title: Dysregulated B7-1 and B7-2 expression on nonobese diabetic mouse B cells is associated with increased T cell costimulation and the development of insulitis.
abstract: Little is known about the pathogenic role of B cell dysfunction in T cell-mediated autoimmune disease. We previously reported that B cell hyper-responsiveness, resistance to apoptosis, and accumulation in islets occur during the onset of insulitis, but not in type 1 diabetes (T1D), in NOD mice. In this study we extended these studies to further determine how islet-infiltrated B cells contribute to this inflammatory insulitis. We demonstrate the presence of an increased percentage of B7-1(+) and a decreased percentage of B7-2(+) B cells in the spleen of autoimmune disease-prone NOD and nonobese diabetes-resistant mice compared with the spleen of nonautoimmune disease-prone C57BL/6 and BALB/c mice. An age-dependent differential expression of B7-1 and B7-2 was associated with the development of insulitis and CD4(+)CD25(+) T cell deficiency in autoimmune disease-prone mice. Whereas BCR and LPS stimulation increased B7-2 expression on B cells from autoimmune disease-prone and nonautoimmune disease-prone mice, LPS-induced B7-1 expression was higher on NOD than C57BL/6 B cells. Interestingly, increased expression of B7-1 and B7-2 was found on islet-infiltrated B cells, and this increase was associated with enhanced T cell costimulation. Islet-infiltrated B cells were shown to be a source of TNF-alpha production in islets. B7 blockade of BCR-stimulated NOD B cells by anti-B7-1 and anti-B7-2 mAbs during coadoptive transfer with diabetogenic T cells into NOD.scid mice protected these recipients from T1D. These results suggest that increased B7-1 and B7-2 expression on islet-infiltrated NOD B cells is associated with increased T cell costimulation and the development of inflammatory insulitis in NOD mice.
authors.affiliation: Autoimmunity/Diabetes Group, Robarts Research Institute, University of Western Ontario, London, Canada.
authors.forename: Shabbir
authors.initials: S
authors.lastname: Hussain
authors.forename: Terry L
authors.initials: TL
authors.lastname: Delovitch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019138:Antibodies, Blocking; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C044203:anti-IgM