COBRE: DMS: CHEMOKINE RESPONSIVENESS OF PLASMA CELLS IN AUTOIMMUNITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. B lymphocytes constitute a major cellular component of the immune system, whose function is to produce secreted proteins called antibodies that protect the host against pathogens. A hallmark of this antibody-based protection is the capacity of specialized B cells, plasma cells (PC), to have a prolonged lifespan and is the raison d'¿tre for vaccines to establish long-term immunity. In healthy individuals, the persistence of PCs is an asset for protective humoral immunity but is a significant liability in PC disorders. Thus, understanding the factors that determine PC development and survival takes on considerable importance in terms of both biology and therapeutics. Our laboratory studies two PC disorders: first, is the PC malignancy, multiple myeloma (MM) and second, is the antibody-mediated autoimmune disease, systemic lupus erythematosus. We have identified a rapidly growing, self-renewing cell population - present in low numbers in the bone marrow (BM) - as the precursors to normal PCs (PCpre). These cells can undergo self-renewal or can terminally differentiate to very long-lived PCs. Thus, this cell population has similar properties to stem cells since they give rise both to more progenitors and to the majority of PCs within the bone marrow. This discovery is the basis for our current work to determine the cellular and molecular signals that control these PCpre. To this end, we have determined that a newly-identified member of the TNF family, BCMA, is critical for the survival of end-stage PCs. We hypothesize that BCMA plays a role at the progenitor phase of PC development where decisions are made to either replenish or terminally differentiate to antibody-secreting PCs. This model is highly innovative because for the first time the cellular origin of long-lived PCs is known and therefore can be targeted in the treatment of PC disorders. Our long-range goal is to understand how PCpre are controlled. We have begun to address these questions by focusing on three specific aims. 1) To determine the function of BCMA in normal PCpre self-renewal and differentiation. 2) Establish how BCMA-BAFF interactions affect the development and survival of autoreactive PCs. 3) To investigate the role of BCMA-BAFF interactions in supporting the survival of multiple myeloma. We plan to test each of these aims using a variety of murine models, since PCpre can be genetically-modified and isolated in quantities sufficient for in vitro and in vivo characterization. Taken together, we expect that the results from the studies proposed here should enhance our understanding of BCMA function in PCpre, as well as provide a better understanding of the target cell population where loss of tolerance, or transformation, first occurs.