Autoimmune disease or anti-nuclear antibodies and non-coeliac wheat sensitivity

"Higher proportions of patients with NCWS [wheat sensitivity among people without celiac disease] or celiac disease develop autoimmune disorders, are ANA [anti-nuclear antibodies] positive, and showed DQ2/DQ8 haplotypes compared to patients with IBS [irritable bowel syndrome]."

Those were the conclusions reached in the paper by Antonio Carroccio and colleagues [1] who sought to evaluate: "the prevalence of autoimmune diseases among patients with NCWS, and investigated whether they carry anti-nuclear antibodies (ANA)." Continuing a theme that the classic autoimmune condition known as coeliac (celiac) disease (CD) may be only one part of a 'issues with gluten' spectrum, researchers reviewed the files of over 100 participants diagnosed with NCWS (or even NCGS) "to identify those with autoimmune diseases" and compare rates with those diagnosed with CD and/or IBS. Further, serum samples were analysed prospectively for 42 participants diagnosed with NCWS and "ANA levels were measured by immunofluorescence analysis" again, compared with CD / IBS control data. ANA by the way, are antibodies against 'self' tissue and in particular, antibodies against the contents of the cell nucleus.

Results. The rates of autoimmune disease in cases of NCWS were comparable with those reported in CD, hovering around the 20-30% frequency mark in each case. The frequency rates for autoimmune disease in the IBS group were quite a bit lower; between 2-4%.

Testing positive for ANA was however a slightly different ballgame as per the findings that those with NCWS were quite a bit more likely to show ANA than either CD or IBS participants. Depending on which arm of the study was used (retrospective vs. prospective) researchers reported that: "serum samples tested positive for ANA in 46% of subjects with NCWS..., 24% of subjects with celiac disease..., and 2% of subjects IBS... ; in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with celiac disease..., and 6% of subjects with IBS." They also noted a relationship between ANA positivity and the presence of DQ2/DQ8 haplotypes (part of the so-called genetics of CD).

These are interesting results. Not only because of the overlap between autoimmune diseases and CD and NCWS (birds of an autoimmune feather flocking together and all that) but also that a higher burden of anti-nuclear antibody positivity might accompany NCWS in even greater frequency than CD. That Hashimoto's thyroiditis was the most common autoimmune condition identified is also an interesting prospect and ripe for further study in light of some research history in this area [2].

Wearing my autism research hat, I might also forward the idea that the Carroccio data intersects with quite a few potentially important papers published with [some] autism in mind. So, NCGS as a feature of some autism... well, there have been some hints of this in the peer-reviewed research literature as per the 'not quite coeliac disease' paper (see here) and other commentaries (see here). What I will also say is that although there are some gaps in the research in this area including how one clinically defines NCGS, we can perhaps assume that autism is not protective against developing something like NCGS. ANA and autism... I can direct you to the paper by Mostafa and colleagues [3] covered in a previous post (see here) and how: "anti-ds-DNA antibodies and ANA were found in the sera of a subgroup of autistic children." It strikes me that further study of NCGS, autoimmune comorbidty and anti-nuclear antibodies in cases of autism is a way to resolve any correlation or not.

Music: Oasis - Champagne Supernova.

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[1] Carroccio A. et al. High Proportions of People with Non-Celiac Wheat Sensitivity Have Autoimmune Disease or Anti-nuclear Antibodies. Gastroenterology. 2015 May 27. pii: S0016-5085(15)00767-2.

[2] Hakanen M. et al. Clinical and subclinical autoimmune thyroid disease in adult celiac disease. Dig Dis Sci. 2001 Dec;46(12):2631-5.

[3] Mostafa GA. et al. Systemic auto-antibodies in children with autism. J Neuroimmunology. 2014; 272: 94-98.

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Carroccio A, D'Alcamo A, Cavataio F, Soresi M, Seidita A, Sciumè C, Geraci G, Iacono G, & Mansueto P (2015). High Proportions of People with Non-Celiac Wheat Sensitivity Have Autoimmune Disease or Anti-nuclear Antibodies. Gastroenterology PMID: 26026392

Autoantibodies and autism again

Autoantibodies - that is, antibodies directed at the body itself - are no stranger to autism research. I've talked about various types of autoantibody being detected in elevated levels in certain groups and cases of autism (see here for example). The paper by Gehan Mostafa and colleagues [1] adds to the roll call with their findings: "The seropositivity of anti ds-DNA and/or ANA [antinuclear antibodies] in autistic children was 42%".

Charge ! @ Wikipedia 

Before progressing to some of the details of this study I should mention that this research team have some 'form' in this particular area of autism research [2] (open-access here). In fact, I've talked about their work several times on this blog; the entry perhaps most relevant to the latest paper was on some of their data on the presence of anti-MAG (anti-myelin associated glycoprotein) and anti-MAP (anti-myelin basic protein) antibodies in cases of autism (see here).

A few points to note from the latest paper:

• Blood samples were provided by 100 children diagnosed with an autism spectrum disorder (ASD) aged between 4-11 years old. Serum levels of anti-ds-DNA and antinuclear antibodies (ANA) were measured and levels compared with a control group of 100 asymptomatic children. As the names suggest, anti-ds-DNA antibodies and ANA(s) target the cell nucleus and in particular double-stranded DNA (as per the ds in the title). 
• "The seropositivity of anti ds-DNA antibodies and ANA in autistic children was 34% and 25%, respectively. In addition, 42% of autistic children were seropositive for anti ds-DNA antibodies and/or ANA".
• The relationship (if I can call it that) between seropositivity to anti ds-DNA antibodies and a familial history of autoimmune conditions was also interesting.

The authors call for further work in this area which I would very much second "to validate whether these antibodies are a mere association or have a pathogenic role in some autistic children". As far as I can ascertain ANA and anti ds-DNA antibodies are very much tied into the condition systemic lupus erythematosus (SLE) as per studies like this one [3] (open-access). The insinuation being that where present one might consider other screening to rule out a comorbid diagnosis of SLE alongside autism; even the possibility of clusters of SLE pathology [4]. I might also at this point bring in some interesting work on anti-phospholipid antibodies (APLAs) which was talked about on this blog a few months back (see here) in light of a proposed SLE-autism connection.

The suggestion of a widened link between anti ds-DNA antibodies "pathogenic to the brain as well as to the kidney" was also something which caught my eye. The very interesting paper by Diamond and colleagues [5] for example, hinted at cross-reactivity of anti ds-DNA antibodies and "N-methyl-d-aspartate receptor (NMDAR) on neurons". On reading this, I was immediately brought back to the case report by Scott and colleagues [6] concerning anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis and autistic regression (see here). I'm not necessarily saying that the two issues are one and the same, merely that there might be a bigger picture here potentially connecting the various dots.

Finally, as per their previous paper reporting: "Serum levels of antinucleosome-specific antibodies were increased in some autistic children" [2] the family history of autoimmunity also crops up again in their current publication. There is no getting away from the fact that autoimmunity crops up time and time again when talking about autism and the extended family (see here). The fact that a family history of autoimmunity or autoimmune conditions seemed to play something of a modifying role for the presence of various autoantibodies is perhaps not surprising but could lead down some new research paths.

To close, a tribute to the lifetime of work from Lorna Wing and her invaluable contribution to autism (RIP).

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[1] Mostafa GA. et al. Systemic auto-antibodies in children with autism. J Neuroimmunology. 2014. April 26.

[2] Al-Ayadhi LY. & Mostafa GA. Serum antinucleosome-specific antibody as a marker of autoimmunity in children with autism. J Neuroinflammation. 2014 Apr 3;11(1):69.

[3] Al-Shamahy H. et al. Clinical and Laboratory Manifestations of Yemeni Patients with Systemic Lupus Erythematosus. Sultan Qaboos Univ Med J. Feb 2014; 14(1): e80–e87.

[4] Li PH. et al. Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese. Rheumatology (Oxford). 2013 Feb;52(2):337-45.

[5] Diamond B. et al. Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med. Jan 2011; 269(1): 36–44.

[6] Scott O. et al. Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler. J Child Neurol. 2014 May;29(5):691-4.

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Mostafa, G., El-Sherif, D., & Al-Ayadhi, L. (2014). Systemic auto-antibodies in children with autism Journal of Neuroimmunology DOI: 10.1016/j.jneuroim.2014.04.011