Tracking Extracellular Vesicles Derived From B Cells in Autoimmunity

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PROJECT ABSTRACT Immune complexes (ICs) cause inflammation and are critical for the damage of multiple organs in systemic lupus erythematosus (SLE). Despite clear evidence linking ICs to the pathogenesis of SLE, identification of how ICs form and the factors that influence IC localization and pathogenicity in tissues has remained elusive. Our preliminary studies demonstrate that activated B cells secrete extracellular vesicles (EVs) that express antigen- specific surface IgG and bind antigen. Moreover, we have identified circulating IgG+ EVs from lupus-prone mice that bind nuclear antigens, are taken up by neutrophils, and localize to the kidney. Recent studies of SLE patients have also identified circulating EVs that co-express IgG and nuclear antigens on their surface which correlate with increased antinuclear antibody titers in whole plasma. Based on these data, we propose a novel hypothesis that IgG-expressing EVs released by activated B cells upregulate inflammatory pathways either directly (i.e., as an IC), or indirectly by interacting with a variety of cells of the innate immune system that then contribute to the pathogenesis of lupus. We will test this hypothesis using a novel reporter mouse strain that allows for the in vivo tracking, isolation, and functional interrogation of EVs derived from class-switched IgG+ B cells. Since little is known about how ICs form in vivo and how they promote inflammatory immune responses in autoimmunity, we propose a series of exploratory experiments to evaluate the intrinsic biophysical properties of B cell-derived EVs, and the effect of B cell-derived EVs on the formation of ICs and on the control of inflammatory responses of innate immune cells (mononuclear phagocytes; neutrophils) in healthy and autoimmune disease states. We will use cutting-edge technologies to rigorously analyze individual B cell-derived EVs and to molecularly define the B cell subsets that produce IgG-expressing EVs. These experiments will provide an important framework for determining the function and disease-related dysfunction of this potentially novel mode of IC formation. Our long- term goal is to investigate B cell-derived EVs in mediating intercellular communication, regulating deleterious host immune responses in SLE, which may provide new therapeutic strategies to reduce inflammation and tissue injury.