Identification of novel plasma cell subsets in a mouse model of SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease driven by the secretion of anti-nuclear antibodies (ANA) from a subset of terminally differentiated B cells, called plasma cells (PC). PC persist in the bone marrow for the lifetime of the host, posing challenges for the development of therapies for SLE and other autoimmune diseases. The mechanisms of long-term persistence of PC are poorly understood. Utilizing the congenic New Zealand Black Autoimmunity 2 (NBA2) mouse strain, which develops IgG ANA similar to SLE, our lab has identified novel subsets of mature bone marrow PC. which are highly heterogeneous in both phenotype and function. We have characterized these populations of PC based on the expression of CD93 and CXCR3. While CD93+ PC are largely quiescent, CXCR3+ PC are highly proliferative in the bone marrow. In addition, CXCR3+ PC are highly enriched for IgG secretion, while CD93+ PC are enriched for IgA secretion. CD93+ PC are detected in the bone marrow of B6 mice at early time points after immunization with KLH, whereas CXCR3+ PC are nearly absent in the bone marrow yet are present in the spleen. In contrast, significant numbers of both CD93+ and CXCR3+ PC are found in both the spleen and bone marrow of NBA2 mice. Characterization of transcription factors reveals that all PC populations express high levels of BLIMP-1 and IRF-4, demonstrating their commitment to a mature PC fate. These data suggest that distinct subpopulations of PC may be responsible for the pathogenesis of SLE. Current research is focused on elucidating the mechanism by which distinct PC subsets give rise to ANA.