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).