No association between neutrophil Fc gamma RIIa allelic polymorphism and antineutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis

ANCA, implicated as having a pathogenic role in systemic vasculitis, can ac tivate tumour necrosis factor-alpha (TNF-alpha)-primed neutrophils by cross -linking surface-expressed ANCA antigens with neutrophil Fc gamma RIIa rece ptors to release reactive oxygen species. The Fc gamma RIIa receptor exists as polymorphic variants, R131 and H131, which differ in their ability to l igate human IgG2 and IgG3. Neutrophils homozygous for the Fc gamma RIIa-H13 1 allotype bind more efficiently to IgG3 than the Fc gamma RIIa-R131 alloty pe and are the only human Fc gamma R which bind IgG2. Our aim was to determ ine whether the homozygous Fc gamma RIIa-H131 individuals are more suscepti ble to developing ANCA-associated systemic vasculitis and nephritis due to differential IgG binding and activation. Fc gamma RIIa allotype was determi ned by both allele-specific polymerase chain reaction (PCR) and Southern bl otting with allele-specific oligonucleotide probes end-labelled with P-32-g amma ATP, after PCR amplification of genomic Fc gamma RIIa DNA in 107 Cauca sian patients with ANCA(+) vasculitis (of whom 89 had renal disease) and 10 0 ethnically matched controls. Phenotyping of neutrophil Fc gamma RIIa alle les was confirmed in some patients by quantitative flow cytometry using mur ine 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 Fc gamma RIIa allotypes was seen in patients compared with controls. No significant increase of the Fc gamma R IIa-H131 allotype was found amongst patients irrespective of ANCA specifici ty, and no association between the Fc gamma RIIa allotype and nephritis was found. Our data suggest that the Fc gamma RIIa receptor allotype is not a major factor predisposing to the development of ANCA(+) systemic vasculitis , or to nephritis.