Identification of an anergic BND cell-derived activated B cell population (BND2) in young-onset type 1 diabetes

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 and beta cell loss. However, little is known regarding the specificity, phenotype, and function of B cells in young-onset T1D. We performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of 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 levels in T1D subjects. We demonstrate BND2 cells phenotypically and functionally 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 may play a role in the rapid progression of young-onset T1D and warrants further investigation in other autoimmune conditions. Single cell RNA and CITE seq on B cells isolated from PBMCs from a non-diabetic donor. CITE seq antibodies included IgM, IgD, CD21, CD27 and CXCR5. All scripts for analysis are available on github https://github.com/CUAnschutzBDC/Smith_210825_b_cell_analysis Filtered output files from cellranger are provided as supplementary files as well as a metadata file that contains cell statistics (nFeature, nCount, percent.mt), cell type labels, final clusters that align with the paper, and UMAP coordinates that also align with the paper. A description of how to analyze this data is on the github linked above.