title: Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?
abstract: In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.
authors.affiliation: Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Trudeau
authors.forename: J P
authors.initials: JP
authors.lastname: Dutz
authors.forename: E
authors.initials: E
authors.lastname: Arany
authors.forename: D J
authors.initials: DJ
authors.lastname: Hill
authors.forename: W E
authors.initials: WE
authors.lastname: Fieldus
authors.forename: D T
authors.initials: DT
authors.lastname: Finegood
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000209:etiology*; D003920:Diabetes Mellitus / Q000209:etiology*; D007515:Islets of Langerhans / Q000502:physiology*