title: Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency.
abstract: Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage.
authors.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Rosetti
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernandez
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: George
authors.initials: G
authors.lastname: Stavrakis
authors.forename: Jorge
authors.initials: J
authors.lastname: Alcocer-Varela
authors.forename: Diana
authors.initials: D
authors.lastname: Gómez-Martin
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007428:Intradermal Tests; D020014:K562 Cells; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D011817:Rabbits; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology; D044967:Serum / Q000276:immunology*
chemical_list: D018821:CD18 Antigens; C445323:FCGR2A protein, human; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG