Dysregulation of anti-Ro60 B cell autoreactivity in systemic lupus erythematosus

To understand the dysregulation of autoreactive B cells in SLE, we tracked Ro60-specific cells in seropositive (SP) and seronegative (SN) patients and healthy donors (HD), using flow cytometry and monoclonal antibodies. Consistent with permissive central tolerance, Ro60⁺ naïve B cells were present in all groups with increased anergy in HD. HD and SN SLE also had greatly decreased or absent Ro60⁺ memory and ASC, which were greatly increased in active SP SLE, thereby indicating defective distal tolerance in the latter group. Notably, Ro60 autoreactivity was strictly purged from naïve-derived extra-follicular B cells in HD and SN SLE, but expanded in SP SLE, suggesting the importance of autoreactivity censoring in this pathway. SLE clustering of the distribution of Ro60⁺ B cells identified disease heterogeneity in tolerance enforcement in SLE. Finally, we demonstrate a much higher degree of polyreactivity against other lupus antigens in SLE Ro60⁺ naïve cells, which is greatly attenuated in memory cells. Our work represents the first systematic study of antigen-specific autoreactive B cells and ASC in SLE. It enhances our understanding of human B cell tolerance and defines new approaches to measuring autoimmune activity in the course of SLE, including the assessment of immune resetting after B cell depletion therapies.