Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity?

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 gammaR-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 Fc gammaR-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 gamma-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.