Heterogeneity of in vitro generated primary human antibody secreting cells of Systemic Lupus Erythematosus (SLE) patients 2667

Abstract Description SLE is an autoimmune disease characterized by pathogenic autoantibodies (autoAbs) produced by terminally differentiated B lineage antibody-secreting cells (ASCs). The expanded double negative 2 (DN2) B cell subset found in SLE patients gives rise to autoAb-producing ASCs. While many B cell subsets can form ASCs, it’s unclear whether ASCs derived from specific B cell populations, isolated from either SLE or healthy donors (HD), exhibit distinct functional or pathogenic attributes. Using our novel two-step culture system, we generated ASCs in vitro from resting naïve (rNav-ASCs), resting switched memory (rSW-ASCs), and DN2 (DN2-ASCs) primary human B cell subsets isolated from HDs and SLE patients (n = 3-5). Bulk RNA-sequencing revealed differentially expressed genes and enriched pathways between ASCs generated from different B cell subsets. Notably, CXCR3, which directs cells to inflamed tissues, was upregulated in SLE-derived DN2-ASCs relative to rSW-ASCs. Moreover, we identified differences between ASCs generated from phenotypically matched subsets isolated from SLE and HD, with enrichment for inflammatory signatures within SLE rSW-ASCs. Thus, while DN2 cells are thought to be major contributors to SLE pathogenesis, the gene signature of SLE rSW-ASCs suggest rSW memory B cells may also contribute to pathogenesis. We are now performing functional assays to identify key regulators controlling the distinct attributes of ASCs derived from different B subsets in SLE patients. Funding Sources Funding from P01 AI125180 and the Lupus Research Alliance Topic Categories Basic Autoimmunity (BA)