Putting the pieces of the puzzle together - a series of hypotheses on the etiology and pathogenesis of type 1 diabetes.

This paper presents a series of 10 hypotheses on the etiology of type 1 diabetes. We begin with the hypothesis that wheat gluten is one of the elusive environmental triggers in type 1 diabetes. Habitual consumption of wheat gluten increases the intestinal synthesis of dipeptidyl peptidase IV. This enzyme helps to shape the repertoire of peptides released into the small intestine following the ingestion of wheat gluten by catalyzing the release of X-Pro dipeptides from the N-terminus of the proline-rich glutenins and gliadins in wheat gluten. The release of gluten-derived peptides causes the tight junctions of the small intestine to open through a zonulin-dependent mechanism, which allows these peptides to enter the lamina propria where they get presented as antigens by HLA-DQ, -DR and CD1d molecules. Binding of one or more gluten peptides by CD1d leads to abrogation of oral tolerance, and a marked increase in peripheral immune responses to wheat proteins. Furthermore, it is our contention, that in response to beta cell apoptosis during normal remodeling of the pancreas and CCL19/CCL21 expression within the pancreatic lymph nodes (PLNs), gluten-loaded dendritic cells migrate from the small intestine to the PLNs. These dendritic cells present gluten-derived antigens on the surface of the PLNs, which leads to migration of CD4(-)CD8(-) gammadelta and CD4(-)CD8(+) alphabeta T cells to the pancreas where they mediate Fas and perforin dependent cytotoxicity. We also hypothesize that at least one of the type 1 diabetes associated HLA-DR molecules that bind and present wheat-derived peptide(s) also bind and present an islet cell antigen(s), activating plasma cell synthesis of islet cell autoantibodies and irrevocable, complement-dependent destruction of islet cells. Our final two hypotheses state that type 1 diabetes morbidity is reduced in those areas of globe where genetically susceptible individuals get adequate amounts of vitamin D, in the diet and/or through exposure to sunlight, and in areas where people are exposed to bacterial, viral, or parasitic infections in early childhood.