Friday, 25 October 2013

MAR autism and maternal autoimmune conditions: speculations

The term MAR autism - maternal autoantibody-related autism - whilst still a relatively new addition to the autism research vocabulary, has nevertheless already courted some controversy. This follows a decision to try and commercialise the growing research base in this area (see here) which raised a few eyebrows in various quarters.
Speculating on a dead cat bounce?  @ Wikipedia 

As I indicated on my previous post about said commercialisation, there are a few questions which perhaps need answering before this work starts down the path of becoming any sort of reliable 'autism test'. Some of these questions being particularly important if one is to learn the lessons from another proposed autism test which came across a few problems in replication recently (see here).

Away from such discussions, the notion that a proportion of mums of children with autism spectrum disorder (ASD) "have antibodies in their bloodstream that react with proteins in the brain of their babies" is potentially a very important finding. The evidence for such a process is actually becoming quite consistent (see here) following on from other investigations pointing at some role for the maternal immune system when it comes to at least some cases of autism (see here).

The paper by Lior Brimberg and colleagues* adds to the autism - maternal anti-brain antibodies story with their findings suggesting that "Mothers of an ASD child were four times more likely to harbor anti-brain antibodies than unselected women of child-bearing age (10.5 vs 2.6%)" based on the analysis of collected data from one or two quite large autism study initiatives (Simons Simplex Collection and Autism Genetic Exchange Resource). This in itself would be a worthy confirmatory research finding bearing in mind the number of plasma samples that were analysed as part of the study.

But of perhaps equal importance was the observation that "The analysis of ASD mothers with brain-reactive antibodies also revealed an increased prevalence of autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus". This point was covered by other commentary of this study (see here) including findings related to the detection of anti-nuclear antibodies (ANAs) (53% vs 13.4%) in autism mums with and without the anti-brain antibodies respectively.

Those who regularly visit this blog might know about my interest in all things autoimmunity with autism in mind (see here). The suggestion that the presence of brain reactive antibodies seemed to correlate with an increased frequency of maternal autoimmune conditions or their biological links represents yet another possible connection between autoimmunity and autism, at least some cases of autism.

With my speculating hat firmly in place, I wondered about a couple of things as a result of these findings. I wondered for example, whether the anti-nuclear antibodies were also present in offspring of those mums who tested positive for both brain reactive antibodies and ANAs. I note that ANAs have been previously reported in cases of autism as per the findings of Mostafa and Kitchener** who observed: "Children with autism had a significantly higher percent seropositivity of anti-nuclear antibodies (20%) than healthy children (2.5%; P < 0.01)". That and their suggestion: "Anti-nuclear antibody seropositivity was significantly higher in autistic children with a family history of autoimmunity than those without such history (36.8% and 5%, respectively; P < 0.001)" makes for some interesting connections.

Harking back to the ScienceDaily piece on the Brimberg study (see here) I was also intrigued by the suggestion that a 'leaky' blood-brain barrier may "allow the "anti-brain" antibodies to pass through to the babies' brains, possibly causing autism".

Now just before I get too carried away with this, there has been a bit of debate down the years about just when the blood-brain barrier (BBB) actually becomes effective in the foetus and infant. The more recent discussions suggest that there is a "well developed barrier mechanisms in the developing brain". This contrasts with other reports such as the study by Volodin and colleagues*** suggesting that the final establishment of the foetal BBB, under typical circumstances, is carried out in the latter stages of gestation. I'll leave readers to draw their own conclusions on which is the correct position.

This barrier however, partly physical and partly biochemical, is susceptible to 'damage' under certain circumstances as reported in an older post on this topic (see here). That alongside some of the gatekeeper molecules such as P-glycoprotein which help transport things through the BBB (see here) being potentially susceptible to 'alteration' as a function of various factors, means that BBB permeability is influenced by quite a few fluidic variables.

If one assumes that, as in the example of a potential link between maternal SSRI use during the first trimester of pregnancy and offspring autism risk (see here**** and here for my post), early stage pre-completed formation of the infant BBB is a 'risk' time for the developing foetus and its susceptibility to things like anti-brain antibodies and/or ANAs, one might get a sense of how and when such a process "possibly causing autism" may come about. I hasten to add that I'm still speculating at this point.

With leaky membranes in mind and the still-awaited peer-review publication of some conference proceedings from the lab of Paul Patterson (see here) on the suggestion of leaky gut present in their maternal immune activation offspring mouse model, I'm also wondering whether there may be another connection to be had here too. Various autoimmune conditions have been talked about with gut hyperpermeability in mind; ranging from gastrointestinal conditions such as coeliac disease (see here*****) to type 1 diabetes (see here******). It's not necessarily an all-or-nothing relationship but leaky gut and autoimmunity (with other factors such as gut bacteria also in the mix) is certainly on the scientific map.

In a similar vein to the ANA story, I'm wondering whether there may be merit in looking at whether there is any tie-up between gut permeability issues and (a) those mums where brain reactive antibodies have been reported, and (b) children of those mums with reported brain reactive antibodies and/or ANAs. Indeed, if (and it is still a very speculative 'if') there is some association to be found, whether as per the collected de Magistris work, one might envisage a role for dietary intervention to act on the permeability issue and any knock-on effects that might have with regards to autoimmune processes and presented symptoms? The other potential factor in this relationship being the link between gluten (or rather gliadin) and another barrier gatekeeper molecule called zonulin (see here******* open-access and here for a previous post) which is also deserving of some study with autism in mind.

I know that there's been speculation-a-go-go on this entry and I'm very much exceeding the remit of the paper by Brimberg and colleagues. I apologise. It's an easy thing to do when it comes to a blog, open-access, with no peer-review and full editorial control to the owner (i.e. me). I'd like to think however, that this area of immune activation and autoimmunity potentially opens up a whole range of further research questions ripe for scientific inquiry outside of just the formulation of a test for autism risk or not. In these days of autisms over autism and "autism as fractionable into different, largely independent sets of clinical features" new frontiers for autism research abound, and that's just as true for MAR autism and autoimmunity.

And for those interested in the attached picture included with this post and what a 'dead cat bounce' is, it's not as harrowing as you might think... (see here). Meow.


* Brimberg L. et al. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Molecular Psychiatry. 2013; 18: 1171-1177.

** Mostafa GA. & Kitchener N. Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr Neurol. 2009 Feb;40(2):107-12.

*** Volodin NN. et al. Status of the blood-brain barrier in newborn infants of various gestational ages in the normal state and in pathology. Pediatriia. 1989;(3):10-4.

**** Croen LA. et al. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. 2011 Nov;68(11):1104-12.

***** Drago S. et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006 Apr;41(4):408-19.

****** Bosi E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006 Dec;49(12):2824-7.

******* Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75.

---------- Brimberg L, Sadiq A, Gregersen PK, & Diamond B (2013). Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Molecular psychiatry PMID: 23958959