Investigation of the Role of B-Cells in Type 1 Diabetes in the NOD Mouse

Abstract

B-cells are important in the development of type 1 diabetes, but their role is not completely defined. Although B-cells produce autoantibodies, these are not thought to be pathogenic; however, their antigen-presenting function is postulated to be critical. To examine the relative importance of these functions of B-cells, we have generated nonobese diabetic (NOD) B-cell-deficient mice that express a transgene encoding a mutant heavy chain immunoglobulin transgene on the cell surface but cannot secrete immunoglobulins (mIgs). This allowed us to dissect the importance of the relative roles of antigen presentation, dissociated from antibody production. We found that the expression of the mIg transgene increased insulitis and the incidence of diabetes compared with transgene-negative NOD B-celldeficient mice, indicating that the ability to produce antibodies is not necessary for B-cells to have some effect on the development of diabetes. However, diabetes was not restored to the level seen in normal NOD mice. This may relate to reduced ability to activate an islet-specific T-cell repertoire, presumably due to the reduced islet-specific B-cell repertoire. Our results implicate a specific antigen-presenting function for Bcells. Diabetes 53

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

“…Previous studies have highlighted the importance of B cells as antigen-presenting cells in the pathology of diabetes [5,24,28,29]. Our work demonstrates that peritoneal B cells are indeed capable of triggering a T cell response.…”

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

“…B cells can bind antigen with high affinity and are more effective than dendritic cells and macrophages at capturing and presenting rare antigens (39,40). An impact of B cells via antigen presentation and T cell priming and/or expansion has been invoked to explain the B-cell dependence of autoimmune diabetes in the NOD mouse (16,41), although more recently it was suggested that B cells in this context might also play a role in controling regulatory T cells (21), which may or may not be a reflection of the same molecular process(es). Our results in the AireϪ/Ϫ setting are consistent with an effect of B cells on the priming/expansion of autoreactive T lymphocytes: T cells alone can transfer multiorgan autoimmunity in an effector phase that appears to be B-cell independent.…”

COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

“…The finding that T-cell epitopes often occur close to B-cell epitopes, for both extrinsic and autoantigens (28), directs attention to the role of B-cells in modulating T-cell responses (29 -34). In antigen-presenting cells, antigen-antibody complexes can remain intact after the internalization and fragmentation by proteases along the antigen-processing pathway (32,33), thus protecting residues from proteolysis and modulating presentation of peptides and ensuing T-cell responses. Studies on B-cell modulation of the T-cell response to GAD65 indicate that B-cell clones producing mAbs DPA and DPD (but not DPC) can present the T1 (residues 115-130), T2 (residues 270 -283), and T5 (residues 556 -575) peptide epitope sequences to DRB1*0401-restricted T-cell clones (30).…”