The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen-specific immunoglobulin receptors

Abstract

B lymphocytes partially contribute to autoimmune type 1 diabetes (T1D) as a subset of APC with a preferential ability to trigger pathogenic CD4 T cells. We hypothesized that this resulted fromthe unique ability of B lymphocytes to take up pancreatic β cell proteins through Ig mediated capture. T1D was significantly delayed, but not prevented, in a NOD stock in which the B lymphocyteIg repertoire was strongly restricted because of the allelic exclusion induced by transgenic Ig molecules specific for the disease irrelevant hen egg lysozyme (HEL) protein (NOD.IgHEL mice). However, introducing the Igμnull mutation to eliminate the small residual numbers of non‐transgenic B lymphocytes in the NOD.IgHEL stock strongly suppressed T1D to the same low levels that characterize B lymphocyte deficient NOD.Igμnull mice. In contrast to standard NOD mice, both the NOD.IgHEL.Igμnull and NOD.Igμnull stocks were unable to generate T cell responses against the candidate diabetes autoantigen, glutamic acid decarboxylase. These results indicate that Ig‐mediated capture of β cell autoantigens accounts for why B lymphocytes have a greater capacity than other APC subtypes to trigger diabetogenic T cells. Hence, defects in B lymphocyte, as well as T lymphocyte, tolerance induction mechanisms may contribute to T1D in NOD mice.

B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice

“…13 and 16) were kindly supplied by C. Goodnow (John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia). Derivation of a N9 NOD.IgHEL congenic stock has also been reported (10). The sHEL and mHEL transgenes were also congenically transferred to the NOD/Lt genetic background (designated NOD.sHEL and NOD.mHEL, respectively).…”

“…Third, due to their ability to use an Ig-mediated capture mechanism, B cells serve as the subset of APC that most efficiently processes and presents certain pancreatic ␤ cell Ags in a MHC class II-restricted fashion to diabetogenic CD4 T cells in NOD mice (7)(8)(9). The importance of this Ig-mediated capture mechanism was demonstrated by analyses of NOD mice in which the combined presence of a transgenic (tg) Ig construct and the Ig null mutation restricted the B cell repertoire to recognition of the pathologically irrelevant hen egg lysozyme (HEL) Ag (10). T cell responses to pancreatic ␤ cell autoantigens and T1D development were abrogated in such NOD.IgHEL.Ig null mice.…”

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

“…NOD and B6 mice carrying IgHEL or sHEL Tg, as well as B6.insHEL and NOD.H2 k .insHEL mice, have been described previously [3,8,12,13,31]. NOD.H2 k .insHEL mice were backcrossed to NOD/Lt mice to replace the H2 k congenic region with the H2 g7 haplotype.…”

“…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.…”