Uncovering the role of BND2 cells in autoimmunity

Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disorder characterized by destruction of the pancreatic beta cells, leading to decreased production of insulin and hyperglycemia. Although T cells are the primary effectors of beta cell destruction in T1D, autoreactive B cells are also essential to the pathogenesis of T1D. Recent evidence suggests a more important role for B cells in individuals who develop T1D at a younger age and demonstrate rapid progression. However, little is known regarding the specificity, phenotype, and function of B cells in young-onset T1D. Previously we performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of newly-diagnosed T1D and controls using mass cytometry. Unsupervised clustering revealed the existence of a highly activated B cell subset, we term BND2, that falls within the previously defined anergic BND subset. We found a specific increase in the frequency of insulin-reactive BND2 cells in the blood of young-onset T1D donors, which was further enriched in the pancreatic lymph nodes of T1D donors. The frequency of insulin-binding BND2 cells correlated with anti-insulin autoantibody level and phenotypically BND2 cells appear to be capable of potent presentation of autoantigen to T cells. These findings suggest that activation of insulin-reactive anergic B cells likely plays a role in the rapid progression of young-onset T1D. In this proposal we seek to elucidate the mechanism by which these autoreactive B cells become activated and break anergy (aim 1), determine their fate and function, i.e. whether they are, indeed, capable of acting as potent antigen- presenting cells to T cells (aim 2), and determine whether they serve as a biomarker for development of T1D (aim 3). The potential impact of these studies lies in understanding the role of insulin-binding BND2 cells in the rapid progression of disease, which will inform our understanding of the aggressiveness of early-onset T1D and increase the precision of future age appropriate therapeutics.