B cell selection defects underlie the development of diabetogenic APCs in nonobese diabetic mice.

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Antigen-Presenting-Cells, Autoantigens, B-Lymphocyte-Subsets, Cell-Differentiation, Clonal-Anergy, Clonal-Deletion, Diabetes-Mellitus-Type-I, Female, Membrane-Proteins, Mice, Mice-Inbred-C57BL, Mice-Inbred-NOD, Mice-Transgenic, RNA-Editing, Receptors-Antigen-T-Cell, Solubility

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J Immunol 2004 Apr; 172(8):5086-94.


One mechanism whereby B cells contribute to type 1 diabetes in nonobese diabetic (NOD) mice is as a subset of APCs that preferentially presents MHC class II-bound pancreatic beta cell Ags to autoreactive CD4 T cells. This results from their ability to use cell surface Ig to specifically capture beta cell Ags. Hence, we postulated a diabetogenic role for defects in the tolerance mechanisms normally blocking the maturation and/or activation of B cells expressing autoreactive Ig receptors. We compared B cell tolerance mechanisms in NOD mice with nonautoimmune strains by using the IgHEL and Ig3-83 transgenic systems, in which the majority of B cells recognize one defined Ag. NOD- and nonautoimmune-prone mice did not differ in ability to delete or receptor edit B cells recognizing membrane-bound self Ags. However, in contrast to the nonautoimmune-prone background, B cells recognizing soluble self Ags in NOD mice did not undergo partial deletion and were also not efficiently anergized. The defective induction of B cell tolerance to soluble autoantigens is most likely responsible for the generation of diabetogenic APC in NOD mice.