The way in which ingested gluten protein triggers events in the body that may ultimately bring about damage to the absorptive epithelium of the small intestine is unknown. The first important hypothesis put forward postulated that a key enzyme, a protease that could degrade proteins, was absent in celiac patients. As a consequence, certain harmful gliadin peptides that would, in the normal person, have been broken down and rendered harmless, continued to exist with a consequence of either direct toxicity on the absorptive epithelial cells or initiation of immune responses that secondarily damaged the epithelium (Cornell 1988). Although it is difficult to disprove this hypothesis beyond any reasonable doubt, no missing enzyme has ever been found despite considerable research effort to locate it. Furthermore, the likelihood that limited digestion of proteins in the stomach results in exposure of at least the proximal small intestine (duodenum) to fairly large peptides raises the question of why most people do not suffer some damage from such peptides.
The missing enzyme hypothesis was largely supplanted by the proposal that binding of gluten proteins or peptides to the enterocytes targeted them specifically for destruction and that enhanced proliferation of crypt cells, in response to destruction of the villous enterocytes, resulted in flattening of the mucosal surface, one of the major characteristics of advanced disease. Unfortunately, no evidence for the binding of gluten proteins or peptides to enterocytes in vivo has been found. The finding that enterocytes were capable of expressing MHC class II antigens that might be capable of presenting small gluten peptides of perhaps 10 to 20 amino acid residues to T cells raises the question of how effective the search for the binding of peptides to enterocytes has been, insofar as the methods used (often based on antibody probes produced in response to stimulation with intact proteins) were unlikely to recognize such small gluten peptides.
The strong correlation of celiac disease with particular class II histocompatibility antigens, which present peptides to T cells (lymphocytes), thereby activating them, has resulted in a currently favored hypothesis in which this presentation to T cells and binding of gliadin/gluten peptides to T cells is the initiating process that results in damage to the mucosal tissues, especially those underlying the epithelial cells (enterocytes). Binding of peptides by T cells may, however, activate a number of pathways, and beyond the activation step, the details of the hypothesis become rather vague.
World History
