Functional genomics deciphers pathogenic B cell dynamics in lupus bone marrow 3662

Abstract Description Systemic lupus erythematosus (SLE) is an autoimmune disease involving immune and non-immune cells, with complex pathogenesis and limited therapies. Dysregulated B cells, particularly double-negative 2 (DN2) B cells (CD19?, CD27?, IgD?, CD21?, CD11c?), are central to SLE by driving autoimmune processes. However, the origins and development of DN2 B cells remain poorly understood. B lymphopoiesis occurs in the bone marrow and is strongly regulated by mesenchymal stromal cells (MSCs). MSCs are non-hematopoietic immunosuppressive cells, which regulate immunity, including promoting regulatory B cells over plasma cells. In SLE, MSCs fail to suppress B cell activation into plasma blasts, but their immunomodulatory properties remain underexplored. We hypothesize that pathogenic DN2 B cells partly originate from a dysregulated bone marrow niche due to impaired stromal cell function. Single-cell transcriptomics and proteomics of healthy bone marrow identified resident DN B cells (∼30% of total B cells), with a small percentage being DN2. SLE plasma-primed MSCs while maintaining their phenotype, showed reduced PGE2 and TGF-β production and promoted naïve B cell differentiation into DN2 B cells, unlike healthy plasma-primed MSCs. These findings suggest that SLE MSCs exhibit impaired immunomodulatory capacity, contributing to the expansion of pathogenic DN2 B cells. This study provides new insights into DN2 biology and MSC dysfunction, highlighting potential therapeutic targets for SLE. Funding Sources LRA and Boston Children’s Hospital Cell Discovery Network Topic Categories Hematopoiesis and Immune System Development (HEM)