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SUMMARYNeutrophils constitutively express FcgRIIa and FcgRIIIb receptors. Both receptors exhibit allelic variants which have different quantitative functional capacities: the biallelic FcgRIIa-R131 and -H131 alleles, and the neutrophil antigen (NA) NA1/NA2 alleles. ANCA activation of neutrophils requires ligation of FcgRIIa receptor, but recent data have shown that ANCA can also bind FcgRIIIb receptor. The aim of this study was to determine whether the FcgRIIIb polymorphism was a risk factor for the development of ANCA-associated systemic vasculitis, or the associated nephritis. FcgRIIIb receptor genotyping was determined by allele-specific polymerase chain reaction. Genomic DNA was extracted from 101 Caucasian patients with ANCA 1 vasculitis (of whom 84 had renal disease) and 100 ethnically matched controls. Of the patients with ANCA 1 systemic vasculitis, 71 had ANCA with specificity for proteinase 3 and 30 with specificity for myeloperoxidase (MPO). Overall no significant difference in genotype distribution or allele frequencies was found between patients and controls, or between patients with renal disease and controls. However, there was a trend for an increase in homozygosity for the NA1 allele in patients with a vasculitis and this was significant in patients who had anti-MPO antibodies. The FcgRIIIb receptor polymorphism is not a major factor predisposing to the development of ANCA 1 systemic vasculitis or the associated nephritis. The over-representation of the FcgRIIIb homozygous NA1 allele in patients with anti-MPO antibodies may have implications for disease susceptibility.

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.

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