Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice

Abstract

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.

B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice

“…These defects are likely to underlie the development of B cells expressing Ig molecules specific for pancreatic ␤ cell autoantigens. The ability of such B cells to take up autoantigens by an Ig-mediated capture mechanism allows them to be the APC subpopulation that most efficiently expands diabetogenic CD4 T cell responses in NOD mice (10) and that also contributes to disease through the secretion of maternally transmitted autoantibodies (6).…”

“…One mechanism whereby B cells contribute to T1D in NOD mice is through production of maternally transmitted autoantibodies (6). However, there are several reasons that autoantibody production is unlikely to be the sole pathogenic role of B cells.…”

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

“…In the NOD model of autoimmune diabetes, which is also dependent on B lymphocytes, maternally transferred antibodies promote disease (19). Thus, we asked whether maternal Igs, transmitted from an AireϪ/Ϫ mother, could influence the timing and severity of chronic inflammation in her AireϪ/Ϫ offspring.…”

Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex

“…Therefore, ZP3 immune complex can trigger activation of autoreactive T cells, probably via Fc␥R-positive APC. In parallel to the neonatal AOD study, Greeley et al (11) reported that T cell-dependent diabetes in NOD mice is significantly ameliorated by prevention of transfer of maternal autoantibodies to both female and male progeny. These findings have prompted the hypothesis that neonatal autoimmunity induced by maternal Ab, which results in progressive and destructive disease, such as diabetes in NOD mice and the congenital heart block in the setting of lupus Abs to Ro and La, may include de novo autoreactive T cell activation.…”