I should like to better explain my question. IgA deficiency is associated to celiac disease in the 30%, common variable immunodeficiency and celiac disease have a conroversial link, IgM deficiency has been described only in 200 subjects and associated to celiac disease in the 5%. But there is a high possibility that the disorder cannot be detected for two main reasons:

a) the possibility that serologic markers of the disease are not found for an alteration in immune response

b) the possibility that CD3/CD8 mucosal amount may be not dtectable for the well known predominance of immature lymphocytes in immunoglobulin deficiency.

Despite these relevant problem there are cases where gluten free diet is of absolute benefit for the patient.

No opinion about this topic?

I like your question. I suspect that the loss of tight junctions in celiac and gluten sensitivity disrupts the mucosal layers enough that IgA production is "used up" disproportionally to the bodies requirement. I tried to look for references. this one was interesting but not a direct answer to your question.

Front Immunol. 2013; 4: 185.

Published online 2013 July 12. Prepublished online 2013 June 6. doi: 10.3389/fimmu.2013.00185

PMCID: PMC3709412

Multi-Faceted Functions of Secretory IgA at Mucosal Surfaces

Blaise Corthésy1,*

Abstract.

Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer’s patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.

Keywords: secretory IgA, mucosal homeostasis, antibody, epithelium, infectious agents, commensal bacteria

Dear Patricia, at the best of my knowledge a deficiency of IgA of immunoglobulins "in toto" (common variable immunodeficiency) may alter the conventional presentation of celiac disease. In fact, often these condition are associated to the absence of conventional serological markers (anti-transglutaminase IgA) and even the intaepitjelial CD3/CD8 count (25/100 enterocytes is the conventional cut-off for Marsh 1 celiac disease) are absent for deficient immnoglobulin production as well as for the presence of immature forms of lymphocytes in intestinal mucosa. A relevant question in this case is what to do in the presence of villous atrophy and absence of infectious of inflammatory reasons other than celiac disease. Is gluten free diet a reliable option? And when villous atrophy is absent, but there are clinical signs suitable for celiac disease and HLA compatibility with the disorder. may diet be a therapeutic attempt to try? Your opinion as well as a discussion on these interesting aspects is wellcome.

Hi Ierardi,

As a clinician, I have seen dramatic health improvements on gluten free diet, such as: resolved psoriasis, resolved rheumatoid arthritis, reversal of failure to thrive. These people were negative for anti-IgA and anti-IgG and anti-tTG.

A while back I E-mailed a professor in the UK about his research concerning these questions, and here is his response (I thought you'd like to read from him and not my paraphrasing):

Dear Patricia,

I have been given your query regarding detection of TG6 antibodies.

I will try to explain a complex problem as briefly as I can but I am happy to provide further details or provide help as needed:

Firstly Western blotting:

You will find that most antibodies to TG's are conformation-dependent antibodies. Even among classical CD patients with high titres for TG2, the signal for TG2 IgA is very low or absent by Western blotting in most cases. The same applies to autoantibodies against TG6. Hence, Western blotting is a poor choice for analysis in this context (protein is denatured).

An ELISA assay is better (not perfect as protein is immobilized on plastic surface) as at least some of the protein will be in a conformation that can bind autoantibodies. In the case of TG's this issue is particularly relevant as the protein is an enzyme that adopts vastly different conformations during the process of catalysing it's reaction (Pinkas DM, Strop P, Brunger AT, and Khosla, C. Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 2007; 5: Dec epub e327). In fact, we have shown that antibodies against a compact, so-called 'closed conformation' or intermediate structure as well as the extended 'open conformation' can be present in patients. Not all patients have both types of antibodies. Hence diagnostic sensitivity can be improved by testing for both conformations. This is true for both TG6 and TG2, e.g. Zedira is now selling an ELISA assay for detecting open conformation TG2 autoantibodies for CD diagnosis (see www.zedira.com). In the case of TG2, the latter is of lesser importance diagnostically because in most instances the antibody titres are extremely high and assay sensitivity is rarely an issue. TG6 antibody titres are often moderate (which may relate to commonly observed absence of overt gut disease in such patients) and hence sensitivity of detection is more important.

Most conventional ELISA assays compare a single absorbance value determined on antigen against either a set threshold value or a series of standards, with a cut-off value identifying positive samples. There are a number of factors contributing to false positive results in such assays (high absorbance readings in the absence of autoantibodies). One common problem is non-specfic adsorption of IgG in patients with high IgG titres. Unfortunately in patients with autoimmune disease high IgG titres are common and this is clearly the target population for screening. IgA titres are generally 10-fold lower and hence this is much less of an issue when detecting IgA-type antibodies. In all our ELISA assays we run blank wells (blocked but no antigen) to identify patients with elevated levels of non-specific binding. Minor impurities in antigen preparations can also be an issue. The latter is a more prevalent issue with TG6 (in contrast to TG2) as TG6 is very difficult to produce recombinantly in a native enzymatically active folded state and because of the specific conditions required, purity not as high as that of TG2 preparations.

Aside from the technical issues, we are confident that TG6 autoantibodies can be an important diagnostic tool and we have some data (unpublished) that suggests that TG6 autoantibodies can be predictive of forthcoming neurological disease. However, we have recently also tested a cohort of classical CD samples from Finland and found fewer samples positive for TG6 autoantibodies when compared to similar cohorts in the UK. Hence, there may be geographic variation in prevalence. The reason for this is unclear at present.

We have only recently started working on assay conditions for CSF. All our previous work was on serum samples and hence, I have less experience with CSF samples. However, it is our intention to work up conditions to enable CSF analysis.

I hope this is of help. Please let me know if you have further questions.

Best regards,

Daniel Aeschlimann

Daniel Aeschlimann

Professor of Biological Sciences

Matrix Biology &Tissue Repair Research Unit

School of Dentistry, College of Medicine

Cardiff University

Heath Park

Cardiff, CF14 4XY

Wales, UK

Phone: +44 29 2074 4240 / 2074 2442

Fax: +44 29 2074 8168

e-mail [email protected]

For Prof. Daniel Aeschlimann: Why is the detection of anti-TG6 IgG so

poor?

Patricia Hart

to:

[email protected]

27/11/2012 21:32

Dear Prof. Aeschlimann, a simple question: were your interesting basic studies directed to patients with celiac disease? And in this case, what relationship did you find with histological picture of second duodenum and expecially with intraepithelial DC3 lymphocyte count? A question to Patricia: when you have seen a dramatic improvement after gluten free diet, which were the bases of diet prescription? Only clinical symptoms or also an histological/immunohistochemical evaluation? Any way, thank you very much for your interesting partecipation to this forum.

This topic does not seem to encounter the interest of many RG members. I just attach this short finding by our group with the attempt to stimulate the follower's opition.

Ierardi,

Thanks!

I think the lack of funding on the issue of gluten sensitivityis one of the key reasons there are more researchers interested in this Area. However, the number of patients I have who are dramatically healthier by being gluten free and eating fermenting foods gives me encouragement to continue researching this topic for the rest of my life.

Dear @Patricia, I hope to have soon the possibility to show you new researches of my group about seronegative celiac disease and its relationship with immunoglobulin deficiency. I have two papers under review and my hope is that they will be finally published.

Of interst for the question.

I hope this helps---I regard celiac and CVID as 2 distinct clinical entities with some similar  features-----both cause small bowel damage--villous atrophy; CVID would be in the differential dx of non-celiac enteropathy, the distinguishing path finding in CVID would be lack of plasma cells in lamina propria,  in celiac the TTG would likely be positive, CVID is unlikely to respond to GFD, whereas CVID may respond to antibiotic tx  because of presence of gi infection especially giardia; I think you have overestimated presence of IgA deficiency in celiac at 30%---closer to 3%;not aware of any close association of IgM deficiency with celiac