No association between neutrophil FcγRIIa allelic polymorphism and anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis

Abstract

SUMMARYANCA, implicated as having a pathogenic role in systemic vasculitis, can activate tumour necrosis factor-alpha (TNF-a)-primed neutrophils by cross-linking surface-expressed ANCA antigens with neutrophil FcgRIIa receptors to release reactive oxygen species. The FcgRIIa receptor exists as polymorphic variants, R131 and H131, which differ in their ability to ligate human IgG2 and IgG3. Neutrophils homozygous for the FcgRIIa-H131 allotype bind more efficiently to IgG3 than the FcgRIIa-R131 allotype and are the only human FcgR which bind IgG2. Our aim was to determine whether the homozygous FcgRIIa-H131 individuals are more susceptible to developing ANCAassociated systemic vasculitis and nephritis due to differential IgG binding and activation. FcgRIIa allotype was determined by both allele-specific polymerase chain reaction (PCR) and Southern blotting with allele-specific oligonucleotide probes end-labelled with 32 P-gATP, after PCR amplification of genomic FcgRIIa DNA in 107 Caucasian patients with ANCA þ vasculitis (of whom 89 had renal disease) and 100 ethnically matched controls. Phenotyping of neutrophil FcgRIIa alleles was confirmed in some patients by quantitative flow cytometry using murine MoAbs 41H16 and IV.3. Of the patients with ANCA þ systemic vasculitis, 75 had ANCA with specificity for proteinase 3 and 32 with specificity for myeloperoxidase. Overall, no skewing in FcgRIIa allotypes was seen in patients compared with controls. No significant increase of the FcgRIIa-H131 allotype was found amongst patients irrespective of ANCA specificity, and no association between the FcgRIIa allotype and nephritis was found. Our data suggest that the FcgRIIa receptor allotype is not a major factor predisposing to the development of ANCA þ systemic vasculitis, or to nephritis.

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

“…Disease. Genotyping the NA1 allele of FCGR3B, which produces a stronger phagocytic, respiratory burst, and degranulation response compared with the NA2 allele (12), revealed similar allele frequencies for the WGGER (0.38), VCRC (0.36), and control (0.41) populations, indicating that this locus does not associate with overall disease susceptibility, similar to a previous study of 101 European patients with multiple forms of ANCA-associated vasculitis (24). However, among our patients with GPA, the presence of this proinflammatory allele was related to the presence of severe renal disease in GPA: 26% of NA1 homozygote-positive patients developed severe renal disease, compared with 11.5% among those not homozygous for NA1 (P = 0.064).…”

Recent progress in the genetics of Wegener's granulomatosis and Churg–Strauss syndrome

“…Therefore FCGR genes have been intensively studied in AASV. In addition to a trend of increased homozygosity of the FcgRIIIb-NA1 allele in MPO ANCA þ AASV patients, no significant allele distribution of any SNP was found in the FCGR genes [47,48]. An association of a copy number polymorphism of the FCGR3B locus, the copy number of which was significantly reduced in Wegener's granulomatosis (and other conditions of systemic autoimmunity), has attracted much attention [14].…”

Translating basic science into patient therapy for ANCA-associated small vessel vasculitis

“…Neutrophils homozygous for His 131 bind IgG 3 more efficiently [60]. The IgG 3 subclass of ANCA is known to be elevated during the acute phase of WG [61] and is particularly associated with renal involvement; however, studies of Fcγ RIIa allotypes in ANCA-associated SVV have not shown an increase in the His 131 allotype irrespective of ANCA specificity or nephritis [62]. Despite lack of evidence for an aetiological role, there are suggestions that patients with homozygous Fcγ RIIa-Arg 131 and Fcγ RIIIa-Phe 158 may be more susceptible to relapse of SVV [63].…”