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.