title: IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis.
abstract: Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Kelley
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.forename: Chuanyi
authors.initials: C
authors.lastname: Ji
authors.forename: Yebin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Sumiaki
authors.initials: S
authors.lastname: Tanaka
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Mahr
authors.forename: Sharleen
authors.initials: S
authors.lastname: Johnson
authors.forename: Carol
authors.initials: C
authors.lastname: McAlear
authors.forename: David
authors.initials: D
authors.lastname: Cuthbertson
authors.forename: Simon
authors.initials: S
authors.lastname: Carette
authors.forename: John C
authors.initials: JC
authors.lastname: Davis
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.forename: Nader
authors.initials: N
authors.lastname: Khalidi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Langford
authors.forename: Phillip
authors.initials: P
authors.lastname: Seo
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ytterberg
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D000483:Alleles; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation; D023281:Genomics; D014890:Granulomatosis with Polyangiitis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry*; D007074:Immunoglobulin G / Q000276:immunology*; D007249:Inflammation; D007674:Kidney Diseases / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D008957:Models, Genetic; D009504:Neutrophils / Q000378:metabolism; D011961:Receptors, Fc / Q000737:chemistry
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011961:Receptors, Fc