title: Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity?
abstract: 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.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Frisoni
authors.forename: Lenese
authors.initials: L
authors.lastname: McPhie
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Colonna
authors.forename: Uma
authors.initials: U
authors.lastname: Sriram
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.forename: Stefania
authors.initials: S
authors.lastname: Gallucci
authors.forename: Roberto
authors.initials: R
authors.lastname: Caricchio
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism* / Q000502:physiology; D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology / Q000528:radiation effects; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D001666:Binding Sites, Antibody; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D009895:Opsonin Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D009895:Opsonin Proteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins