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* Division of Rheumatology, Department of Medicine, University of Pennsylvania, and
Laboratory of Dendritic Cell Biology, Division of Rheumatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140
Autoreactivity in lupus requires the delivery of autoantigens to APCs in a proinflammatory context. It has been proposed that apoptotic cells are a source of lupus autoantigens and targets for autoantibodies. Using a histone H2B-GFP fusion protein as traceable Ag, we show here that lupus autoantibodies, directed against nuclear autoantigens, can opsonize apoptotic cells, enhance their uptake through induction of proinflammatory Fc
R-mediated phagocytosis, and augment Ag-specific T cell proliferation by increasing Ag loading. Apoptotic blebs and bodies seemed to be a preferred target of DC phagocytosis, via both "eat-me signals" and FcR-mediated mechanisms; furthermore, inhibition of nuclear Ag redistribution, by blockade of chromatin fragmentation, could stop binding and opsonization of apoptotic cells by autoantibodies, and inhibited Fc-R-mediated enhancement of phagocytosis. Our results suggest that DC uptake of opsonized histones and other nuclear Ags from apoptotic cells is a novel pathway for the presentation of nuclear Ags in a highly inflammatory context. Blockade of chromatin fragmentation in lupus is a potential therapeutic approach, which could theoretically limit DC access to autoantigens delivered in proinflammatory context, while leaving available for tolerization those delivered in a noninflammatory context.
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