The role of plasma cell precursors in a mouse model of lupus

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease, which occurs when terminally-differentiated B cells, called plasma cells (PC), secrete anti-nuclear antibodies (ANA). Once formed, PCs persist in the bone marrow for the lifetime of the host, but the mechanisms of this long-term persistence are poorly understood. Our lab and others have identified a novel subset of terminally-differentiated B-lineage cells. These cells, called plasma cell precursors (PCpre) are a post-germinal center cell population, which are both long-lived and capable of self-renewal. While PCpre do not actively secrete antibody, they can terminally differentiate into mature, long-lived PCs. The role of PCpre in the production of ANA has yet to be elucidated. To understand the role of PCpre in autoimmunity, our lab utilized the congenic New Zealand Black Autoimmunity 2 (NBA2) mouse strain, which develops B cell abnormalities similar to SLE. NBA2 mice develop significantly higher frequencies and numbers of PCpre compared to controls. PCpre from NBA2 mice express the transcription factors IRF-4, BLIMP-1, and XBP-1 that are known to be upregulated in PC. In addition, PCpre express high levels of B220 and MHC class II. Adoptive transfer of PCpre cells from NBA2 mice into B6 controls results in ANAs in recipient mice by day 14, demonstrating the pathogenic potential of PCpre in mouse models of SLE. Furthermore, these PCpre are capable of long-term survival as they persist in the recipient for at least 40 days. Based on these findings, we hypothesize that PCpre are involved in the renewal of the PC niche in the NBA2 model of SLE. Current research is focused on the mechanisms by which PCpre undergo proliferation and terminal differentiation.