Role of autoreactive memory and double negative (DN) B cells in quiescent and active SLE patients indicative of breach of peripheral tolerance 2805

Abstract Description Systemic lupus erythematosus (SLE) is an autoimmune disease where autoantibodies target self-antigens, leading to widespread tissue damage. Autoreactive B cells have central role in SLE pathogenesis, making them key targets for therapeutic interventions. In this study, we investigate B cells specific to the ubiquitously expressed autoantigen Ro60 in inactive and active SLE. Anti-Ro60 antibodies are highly prevalent in SLE, often appearing early in disease progression. We analyze Ro60+ B cells in the blood of 224 SLE patients and 27 healthy donors by antigen-specific flow cytometry. Ro60+ B cells were present at higher levels (0.1%-0.4%) in Ro60 seropositive (SP) SLE, with a marked increase in active compared to inactive SP SLE. We show prominent presence of Ro60+ memory B cells in both active and inactive SP SLE. While naïve Ro60+ B cells were present in both SLE and healthy donors, they were significantly activated only in active SP SLE. This correlated with elevated DN2 B cells in active SP patients, suggesting expansion of activated B cells. We also observed a robust generation of Ro60+ antibody-secreting cells (ASCs) in inactive SP SLE, which increased in active SP SLE. Our findings provide original insights into the physiological censoring and pathological dysregulation of anti-Ro60 autoreactivity, marking the first study of discreet autoantigens. This work offers potential for antigen-specific therapies and tracking tolerance restoration post-B cell depletion therapy. Funding Sources Supported by U19 grant (3U19AI110483-08S2) and U54-762 CA260563-01 Emory SeroNet Topic Categories Basic Autoimmunity (BA)