The study investigates the impact of CD19 CAR T cell-mediated B cell depletion on the immune signature in systemic lupus erythematosus (SLE) patients. Using single-cell RNA-Seq and T/B cell repertoire analysis, the researchers found that this therapy selectively resets the B cell response, leading to a significant reduction in type I IFN signaling in monocytes and T cells. This reduction in IFN signaling suggests that the increased IFN signature observed in SLE is a consequence rather than a cause of B cell activation. The study also highlights the effectiveness of CD19 CAR T cell therapy in eliminating memory B cells, which may explain its clinical efficacy. The findings provide insights into the molecular mechanisms underlying SLE and support the combination of targeted therapies with advanced molecular profiling to better understand and treat immune-mediated inflammatory diseases.The study investigates the impact of CD19 CAR T cell-mediated B cell depletion on the immune signature in systemic lupus erythematosus (SLE) patients. Using single-cell RNA-Seq and T/B cell repertoire analysis, the researchers found that this therapy selectively resets the B cell response, leading to a significant reduction in type I IFN signaling in monocytes and T cells. This reduction in IFN signaling suggests that the increased IFN signature observed in SLE is a consequence rather than a cause of B cell activation. The study also highlights the effectiveness of CD19 CAR T cell therapy in eliminating memory B cells, which may explain its clinical efficacy. The findings provide insights into the molecular mechanisms underlying SLE and support the combination of targeted therapies with advanced molecular profiling to better understand and treat immune-mediated inflammatory diseases.