophenotypes when it comes to autism as per the quite significant heterogeneity (and comorbidity) present across the spectrum.

By your command @ Wikipedia  

Today's offering is focused on the paper by Nordahl and colleagues* looking at how the presence of specific maternal IgG autoantibodies to foetal brain protein might be (a) linked to cases of autism and (b) form a specific endophenotype of autism with a focus on brain enlargement.

Before wandering through the latest offering, I should point out that both the concept of maternal autoantibodies and brain enlargement have been talked about before on this blog with the MIND link in mind(!) Indeed the last time I posted about the work of Christine Wu Nordahl was on how regression (yes it does happen) might link into brain overgrowth in cases of autism (see here) bearing in mind the complexity and heterogeneity within the field of looking at head size (see here).

As for maternal autoantibodies, well I've talked before about what happens to the offspring of pregnant mice (yes, mice) when they receive a transfusion of IgG brain reactive antibodies derived from mums with a child diagnosed with autism (see here) but I should also say that I'm very glad that I MET you... (see here). Other related findings on this topic are also worth mentioning (see here).

• The latest Nordahl paper reports that in an independent cohort of mums of 181 young children (most of whom had a child diagnosed with an autism spectrum disorder, ASD; n=131), there were some interesting findings related to the presence of specific maternal IgG autoantibodies (37 + 73-kDa) overlapping with offspring ASD. 
• A reported 7% of children (n=10) with ASD were "born to mothers with the 37/73kDa IgG autoantibodies" compared with none in the control, typically developing group. 
• More than that, when the ASD-IgG (those born to IgG positive mothers) were compared with the non ASD-IgG-ers, there were some differences between the rate of abnormal brain enlargement (12.1% vs. 4.4%) compared to controls. 
• Without professing any knowledge or wisdom on the specific structure of the pink stuff floating in our skull (yes, pink), I note the authors reported that "the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected". 

I'm interested in these findings. Interested because not only was there a subgroup of mums with children with autism who were positive for these autoantibodies but also because "all TD [typically developing] controls were negative for these paired autoantibodies".

Of course such interest needs to be balanced; and in particular the temptation to make too much out of these findings based on the numbers reported on this particular occasion. So for example, 10/131 (7%) of the ASD group were reported to be born to IgG positive mothers. Applying this rate to the control group (n=50) would, by my crude calculations, mean that 3 or 4 of those 50 typically-developing children would have been expected to show the same rate had there been no differences between the groups. You can perhaps see that the difference in the numbers of cases is not exactly overwhelming from this point of view. Indeed, similar principles go for the reported rate of brain enlargement between the IgG positive and negative ASD groups. More shades of grey over a stark black-and-white difference. Even the MRI findings on brain enlargement need to be brought into context with other reviews on structural issues being related to autism as per my post on the Vasa paper (see here).

All that being said and following the whole sub-group / endophenotypes mantra, I'm taken back to some interesting commentary by another of the study authors, David Amaral elsewhere, and his notion of "autism type A, or type B, or type C" as the endpoint of much of this autism subtype research.

I suppose the next set of questions should be something along the lines of how such antibodies come about, how exactly maternal autoantibodies to foetal brain might lead to brain enlargement, and what if anything can be done to mitigate any effect on the developing child. Without wishing to speculate too much, the family of IgG antibodies are normally part and parcel of the on-going struggle against the various bacterial and viral infections which we're all faced with day-to-day. They also have the quite exceptional ability to cross the placenta from mum to baby which the Braunschweig study** seemed to reiterate. Certainly knowing all that, there seems enough to go on with as to where research should be looking with regards to a potential source. The peer-reviewed literature also suggests a couple of other potential angles which may or may not be important (see Zhang and colleagues*** for example) but like everything linked to autism research, it's probably going to be complicated.

Again with my non-expert hat on, and armed with that pinch/dollop of salt, one has to wonder whether for example, there is a role for maternal autoimmune disease in the formation of such autoantibodies as per the research in other autoimmune conditions such as systemic lupus erythematosus (SLE). I was particularly taken by the paper from Lee and colleagues**** (open-access) who reported a really interesting connection between maternal SLE and N-methyl-D-aspartate receptor (NMDAR)-specific autoantibodies (in a mouse model). Indeed Palmeria and colleagues***** (open-access) present quite a good overview of IgG placental transfer with some discussion on maternal autoimmunity and its possible effects. Likewise whether maternal immune activation during critical periods of pregnancy might have some role in this process of IgG brain autoantibodies remains to be seen, following the recent maternal C-reactive protein findings published by Prof. Alan Brown and colleagues (see here).

Speculations aside, the Nordahl results add to the growing body of literature on immune function showing some connection to cases of autism and how the earliest days might well be important for at least some of the autisms and beyond (stress on some of the autisms) as per the news recently on folic acid. The precise mechanics of this biological relationship currently still remain, in the most part, hidden from view, and complicated by all that heterogeneity and comorbidity present in cases. The continued focus however on subgroups and endophenotypes represents the way forward in autism research, combining also with the notion that the presentation of autism may be much greater than the sum of its behavioural dyad.

Final note: the pretty picture of a cylon included in this post, which bears no relation to the content of the post, is simply there because I've recently been revisiting some of the golden days of TV Sci-Fi and wanted to share some of them with you. The original Battlestar Galactica series with Lorne Green was a favourite, but then again so was another series about a chap returning to earth some 500 years later, give or take a year or two, and making some new friends.

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* Nordahl CW. et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav Immun. February 2013.

** Braunschweig D. et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J Neuroimmunol. 2012; 252: 56-65.

*** Zhang Y. et al. Induction of autoimmunity to brain antigens by developmental mercury exposure. Toxicol Sci. 2011; 119: 270–280.

**** Lee JY. et al. Maternal lupus and congenital cortical impairment. Nat Med. 2009; 15: 91–96.

***** Palmeria P. et al. IgG Placental transfer in healthy and pathological pregnancies. Clinical and Developmental Immunology. 2012: 985646.

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Nordahl, C., Braunschweig, D., Iosif, A., Lee, A., Rogers, S., Ashwood, P., Amaral, D., & Van de Water, J. (2013). Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2013.01.084