B-Lymphocytes Expressing an Ig Specificity Recognizing the Pancreatic β-Cell Autoantigen Peripherin Are Potent Contributors to Type 1 Diabetes Development in NOD Mice

Abstract

Although the autoimmune destruction of pancreatic β-cells underlying type 1 diabetes (T1D) development is ultimately mediated by T cells in NOD mice and also likely in humans, B cells play an additional key pathogenic role. It appears that the expression of plasma membrane–bound Ig molecules that efficiently capture β-cell antigens allows autoreactive B cells that bypass normal tolerance induction processes to be the subset of antigen-presenting cells most efficiently activating diabetogenic T cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or are not (hen egg lysozyme [HEL]) expressed by β-cells have proven useful in dissecting the developmental basis of diabetogenic B cells. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B cells in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin-autoreactive B cells infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach.

Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy

“…Interestingly, FO, but not MZ B-lymphocytes preferentially expanded in mice that received transient combo therapy compared to controls (Figure 6B). Our past studies indicate B-lymphocytes entering the pancreatic islets of NOD mice have an FO-like phenotype (47). These rebounding, potentially diabetogenic, FO B-lymphocytes may explain the difference in T1D protection in NOD mice that underwent sustained versus transient combo treatment.…”

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

“…Of note, highly activated GC B cells do have increased ability to present antigens beyond those recognized by their BCRs, can cross present antigen to CD8 + T cells, and also produce inflammatory cytokines ( 14 , 15 ). It is also possible, as stated by Leeth et al ( 10 ), that the PerIg BCR cross-reacts with β-cell antigens or that β-cell antigens form complexes with peripherin that are internalized by the anti-peripherin BCR. These scenarios would promote epitope-spreading and widespread β-cell destruction by T cells that recognize autoantigens beyond peripherin.…”

“…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 support diabetes development.…”

“…Peripherin is expressed in peri-insular areas of islets, and in central and peripheral nervous system cells, similar to the important human autoantigen GAD65. The BCR transgene, designated PerIg, was developed from a BCR cloned from islet-invading B cells in NOD mice ( 10 – 13 ). NOD.…”

Follicular T Helper Cells: A New Marker of Type 1 Diabetes Risk?

“…Recent work has revealed that diabetes is associated with loss of anergy in insulin-binding B cells (13), and skewing B-cell specificity toward islet antigens can promote diabetes in mouse models (14,15). Although it is not believed that B cells or autoantibodies directly trigger b-cell destruction, recent evidence suggests that a high relative frequency of B cells within inflamed islets is associated with more aggressive and earlier onset T1D (16).…”