Neonatal beta-cell apoptosis - A trigger for autoimmune diabetes?

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling tha t includes a wave of apoptosis. Using both mathematical modeling and histoc hemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking a t similar to 2 weeks of age. Other tissues, including the kidney and nervou s system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neo natal beta-cell apoptosis is also present in animal models of autoimmune di abetes, including both the BB rat and NOD mouse. Traditionally, apoptosis h as been considered a process that does not induce an immune response. Howev er, recent studies indicate that apoptotic cells can do the following: 1) d isplay autoreactive antigen in their surface blebs; 2) preferentially activ ate dendritic cells capable of priming tissue-specific cytotoxic T-cells; a nd 3) induce the formation of autoantibodies. These findings suggest that i n some circumstances physiological apoptosis may, in fact, initiate autoimm unity. Initiation of beta-cell-directed autoimmunity in murine models appea rs to be fixed at similar to 15 days of age, even when diabetes onset is dr amatically accelerated. Taken together, these observations have led us to h ypothesize that the neonatal wave of beta-cell apoptosis is a trigger for b eta-cell-directed autoimmunity.