Serum IgA, humoral immunity and autism

The important contribution of the late Reed Warren to autism research has been discussed previously on this blog. The findings from Warren and his team in relation to the C4B null allele in autism (and other conditions) were interesting and quite influential in opening the door to questions about the genetics of the immune system being implicated in some cases of autism. In light of the focus on epigenetics in recent years, I perhaps do question whether genomic differences might be the only influence on such gene function, but that's beside the point.

Another of Warren's astute observations on autism featured in this paper* from 1997 discussing a subset of people with an autism spectrum condition also presenting with a deficiency in immunoglobulin A (IgA). Indeed bringing things right up to date, another research group have reported similar findings as per this paper by Jolanta Wasilewska and colleagues** (full-text) specifically in relation to a group of children defined with regressive autism. A small additional point before progressing, Dr Wasilewska and other authors are no strangers to autism research as per their involvement with another interesting area related to oxalates and autism (see blog post here).

Let's just back up slightly and define IgA deficiency. A selective deficiency of IgA  represents an immunodeficiency and implies low or absent levels of IgA specifically tied into protection being afforded to various mucus membranes such as the airways or digestive tract. Described as being relatively common, selective IgA deficiency seems to be more apparent in conditions like coeliac (celiac) disease (here) and lupus (here) stressing the connection with autoimmune disease as per this review by Wang and colleagues*** (full-text).

A summary of the findings from Wasilewska et al:

• The primary objective of their study was to ascertain whether tests of humoral immunity - immunity tied into secreted antibodies - might be able to identify children with autism, particularly those presenting with a regressive aspect to their symptom onset. A secondary objective relates to the examination of gluten-specific IgG antibodies in cases of autism which has been of some interest to this blog already (here).
• Twenty-four children diagnosed with autism (and regression defined by a loss of previously acquired skills) were compared against 24 asymptomatic controls matched on various factors including age and importantly, gender.
• Morning blood samples were drawn and collected from participants and serum IgA, IgG and IgM levels measured alongside various other measures including serum C-reactive protein (CRP) levels, lymphocytes and other measures of blood morphology.
• Results: not too much significant group difference among quite a lot of the measures being looked at including CRP and white blood cell (WBC) counts. Interestingly, IgG anti-gluten antibodies were also not significantly different between the groups. 
• Serum IgA levels were however significantly lower in autism as a group compared to controls; IgE levels just escaped being significantly elevated in the autism group compared to controls (p=0.08) with one spectacular outlier reported whose IgE levels were over double the amount of the second highest level seen across the groups. Also interestingly, eosinophilia - previously discussed in this post - seemed to be more prevalent in the autism group over controls despite no significant overall difference reported in blood eosinophils (p=0.08). Elevations in CD19 / CD23 - proteins found on the surface of B cells - were also noted in the autism group compared to controls (p=0.0134) confirming a role for humoral immunity (at least in some cases).
• Some exploratory data on the usefulness of the various immunoglobulins measured were carried out to see how predictive they may be to regressive autism but unfortunately AUC values were not as stunning as other work in other areas.

Bearing in mind the small participant group included as part of this trial and how one defines regression, this is quite a comprehensive paper with some potentially important findings. The area of immunoglobulins in relation to autism is full of contrasting findings probably reflective of the fact that any issues with the immune system are probably not uniform in cases of autism and also focused on its nature according to the environment it works in. The mucus link to IgA is particularly interesting given that both airways and gut have cropped up more than once in autism research circles (here and here). That and the associations that have been made between certain medications - certain antiepileptic pharmacotherapy - inducing IgA deficiency for example, makes for some interesting speculations.

The IgE "nearly" findings take me back to the previous work done in this area and in particular that rather interesting area of research looking at mast cell activation in relation to autism. Of course there could be lots of reasons to account for the nearly findings in this recent trial and one should not perhaps speculate too much. I do however think that the eosinophilia data in the current study is an important finding given the links in other conditions between IgE, mast cells and eosinophilia; also adding to the previous (limited) literature on this topic with autism in mind, including another paper produced by Dr Wasilewska and colleagues.

I should finally comment on the CRP results obtained by Wasilewska and colleagues in light of my recent post on the paper by Khakzad and colleagues. Wasilewska reported no significant difference in CRP levels between the groups (means: autism = 0.1 mg/L vs. controls = 0.05 mg/L). Khakzad and colleagues reported  mean group CRP levels of 540.1 ng/L (autism) vs. 1.3 ng/L (controls). Noting the differences in concentration units (milligrams vs. nanograms), a quick re-calculation (using this handy tool 'cos I was too lazy to just divide by 1000) suggests that Khakzad was reporting CRP levels as quite a lot higher in their participant group (0.5401 mg/L) than in the Wasilewska participant group. Whether this is reflective of the different participant groups, differing ethnicities or geographical locations or other factors remains to be seen.

The growing (and growing) focus on the immune system and autism continues at a pace. Accepting a degree of individuality in how the immune system, different sides of the immune system, are positioned in cases of autism, it strikes me that once again, another set of parameters potentially reveal themselves which have been shown to be ripe for further tantalising endophenotype studies that are already starting to be done with autism in mind.

To finish, 'The Boss' is in town today so get your guitar and flag ready.

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* Warren R. et al. Brief report: Immunoglobulin A deficiency in a subset of autistic subjects. JADD. 1997; 27: 187-192.

** Wasilewska J. et al. Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Archives of Medical Science. 2012; 9: 324-331.

*** Wang N. et al. Selective IgA deficiency in autoimmune diseases. Molecular Medicine. 2011; 17: 1383-1396.