| The nonobese diabetic (NOD) mouse has become the most favored model for the study of type I diabetes mellitus, by virtue of the close resemblance of the disease in these mice to that seen in humans. An abundance of evidence has implicated T cells as the main effectors mediating destruction of the insulin producing beta cells in the islets of Langerhans; however, we and others have previously demonstrated a requirement of B cells for spontaneous diabetes in NOD mice. In Chapter III, we show that while B cell-deficient NOD mice are completely protected from spontaneous diabetes, they retain signs of an autoimmune process that may be disrupted by an impairment in the activation of islet-reactive T cells in the NOD lymph node microenvironment. Furthermore, in Chapter V, we find that NOD B cell-deficient mice bypass normal B cell development to produce class-switched IgG that may not have been subject to normal tolerogenic mechanisms. In Chapter IV, we consider that the influence of maternally transmitted immunoglobulins (Ig) on the development of autoimmune diabetes mellitus in genetically susceptible progeny remains unknown. Given the presence of islet beta cell antigen-reactive autoantibodies in both prediabetic humans and nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of NOD progeny to diabetes. Utilizing three complementary strategies involving B cell-deficient NOD, Ig transgenic NOD, and non-autoimmune strain mothers, we demonstrate the importance of maternal Ig in diabetes progression, as the NOD progeny in all three groups were protected from spontaneous diabetes. Our data highlight a potential pathogenic role for maternally transmitted autoantibodies in the ontogeny of T cell-mediated autoimmune diabetes in susceptible individuals. In light of the present work using the NOD paradigm, it will be important to determine whether the transmission of autoantibodies from non-diabetic mothers harboring high titers of islet-reactive antibodies impacts upon diabetes progression in susceptible human offspring. |
