Cutting Edge: B Cell Specificity Contributes to the Outcome of Diabetes in Nonobese Diabetic Mice

Abstract

Type I diabetes mellitus (TIDM) is an autoimmune disorder characterized by T cell-mediated destruction of insulin-producing β cells in the pancreas. In the nonobese diabetic (NOD) model of TIDM, insulitis and diabetes are dependent on the presence of B lymphocytes; however, the requirement for specificity within the B cell repertoire is not known. To determine the role of Ag-specific B cells in TIDM, VH genes with different potential for insulin binding were introduced into NOD as H chain transgenes. VH125 H chain combines with endogenous L chains to produce a repertoire in which 1–3% of mature B cells are insulin specific, and these mice develop accelerated diabetes. In contrast, NOD mice harboring a similar transgene, VH281, with limited insulin binding develop insulitis but are protected from TIDM. The data indicate that Ag-specific components in the B cell repertoire may alter the course of TIDM.

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

“…Both pathogenic functions depend on the production of self-reactive Ig by B lymphocytes [2,3], indicating that defective B-lymphocyte self-tolerance is a mechanism that contributes to susceptibility to this disease. Several lines of evidence also point to a pathogenic role for B lymphocytes in human T1D.…”

“…Type 1 diabetes Supporting Information available online Introduction B lymphocytes make important contributions to pancreatic b-cell pathogenesis in the NOD mouse model of type 1 diabetes (T1D): first, through secretion of auto-Ab which enhance capture of auto-Ag by DC and NK cells; second, and more importantly, through their action as efficient APC capable of activating and expanding b-cell-reactive CD4 1 T cells [1]. Both pathogenic functions depend on the production of self-reactive Ig by B lymphocytes [2,3], indicating that defective B-lymphocyte self-tolerance is a mechanism that contributes to susceptibility to this disease. Several lines of evidence also point to a pathogenic role for B lymphocytes in human T1D.…”

Impaired Intracellular Calcium Mobilization and NFATc1 Availability in Tolerant Anti-Insulin B Cells

“…B cells in 125Tg mice show no signs of allelic inclusion (25) and maintain high levels of allelic exclusion for long periods of time (Ͼ30 wk); Ն 95% of B220 ϩ lymphocytes express only IgM a as revealed by staining with anti-IgM a vs anti-IgM b (27,28). Nontransgenic (non-Tg) C57BL/6 mice (Taconic Farms) were used as controls.…”

“…The 125Tg mice used in this study harbor conventional anti-insulin Ig transgenes (Ig only) derived from mAb 125 on a C57BL/6 background (backcross Ͼ27) and were generated and maintained as described previously (27,28). B cells in 125Tg mice show no signs of allelic inclusion (25) and maintain high levels of allelic exclusion for long periods of time (Ͼ30 wk); Ն 95% of B220 ϩ lymphocytes express only IgM a as revealed by staining with anti-IgM a vs anti-IgM b (27,28).…”

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…Studies in Ig transgenic (Tg) mouse models have defined anergy as a state of unresponsiveness that regulates autoreactive B cells in the periphery (15)(16)(17)(18)(19). Anergic B cells fail to secrete Ab in response to LPS or Ag immunization due to receptor unresponsiveness (17,18,20).…”