B-Cells Are Required for the Initiation of Insulitis and Sialitis in Nonobese Diabetic Mice

Abstract

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.

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

“…The importance of B cells for the development of type 1 diabetes in NOD mice has become increasingly evident over the last 10 years [1][2][3][4][5][6]. Several reports have demonstrated that eliminating B cells protects against type 1 diabetes in mice [1,3,6].…”

“…Several reports have demonstrated that eliminating B cells protects against type 1 diabetes in mice [1,3,6]. B1 cells moreover produce natural antibodies and recognise common bacterial antigens as well as self-antigens [7].…”

Retinoic acid-producing,ex-vivo-generated human tolerogenic dendritic cells induce the proliferation of immunosuppressive B lymphocytes

“…Given their role in producing pathogenic antibodies, especially in rheumatic diseases and systemic lupus erythematosus (SLE) [3,4], B lymphocytes have been targeted for immunomodulation by therapeutic depletion and other methods [5][6][7][8]. The involvement of B lymphocytes in type 1 diabetes mellitus (T1D) aetiopathogenesis was shown initially in the non-obese diabetic (NOD) mouse strain, where B lymphocyte-deficient mice or those treated with anti-immunoglobulin (Ig)M antibodies were protected significantly from disease [9,10]. In T1D, which is a T cell-driven autoimmune disease targeting the insulin-producing beta cells of the pancreatic islets of Langerhans, the pathogenic role of B lymphocytes has rested so far largely in their ability to act as antigenpresenting cells [11][12][13][14][15][16], producers of autoreactive antibodies [17,18] and modulators of the type of T cells that enter and are active within the pancreatic and islet environment [19].…”

Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

“…B cells must be present for disease to occur in the NOD model (32)(33)(34), must have autoreactive specificities (35,36), must express appropriate MHCII alleles (37), and are essential for the processing and presentation of at least one islet Ag (38). Thus, a key role for B cells is most likely that of Ag presentation (39,40), which requires an organized lymphoid setting to promote T-B cell interactions.…”