B Cell Autoreactivity in Estrogen-Induced Lupus

DESCRIPTION (provided by applicant): The research plan outlined in this proposal will provide the opportunity to incorporate years of postdoctoral training in B cell immunology and predoctoral training in cellular, molecular and biological chemistry and to explore challenging new areas of B cell biology and autoinimunity. Interactions with the many, accomplished scientists at the Albert Einstein College of Medicine have provided a foundation to investigate cellular and molecular aspects of B cell regulation and tolerance induction. In conjunction with the dynamic research environment at AECOM, training will be enhanced by departmental and institutional seminars and courses. The long-term goal is to continue a research career as an immunologist and as an independent investigator in a medical research institution. Plans are described to perform research related to the understanding of the regulator, mechanisms associated with B cell development, B cell activation and autommunity using model systems of systemic lupus erythematosus (SLE). The effects of estrogen (E2) in the immune system and its role in SLE are poorly understood. Since there has long been suggestive evidence for a role of E2 in SLE, they have been studying the impact of E2 treatment on B cell tolerance. Examination of non autoimmunity mice that are transgenic for the heavy chain of a pathogenic anti DNA antibody revealed that a sustained increase in E2 disrupts normal B cell tolerance of anti DNA B cells and leads to an increase in anti DNA antibody titers, an expansion of anti DNA B cells and glomerular immunoglobulin deposition. The autoimmune phenotype observed in E2 treated mice is characterized by the altered distribution of splenic B cell subsets, with a diminished immature transitional population and an increase in marginal zone B cells. This shift in B cell development correlates with the increased number of in vivo activated marginal zone B cells that secrete anti DNA antibody. Since little is known about the role of the T cell independent marginal zone B cell immune response in autoimmunity, the E2 induced mouse model of lupus provides a system to explore the contributions of this B cell subset in B cell mediated autoimmune disorders. In an effort to delineate pathways that regulate the threshold for tolerization and activation, they will explore the hypothesis that E2 induced expression of CD22 and SHP 1 contributes to the escape of autoreactive B cells in this model of lupus. Results from these studies are intended to provide insight into the mechanisms of B cell tolerance, and, importantly, may help identify key regulatory pathways in patients in which disease is hormonally regulated, as well as in patients in which disease is not hormonally regulated.