Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus

While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow and blood plasma cell compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ plasma cells (PC), including putative LLPC (CD19- CD138+ CD38+), between SLE and HD bone marrow (BM). For both SLE and HD, CD138+ PC are at a higher frequency in BM than peripheral blood (PBL). Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. PC phosphorylate STAT1 in response to type I IFN stimulation in vitro. Circulating PC bind type I IFN receptor-blocking antibody anifrolumab, though to a lesser degree than circulating B cells. Anti-nuclear autoantibodies are found in the BM supernatant and PBL serum of SLE patients. SLE BM-derived PC have increased survival compared to their PBL counterparts when treated with selinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE. Overall design: To investigate transcriptomic profiles of plasmablast and plasma cells isolated from SLE patient compared to healthy controls and to compare plasma cells in blood and bone marrow. We FACS sorted plasmablast and plasma cells from blood and bone marrow of SLE patients and healthy controls. We then performed bulk RNA sequencing on the sorted cells