Objective: Coeliac disease (CD) is a multisystemic autoimmune inflammation of the intestinal tract induced by wheat gluten and related cereals in HLA-DQ2/8 positive individuals. The molecular mechanisms relevant to oral tolerance induction towards toxic cereals such as gliadin remain poorly understood. Enterocytes, which express predominantly HLA-DR proteins, are capable of processing, transcytosing and presenting food antigens from intestinal lumen to T lymphocytes of the lamina propria.
Design: We utilize epitope-specific monoclonal anti-gliadin antibodies to unravel the intraepithelial transport processes of gliadin peptides in human duodenal biopsy specimens from coeliac patients and reconstitute the transepithelial and endocytic pathways of gliadin in intestinal epithelial HT29 cells.
Results: The gliadin peptide AA 31-49 is segregated from the peptides AA 56-68 and AA 229-246 along the endosomal pathway. Thus, AA 31-49 bypasses HLA-DR positive late endosomes in intestinal cells and in biopsy specimens of patients with untreated CD. Further, it is localized into early endosomes and consequently escapes antigen presentation at the basolateral membrane, unlike peptides AA 56-68 and AA 229-246 that reach HLA-DR positive late endosomes. Strikingly, conjugated forms of gliadin peptide AA 31-49 with cholera toxin B are sorted into late endosomes of HT29 cells.
Conclusions: Endocytic segregation of gliadin peptide AA 31-49 seems to be a constitutive process. It explains why this peptide cannot stimulate gluten sensitive T cells. Presentation of gliadin peptides by HLA-DR proteins via late endosomes within enterocytes might induce a tolerogenic effect and constitutes a potentially promising therapeutic approach for induction of tolerance towards gliadin.
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