Decoding the B cell endotype in early onset type 1 diabetes

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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 thought to be essential contributors as antigen presenting cells. Moreover, recent findings indicate that B cells appear to play a more pathogenic role in individuals who develop T1D at an earlier age. Studies have shown that young onset T1D subjects have increased B cells in their blood and an increased frequency of B cells in their pancreas compared to later onset T1D subjects. Importantly, this age-specific B cell signature is also associated with rapid progression of disease. Despite the recent evidence for B cell participation in a more aggressive form of disease, little is known regarding the phenotype and function of B cells in subjects at different ages of onset. Recently we developed a robust 38+ B cell panel for high dimensional single-cell mass cytometry to simultaneously identify total and insulin-reactive B cells, the various B cell subpopulations, and their activation and functional status, allowing for a more granular characterization of B cells. Using this comprehensive B cell panel, in aim 1 we will determine whether a specific B cell subset / phenotype exists in the peripheral blood of young onset T1D subjects and a portion of at-risk autoantibody positive prediabetics, which could explain their rapid progression of disease. In aim 2 we will compare the B cell population in paired spleen and pancreatic lymph node samples from early onset, late onset, and control organ donors to determine whether a specific B cell subset has migrated from the periphery (spleen) to the site of inflammation (pancreatic lymph node). 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 early onset T1D and increase the precision of future age appropriate therapeutics.