CROSS-LINKING OF FC-GAMMA RECEPTOR IIA AND FC-GAMMA RECEPTOR IIIB INDUCES DIFFERENT PROADHESIVE PHENOTYPES ON HUMAN NEUTROPHILS

Activation of polymorphonuclear leukocytes (PMN) plays an important ro le in vascular injury associated with systemic vasculitis and in model s of autoantibody-and immune complex-mediated disease, The potential r ole of intravascular activation of PMN, however, is confounded by the observation that some stimuli injected i.v. (e.g., IL-8 and C5a) lead to L-selectin shedding by PMN, which inhibits attachment to endotheliu m and may be functionally anti-inflammatory. To explore the impact of Fc gamma receptor (Fc gamma R)-mediated activation on the PMN adhesive phenotype, Fc gamma RIIa (CD32) and Fc gamma b (CD36) were targeted w ith receptor-specific reagents, and tile expression of adhesion molecu les-mediating rolling (L-selectin) and firm adhesion (CD11b/CD18) was measured, Engagement of either Fc gamma RIIa or Fc gamma RIIIb leads t o activation, demonstrated by degranulation (upregulation of CD66b), a nd to increased expression of total CP11b/CD18 and functional CD11b/CD 18 (I-domain), In contrast, L-selectin shedding induced by PMN FcyR wa s divergent, Despite the 5- to 10-fold greater expression and engageme nt at saturation, activation via Fc gamma RIIIb led to little or no ch ange in 2-selectin expression. Stimulation of PMN with intact murine a nti-receptor IgG1 showed a contribution of Fc gamma RIIa receptor poly morphisms, underscoring the direct influences of Fc gamma R allotypes on receptor function, These observations suggest that Fc gamma RIIIb-m ediated activation of circulating PMN may lead to a proadhesive phenot ype likely to promote systemic vascular damage. This Fc gamma R-mediat ed adhesive phenotype will vary with the receptors engaged and their a llotypes, which, in turn, reflect properties of the immune complex and the genetics of the host.