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Barbara J. Vilen, PhD

Associate Professor

The University of North Carolina at Chapel Hill

Microbiology and Immunology

http://vilenlab.wixsite.com/vilenlab/about

Cross sectional and longitudinal studies of immune complexes in SLE

The removal of apoptotic debris is important in maintaining immune tolerance as defects in clearance provide a source of nuclear antigens that chronically stimulate the B-cell antigen receptor, Toll-like receptors, or form immune complexes that promote Fc[gamma]R signaling. Herein we propose cross sectional and longitudinal studies to define whether a lysosomal acidification defect that underlies murine autoantibody secretion, BAFF production, and lupus nephritis is relevant in human SLE. Our preliminary data show that macrophages from MRL/lpr mice exhibit impaired lysosomal acidification that diminishes the degradation of IgG-immune complexes containing apoptotic debris (IgG-ICs) and promotes their recycling leading to the accumulation of nuclear antigens on the cell membrane. We hypothesize that defective lysosomal acidification contributes to human disease by sustaining Fc[gamma]R signaling and driving the activation of mTOR. As disease remits, surface IgG-ICs diminish, and during flare they increase. We will test this hypothesis by enrolling patients in different stages of disease activity and quantitating surface IgG, DNA, and nucleosome levels, the activation state of signaling effector of the PI3k/mTOR pathway, and the ability of MFs to acidify lysosomes. Patients who show accumulated IgG-ICs will then be followed longitudinally as their disease remits to assess whether the levels of IgG-ICs decline.

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