Antineutrophil cytoplasmic antibodies preferentially engage FcγrIIIb on human neutrophils

Academic Article

Abstract

  • Antineutrophil cytoplasmic Abs (ANCA) are found in the circulation of many patients with systemic vasculitis. ANCA bind to ANCA target, such as proteinase 3 and myeloperoxidase, and activate neutrophils in an FcγR- dependent manner. Human neutrophils constitutively express FcγRIIa (CD32) and FcγRIIIb (CD16), and there is clear in vitro experimental evidence of ANCA-mediated engagement of FcγRIIa. However, direct experimental evidence of ANCA engagement of neutrophil FcγRIIIb has been obscured by technical problems related to activation-induced receptor shedding and activation- induced expression of receptor on the surface of neutrophils. In this study, by blocking receptor shedding and using appropriate reporter anti-FcγR mAb, we show that human cANCA and pANCA, and murine mAb with corresponding reactivities, can indeed engage FcγRIIIb. Furthermore, our data suggest that FcγRIIIb is preferentially engaged by ANCA relative to FcγRIIa presumably due to the nearly 10-fold excess of FcγRIIIb expression relative to FcγRIIa expression. These results clearly demonstrate that the Fc region of ANCA bound to an ANCA target on the neutrophil surface engage FcγRIIIb and indicate that FcγRIIIb and FcγRIIa may both be active participants in ANCA- induced neutrophil activation. However, given the low levels of ANCA target expression on neutrophils from patients with systemic vasculitis, FcγRIIIb is likely to play a critical role in initiating and perpetuating ANCA- induced neutrophil activation.
  • Published In

    Author List

  • Kocher M; Edberg JC; Fleit HB; Kimberly RP
  • Start Page

  • 6909
  • End Page

  • 6914
  • Volume

  • 161
  • Issue

  • 12