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

Publication ,  Journal Article
Kelley, JM; Monach, PA; Ji, C; Zhou, Y; Wu, J; Tanaka, S; Mahr, AD; Johnson, S; McAlear, C; Cuthbertson, D; Carette, S; Davis, JC; Khalidi, N ...
Published in: Proc Natl Acad Sci U S A
December 20, 2011

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).

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 20, 2011

Volume

108

Issue

51

Start / End Page

20736 / 20741

Location

United States

Related Subject Headings

  • Receptors, Fc
  • Neutrophils
  • Models, Genetic
  • Microscopy, Fluorescence
  • Male
  • Kidney Diseases
  • Inflammation
  • Immunoglobulin G
  • Immunoglobulin A
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kelley, J. M., Monach, P. A., Ji, C., Zhou, Y., Wu, J., Tanaka, S., … Kimberly, R. P. (2011). IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci U S A, 108(51), 20736–20741. https://doi.org/10.1073/pnas.1109227109
Kelley, James M., Paul A. Monach, Chuanyi Ji, Yebin Zhou, Jianming Wu, Sumiaki Tanaka, Alfred D. Mahr, et al. “IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis.Proc Natl Acad Sci U S A 108, no. 51 (December 20, 2011): 20736–41. https://doi.org/10.1073/pnas.1109227109.
Kelley JM, Monach PA, Ji C, Zhou Y, Wu J, Tanaka S, et al. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20736–41.
Kelley, James M., et al. “IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis.Proc Natl Acad Sci U S A, vol. 108, no. 51, Dec. 2011, pp. 20736–41. Pubmed, doi:10.1073/pnas.1109227109.
Kelley JM, Monach PA, Ji C, Zhou Y, Wu J, Tanaka S, Mahr AD, Johnson S, McAlear C, Cuthbertson D, Carette S, Davis JC, Dellaripa PF, Hoffman GS, Khalidi N, Langford CA, Seo P, St Clair EW, Specks U, Stone JH, Spiera RF, Ytterberg SR, Merkel PA, Edberg JC, Kimberly RP. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20736–20741.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 20, 2011

Volume

108

Issue

51

Start / End Page

20736 / 20741

Location

United States

Related Subject Headings

  • Receptors, Fc
  • Neutrophils
  • Models, Genetic
  • Microscopy, Fluorescence
  • Male
  • Kidney Diseases
  • Inflammation
  • Immunoglobulin G
  • Immunoglobulin A
  • Humans