IgA cross-reactivity between a nuclear autoantigen and wheat proteins suggests molecular mimicry as a possible pathomechanism in celiac disease

Abstract

Celiac disease patients display IgA antibody reactivity to wheat as well as to human proteins. We used serum IgA from celiac patients and, for control purposes, from patients with Crohn′s disease, ulcerative colitis and from healthy individuals to identify celiac disease‐specific IgA autoantigens in nitrocellulose‐blotted extracts from various human cell types (epithelial, endothelial, intestinal cells, fibroblasts). The pattern, recognition intensity and time course of IgA autoreactivity was monitored using serial serum samples obtained from celiac children before and under gluten‐free diet. By immunoblot inhibition and subcellular (cytosolic, nuclear) cell fractionation we identified a 55 kDa nuclear autoantigen expressed in intestinal, endothelial cells and in fibroblasts which was recognized by IgA antibodies of approximately half of the celiac disease patients and cross‐reacted with wheat proteins. IgA reactivity to the 55 kDa autoantigen disappeared during gluten‐free diet and was inhibited after pre‐absorption of sera with wheat proteins but not with tissue transglutaminase, previously reported as the unique celiac disease‐specific autoantigen. In conclusion, we defined a novel 55 kDa celiac disease‐specific nuclear IgA autoantigen which shares epitopes with wheat proteins and which is different from tissue transglutaminase and calreticulin. Although the newly defined autoantigen was recognized much less frequently than tissue transglutaminase, our data suggest molecular mimicry between wheat and human proteins as a possible pathomechanism for the induction and/or maintenance of mucosal tissue damage in celiac disease.

IgA autoreactivity: a feature common to inflammatory bowel and connective tissue diseases

“…IgA‐EMA were determined by indirect immunofluorescence using fixed cryostat sections of monkey oesophagus (INOVA, San Diego, CA, USA) as a substrate. AGA levels were measured by a commercial gluten EIA (Pharmacia ‐Upjohn Diagnostics, Uppsala, Sweden) [12].…”

“…Nitrocellulose strips were incubated overnight with 100 000 cpm/ml of the 125 I‐labelled anti‐IgA antibody at room temperature. Bound 125 I‐labelled antibodies were visualized by autoradiography as previously described [12].…”

Deamidated Gliadin Peptides Form Epitopes That Transglutaminase Antibodies Recognize

“…The production of TG2-specific antibodies is gluten dependent and stops after a sufficiently long time on a gluten-free diet (3), but the exact mechanisms of the autoantibody production are not fully elucidated. The most commonly suggested model is the hapten-carrier model, where gliadin-specific T lymphocytes provide help for the antibody production of both gliadin and TG2-specific B lymphocytes (3,4), but molecular mimicry also was implicated (5)(6)(7)(8)(9)(10)(11). However, neither of these hypotheses has been proven experimentally.…”

Nuclear fluorescence serum reactivity on monkey oesophagus: a new antibody for the follow-up of coeliac disease?

“…Nine years ago the occurrence of a gluten‐dependent serum immunoglobulin (Ig)A cross‐reactivity between wheat proteins and a 55‐kDa nuclear antigen expressed in human fibroblasts, intestinal and endothelial cells has been related to CD [31]. Testing sera of CD patients recently in remission and still positive for EMA, we observed a nuclear fluorescence reactivity (NFR) pattern on monkey oesophagus sections, of as yet unknown significance, that disappears after a GFD [32].…”