title: FcγRIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis.
abstract: Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis involves innate and adaptive immune cells in the induction of autoimmunity and in autoimmune effector responses. Most Fcγ receptors (FcγRs) activate immune cells, but FcγRIIB, found in humans and mice on B cells and innate cells, is an inhibitory receptor. Here we tested whether endogenous FcγRIIB negatively regulates autoreactivity and effector responses in experimental anti-myeloperoxidase (MPO) glomerulonephritis, using wild-type and FcγRIIB(-/-) mice. After MPO immunization, FcγRIIB(-/-) mice developed higher MPO-ANCA titers and increased anti-MPO T-cell responses. Transfer of FcγRIIB-deficient dendritic cells loaded with a nephritogenic MPO peptide (MPO409-428) into wild-type mice induced stronger autoimmunity than dendritic cells derived from wild-type mice. Transferring anti-MPO antibodies into lipopolysaccharide-primed mice resulted in increased glomerular neutrophil accumulation and injury in FcγRIIB(-/-) mice, showing a role for FcγRIIB in suppressing neutrophil activation. Inducing active autoimmunity to MPO followed by triggering T cell-mediated glomerular injury by transfer of sub-nephritogenic doses of lipopolysaccharide and anti-MPO antibodies resulted in more disease in FcγRIIB(-/-) mice. Thus, endogenous FcγRIIB negatively regulates anti-MPO autoimmunity and glomerulonephritis by dendritic cells, B cells, and neutrophils to limit MPO-ANCA production, T-cell responses, and neutrophil activation.
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Eggenhuizen
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: Chang
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Maliha A
authors.initials: MA
authors.lastname: Alikhan
authors.affiliation: Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.affiliation: 1] Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia [2] Monash Health, Department of Nephrology, Melbourne, Victoria, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.affiliation: 1] Center for Inflammatory Diseases, Monash Health, Department of Medicine, Monash University, Melbourne, Victoria, Australia [2] Monash Health, Department of Nephrology, Melbourne, Victoria, Australia [3] Monash Health, Department of Pediatric Nephrology, Melbourne, Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D015703:Antigens, CD / Q000032:analysis; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D007962:Leukocytes / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D015703:Antigens, CD; C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D009195:Peroxidase