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

Abstract

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