Bone marrow plasma cell origins and diversity in humans 3291

Abstract Description Bone marrow plasma cells (BMPCs) produce durable, protective IgM, IgG, and IgA antibodies, and in some cases, pro-allergic IgE antibodies. While sources of allergen-specific memory B cells have been described, it is unclear whether peanut allergen-specific IgE-producing plasma cells take residence in the bone marrow to support long-term allergic sensitization. For this end, we charted single BMPC transcriptional and clonal heterogeneity in food-allergic and non-allergic individuals across CD19 protein expression, due to its inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional profiles, highlighting differences in NF-kB signaling, migration and adhesion, MHC-II expression, and metabolism. Additionally, distribution of somatic hypermutation (SHM) and intraclonal antibody sequence variance suggest that CD19low and CD19high BMPCs may receive direct input from recalled memory and germinal center B cells, respectively. IgE BMPCs showed signs of active metabolism, an immature-like phenotype, and a proclivity to express low surface CD19 and low levels of SHM. Finally, some IgE BMPC-derived sequences coded for peanut antigen-specific antibodies that had relevant in vivo effects in a mouse model. These findings shed light on BMPC origins, characterize IgE BMPCs at the transcriptomic level, and highlight the bone marrow as a likely source of long-lived pathogenic IgE in peanut allergy. Funding Sources National Institutes of Health grants R01AI158811, R01AI170715, and P01AI156072 Food Allergy Science Initiative (FASI) Sanofi Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)