title: Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus.
abstract: Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: SunAh
authors.identifier: 0000-0002-6327-184X
authors.initials: S
authors.lastname: Kang
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Jennifer L
authors.identifier: 0000-0003-1755-7684
authors.initials: JL
authors.lastname: Rogers
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Monteith
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Chuancang
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599; and.
authors.forename: John
authors.identifier: 0000-0002-1425-236X
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599;
authors.forename: Teresa K
authors.identifier: 0000-0003-4067-5363
authors.initials: TK
authors.lastname: Tarrant
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Young K
authors.initials: YK
authors.lastname: Truong
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Marilyn
authors.initials: M
authors.lastname: Diaz
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599; and.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; barb_vilen@med.unc.edu.
authors.forename: Barbara J
authors.identifier: 0000-0003-0014-0022
authors.initials: BJ
authors.lastname: Vilen
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000378:metabolism; D001773:Blood Cells / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008875:Middle Aged; D017452:Receptors, IgG / Q000235:genetics; D055815:Young Adult
chemical_list: D001324:Autoantigens; D053264:B-Cell Activating Factor; C485701:Fcgr1 protein, mouse; C485700:Fcgr3 protein, mouse; D017452:Receptors, IgG; C505720:Tnfsf13b protein, mouse