Streptozocin-induced diabetes accelerated by B cells transgenic for immunoglobulin heavy chain recognizing N-acetyl-D-glucosamine (130.35)

Abstract

Abstract To determine mechanisms of autoreactive B cell selection and their involvement in the pathogenesis of autoimmune diseases, we generated a novel immunoglobulin (Ig) transgenic (Tg) mouse line, HGAC 39. In these mice, B cells express an Ig heavy chain with specificity for N-acetyl-D-glucosamine (GlcNAc) found on the cell wall of Group A Streptococcus (GAS). Tg B cells responded to iv immunization by migrating from the marginal zone to the TB border, and expanding and differentiating to plasmablasts at extrafollicular foci. Since GlcNAcylated proteins are abundant within eukaryotic cells, we hypothesized that B cells with anti-GlcNAc specificities contribute to autoimmune disease by presenting GlcNAc-modified proteins to diabetogenic CD4+ and CD8+ T cells. We induced autoimmune diabetes in Tg C57BL/6 male mice with multiple low doses of streptozocin (STZ), a β cell-specific toxin that increases GlcNAcylation of intracellular proteins, and demonstrated that the presence of HGAC 39 B cells accelerates the onset of hyperglycemia and pancreatic infiltration by HGAC 39 B cells, CD4+, and CD8+ T cells. These changes were not accompanied by increases in anti-GlcNAc plasma cells or serum antibodies. Taken together, our data suggest that HGAC 39 B cells that respond to GAS immunization can also contribute to STZ-induced diabetes by mechanisms other than autoantibody secretion.