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Review
, 361 (9365), 1290-2

Coeliac Disease--A Meeting Point for Genetics, Immunology, and Protein Chemistry

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Review

Coeliac Disease--A Meeting Point for Genetics, Immunology, and Protein Chemistry

Allan McI Mowat. Lancet.

Abstract

Context: Coeliac disease is caused by a genetically determined, specific immune response to antigens present in wheat gluten. This immune response may be focused on a limited region of the alpha gliadin component of gluten, and previous studies have suggested that the generation of epitopes for recognition by CD4+ T cells requires deamidation of the protein by tissue transglutaminase. However, it had not previously been shown that candidate epitope peptides could be generated from gluten in vivo, or that these epitopes were selective products of physiological digestion of gluten by tissue transglutaminase.

Starting point: Lu Shan and colleagues (Science 2002; 297: 2275-79) have recently shown that a 33-mer peptide containing known peptide epitopes is generated by digestion with intestinal enzymes in vivo and in vitro, producing a highly stimulatory antigen for CD4+ T cells. The resulting peptide is resistant to further digestion of a gliadin by intestinal brush border enzymes and is a highly specific substrate for deamidation by tissue transglutaminase. Because the 33-mer peptide is not present in cereal proteins that do not cause coeliac disease, Shan and colleagues suggest that generation of this peptide in vivo underlies the specific association between gluten, immune responsiveness, and tissue transglutaminase in coeliac disease. In addition, the 33-mer peptide can also be produced by digestion of gluten by bacterial prolyl endopeptidases, suggesting possible future strategies for generating non-toxic varieties of gluten. WHERE NEXT? It is now important to determine whether this 33-mer peptide and this pathway accounts for all immune recognition of wheat gluten in coeliac disease, and to explore if the tissue transglutaminase homologues found in other organisms can be used to produce non-toxic preparations of wheat.

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