Is celiac disease due to molecular mimicry between gliadin peptide-HLA class II molecule-T cell interactions and those of some unidentified superantigen?

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Abstract

This paper presents a new hypothesis for the etiology and pathogenesis of celiac disease (CD). It is our contention that CD is triggered by the binding of one or more gliadin peptides to CD-associated HLA class II molecules. Furthermore, we propose that these putative CD peptides bind to oligosaccharide residues on HLA class 11 molecules distal to the peptide-binding groove invoking recognition and binding by specialized subsets of γδ T cell receptor-bearing lymphocytes. The binding of these γδ T cells serves as a signal for abrogation of oral tolerance to ingested proteins setting in motion a series of immune responses directed against the small intestinal epithelium of CD patients. CD patients are victimized by this self-destructed immune response because of inheritance of certain combinations of HLA-DQ and DR haplotypes. Dimers encoded by HLA-DR haplotypes may be the primary restriction elements for lectin-like, gliadin peptides while the degree of immune suppression (or lack thereof) to ingested gliadins is governed by inherited HLA-DQ haplotypes. Finally, we speculate that molecular mimicry between one or more gliadin peptides and some, as yet unidentified, bacterial or viral superantigen plays a role in disease pathogenesis.

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