B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice.
Nonobese diabetic (NOD) mice spontaneously develop an acute onset of hyperglycemia reminiscent of human type I diabetes. The disease is the end result of a mononuclear cell infiltration of pancreatic islets (insulitis), culminating in the selective destruction of islet beta-cells by autoreactive T-cells. NOD mice also exhibit defects in B-cell tolerance as manifested by the presence of autoantibodies against islet cell autoantigens. Based on the potential ability of B-cells to act as antigen presenting cells, we hypothesized that autoreactive B-cells of NOD mice may be necessary for the activation of islet reactive CD4+ T-cells. In the present study, we utilized an anti-mu antibody to induce in vivo depletion of B-cells and found that B-cell depletion completely abrogates the development of insulitis and sialitis in NOD mice. In contrast, control IgG-treated NOD mice developed insulitis and sialitis by 5 weeks of age. Additionally, the discontinuation of anti-mu chain antibody treatment led to the full restoration of the B-cell pool and the reappearance of insulitis and sialitis. Thus, we conclude that B-cells are a requisite cell population for the genesis of the inflammatory lesions of the islets of Langerhans. This finding suggests that autoreactive B-cells may act as the antigen presenting cells necessary for the initial activation of beta-cell-reactive CD4+ T-cells implicated in the pathogenesis of autoimmune diabetes.
Noorchashm
H
H
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Noorchashm
N
N
Kern
J
J
Rostami
S Y
SY
Barker
C F
CF
Naji
A
A
D000367:Age Factors; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology*; D007148:Immunoglobulin mu-Chains / Q000276:immunology; D007249:Inflammation; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011817:Rabbits; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure; D013154:Spleen / Q000166:cytology / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D007106:Immune Sera; D007148:Immunoglobulin mu-Chains; D008070:Lipopolysaccharides