Type I diabetes (TID) is a T cell mediated autoimmune disease characterized by autoantibodies, insulitis leading to beta cell destruction, and hyperglycemia. Through the use of the diabetogenic BDC-2.5 T cell derived from the non-obese diabetic (NOD) mouse, it has been demonstrated that T cells are not directly activated in the pancreas, but in the pancreatic lymph nodes by dendritic cells occurring between 9-15 days of age. At this same kinetic window, there is a normal physiological turnover of beta cells termed """"""""wave of apoptosis"""""""" which has been postulated to be an important step in the release of antigen during insulitis. In addition, beta cells are subjected to endoplasmic reticulum stress (ER-Stress), leading to the unfolded protein response (UPR), which is characterized by cellular survival, recovery, and resistance from stressful insults. Over-activation of the UPR results in apoptosis induced cellular death. We hypothesize that during the physiological wave of beta cell apoptosis, the ER-Stress/UPR pathway becomes activated leading to overexpression of ER-Stress associated proteins that are processed and presented by dendritic cells. Thus neo-antigens are presented to autoreactive T cells and leading to overt TID. ? ? ?
