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, Phillip Seo, E. William St Clair, Ulrich Specks, John H. Stone & 5 others Robert F. Spiera, Steven R Ytterberg, Peter A. Merkel, Jeffrey C. Edberg, Robert P. Kimberly

Research output: Contribution to journalArticle

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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
StatePublished - Dec 20 2011

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Antineutrophil Cytoplasmic Antibodies
Granulomatosis with Polyangiitis
Fc Receptors
Immunoglobulin A
Immunoglobulin G
Neutrophil Activation
Neutrophils
Genotype
Kidney
Mucosal Immunity
Vasculitis
Confocal Microscopy
Haplotypes
Single Nucleotide Polymorphism
Fluorescent Antibody Technique
Enzyme-Linked Immunosorbent Assay
Alleles
Antibodies

Keywords

  • Fc receptor alleles
  • Functional genomics
  • Genetic association

ASJC Scopus subject areas

  • General

Cite this

IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. / Kelley, James M.; Monach, Paul A.; Ji, Chuanyi; Zhou, Yebin; Wu, Jianming; Tanaka, Sumiaki; Mahr, Alfred D.; Johnson, Sharleen; McAlear, Carol; Cuthbertson, David; Carette, Simon; Davis, John C.; Dellaripa, Paul F.; Hoffman, Gary S.; Khalidi, Nader; Langford, Carol A.; Seo, Phillip; St Clair, E. William; Specks, Ulrich; Stone, John H.; Spiera, Robert F.; Ytterberg, Steven R; Merkel, Peter A.; Edberg, Jeffrey C.; Kimberly, Robert P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 51, 20.12.2011, p. 20736-20741.

Research output: Contribution to journalArticle

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 2011, 'IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 51, pp. 20736-20741. https://doi.org/10.1073/pnas.1109227109
Kelley, James M. ; Monach, Paul A. ; Ji, Chuanyi ; Zhou, Yebin ; Wu, Jianming ; Tanaka, Sumiaki ; Mahr, Alfred D. ; Johnson, Sharleen ; McAlear, Carol ; Cuthbertson, David ; Carette, Simon ; Davis, John C. ; Dellaripa, Paul F. ; Hoffman, Gary S. ; Khalidi, Nader ; Langford, Carol A. ; Seo, Phillip ; St Clair, E. William ; Specks, Ulrich ; Stone, John H. ; Spiera, Robert F. ; Ytterberg, Steven R ; Merkel, Peter A. ; Edberg, Jeffrey C. ; Kimberly, Robert P. / IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 51. pp. 20736-20741.
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T1 - IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis

AU - Kelley, James M.

AU - Monach, Paul A.

AU - Ji, Chuanyi

AU - Zhou, Yebin

AU - Wu, Jianming

AU - Tanaka, Sumiaki

AU - Mahr, Alfred D.

AU - Johnson, Sharleen

AU - McAlear, Carol

AU - Cuthbertson, David

AU - Carette, Simon

AU - Davis, John C.

AU - Dellaripa, Paul F.

AU - Hoffman, Gary S.

AU - Khalidi, Nader

AU - Langford, Carol A.

AU - Seo, Phillip

AU - St Clair, E. William

AU - Specks, Ulrich

AU - Stone, John H.

AU - Spiera, Robert F.

AU - Ytterberg, Steven R

AU - Merkel, Peter A.

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

PY - 2011/12/20

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N2 - 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).

AB - 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).

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