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B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice¹

Pablo A. Silveira^2,*, Joseph Dombrowsky^*, Ellis Johnson^*, Harold D. Chapman^*, David Nemazee and David V. Serreze^3,*

^* The Jackson Laboratory, Bar Harbor, ME 04609; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

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 cell Ags to autoreactive CD4 T cells. This results from their ability to use cell surface Ig to specifically capture 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.

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