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RIIIb on Human Neutrophils1
*
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294; and
Department of Pathology, State University of New York, Stony Brook, NY 11794
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 Fc
R-dependent manner. Human neutrophils constitutively express
FcRIIa (CD32) and FcRIIIb (CD16), and there is clear in vitro
experimental evidence of ANCA-mediated engagement of FcRIIa.
However, direct experimental evidence of ANCA engagement of neutrophil
FcRIIIb 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-FcR mAb,
we show that human cANCA and pANCA, and murine mAb with corresponding
reactivities, can indeed engage FcRIIIb. Furthermore, our data
suggest that FcRIIIb is preferentially engaged by ANCA relative to
FcRIIa presumably due to the nearly 10-fold excess of FcRIIIb
expression relative to FcRIIa expression. These results clearly
demonstrate that the Fc region of ANCA bound to an ANCA target on the
neutrophil surface engage FcRIIIb and indicate that FcRIIIb and
FcRIIa 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, FcRIIIb is
likely to play a critical role in initiating and perpetuating
ANCA-induced neutrophil activation.
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