Maternally transmitted immunoglobulins (Ig) are a major component of protective humoral immunity in neonates. The repertoire of these Ig specificities is a direct reflection of the immunologic experience of the mother. In the context of autoimmune disease, maternally derived Ig might contribute to the initiation of autoimmunity in genetically susceptible offspring. Indeed, a major hallmark of autoimmune diabetes in humans and NOD mice is the presence of a myriad of autoantibodies reactive to islet (beta) cell autoantigens. Detection of such islet-reactive antibodies has been utilized as a predictive marker for susceptibility to the development of autoimmune diabetes in genetically predisposed individuals. However, the exact contribution of such autoantibodies to the ontogeny of anti-islet autoimmunity remains to be elucidated. In this regard, maternal transmission of islet-reactive autoantibodies could serve to promote the initiation of (beta) cell inflammation in the susceptible child. The present proposal plans to determine the contribution of maternally derived diabetes associated Ig specificities in the development of diabetes in NOD offspring. The availability of genetically B cell deficient (uMT-/-) NOD mice provides a unique means of specifically eliminating maternal Ig from diabetes susceptible progeny. First, the applicant will assess whether maternal islet-reactive autoantibodies are transferred to NOD offspring. Next, the applicant will examine the impact of eliminating maternal antibodies on the evolution of islet-directed autoimmunity. Finally, the applicant will focus on determining the influence of the islet-reactive subset of maternally derived antibodies on diabetogenesis. In accomplishing these goals, it is hoped to gain insight into the contribution of diabetes associated autoantibodies to the initiation of islet inflammation. Such knowledge will permit the design of preventive measures aimed at reducing the risk of progression to diabetes in genetically susceptible children.
| Greeley, Siri Atma W; Katsumata, Makoto; Yu, Liping et al. (2002) Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 8:399-402 |
