Recent evidence suggests a role for B cells in the pathogenesis of type 1 diabetes (T1D), particularly 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. Recently 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 (unresponsive) 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. We demonstrated BND2 cells are pre-plasma cells and can likely act as antigen-presenting cells 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. Moreover, similar to previous findings by the Noel Morgan group, we have also identified an increase in number of B cells in the pancreas of young-onset T1D donors compared to older onset donors. However, it remains unknown what the phenotype and function of these B cells are within the pancreas. In this proposal, we will analyze the phenotype of total B cells, including whether BND2 cells are present in the pancreas, their activation status, location in relation to other immune cells, and islet health in the pancreas of young-onset versus older-onset T1D and non-diabetic organ donors using the high dimensional imaging platform, Multiplex Ion Beam Imaging (MIBI). The potential impact of these studies lies in identification of the pathogenic B cell(s) responsible for the rapid progression of disease, which will inform our understanding of the aggressiveness of young onset T1D and increase the precision of future age appropriate therapeutics.
