IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis

James M. Kelley, Paul A. Monach, Chuanyi Ji, Yebin Zhou, Jianming Wu, Sumiaki Tanaka, Alfred D. Mahr, Sharleen Johnson, Carol McAlear, David Cuthbertson, Simon Carette, John C. Davis, Paul F. Dellaripa, Gary S. Hoffman, Nader Khalidi, Carol A. Langford, Philip Seo, E. William St Clair, Ulrich Specks, John H. StoneRobert F. Spiera, Steven R. Ytterberg, Peter A. Merkel, Jeffrey C. Edberg, Robert P. Kimberly

Research output: Contribution to journalArticle

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 inANCA-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 flowcytometry 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).

Original languageEnglish (US)
Pages (from-to)20736-20741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number51
DOIs
Publication statusPublished - Dec 20 2011

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Keywords

  • Fc receptor alleles
  • Functional genomics
  • Genetic association

ASJC Scopus subject areas

  • General

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