Defective Regulation of Auto-Reactive Lymphocytes in Type I Diabetes
Type 1 diabetes is a prototypical example of an organ specific autoimmune disease. During the progression of disease in susceptible individuals, T and B lymphocytes become activated to destroy insulin-producing beta cells; meanwhile, these same highly aggressive effector lymphocytes leave other cells of the pancreas untouched. Recent studies have suggested that this is due to an inability to regulate auto-reactive lymphocytes through central and peripheral immunosuppressive mechanisms. We propose that this may be due in part to a defect in B-regulatory cells. We study a model of induced tolerance in which B lymphocytes are absolutely required for specific and permanent acceptance of an allograft in the C57/Bl6(B6) mouse. This tolerance induction, as well as many others, is dysfunctional in the NOD mouse, a model for autoimmune diabetes.
In my study we hypothesize that changes in signaling downstream of the BCR caused by anti-CD45RB therapy define tolerant B-cells. Using NOD mice as a model for a system in which tolerance induction is dysfunctional we will define abnormally regulated signaling pathways by RNA sequencing of purified B-cells. We will then assess the activity of these pathways and their interactors in B-cells of the B6 and NOD mice by phos-flow cytometry.