title: B cell selection defects underlie the development of diabetogenic APCs in nonobese diabetic mice.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Silveira
authors.forename: Joseph
authors.initials: J
authors.lastname: Dombrowsky
authors.forename: Ellis
authors.initials: E
authors.lastname: Johnson
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: David
authors.initials: D
authors.lastname: Nemazee
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics; D017637:Clonal Deletion / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D017393:RNA Editing / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012995:Solubility
chemical_list: D001324:Autoantigens; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell