New Players in the Field of T1D: Anti-Peripherin B Lymphocytes.

Abstract

B lymphocytes (B cells) play a key role in type 1A diabetes (T1D) via antigen presentation to T cells, but our understanding of their mechanism of action is still evolving (1–6). Pathogenic B cells recognize autoantigens, indicated by T1D-predictive autoantibodies against insulin, GAD65, transmembrane tyrosine phosphatase (IA-2), and zinc transporter 8 (ZnT8) (7). These autoantibodies are not thought to cause T1D but, rather, provide evidence of autoreactive T cell–B cell interactions. Each B cell recognizes a single antigenic site, or epitope, on folded proteins via the antibody variable (V) region of its B-cell receptors (BCRs), internalizes the protein, and processes it into peptides for presentation on MHC class II (MHCII) to T cells (Fig. 1). Thus, autoreactive B cells are uniquely suited to activate autoreactive T cells. Likewise, T cells provide help to B cells, driving antigen-specific germinal center (GC) formation and differentiation into plasma cells that secrete autoantibodies identical to the BCR. Transgenic models provide evidence that B cells must be autoantigen specific to support T1D: anti-insulin B cells present antigen, activate T cells, and promote T1D in nonobese diabetic (NOD) mice (5,6,8). Conversely, NOD mice with transgenic B cells that do not recognize an autoantigen fail to develop diabetes (5,9). While there are multiple T1D-related autoantibodies in humans, to date, insulin has been the only reliable B cell–related autoantigen in NOD mice. In this issue of Diabetes , Leeth et al. (10) report on a new transgenic model in which B cells recognize peripherin, a neuronal antigen, and are able to …