title: Cross-linking of Fc gamma receptor IIa and Fc gamma receptor IIIb induces different proadhesive phenotypes on human neutrophils.
abstract: Activation of polymorphonuclear leukocytes (PMN) plays an important role in vascular injury associated with systemic vasculitis and in models of autoantibody- and immune complex-mediated disease. The potential role 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 endothelium 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 RIIIb (Cd16) were targeted with receptor-specific reagents, and the expression of adhesion molecules-mediating rolling (L-selectin) and firm adhesion (CD11b/CD18) was measured. Engagement of either Fc gamma RIIa or Fc gamma RIIIb leads to activation, demonstrated by degranulation (upregulation of CD66b), and to increased expression of total CD11b/CD18 and functional CD11b/CD18 (I-domain). In contrast, L-selectin shedding induced by PMN Fc gamma R was divergent. Despite the 5- to 10-fold greater expression and engagement at saturation, activation via Fc gamma RIIIb led to little or no change in L-selectin expression. Stimulation of PMN with intact murine anti-receptor IgG1 showed a contribution of Fc gamma RIIa receptor polymorphisms, underscoring the direct influences of Fc gamma R allotypes on receptor function. These observations suggest that Fc gamma RIIIb-mediated activation of circulating PMN may lead to a proadhesive phenotype likely to promote systemic vascular damage. This Fc gamma R-mediated adhesive phenotype will vary with the receptors engaged and their allotypes, which, in turn, reflect properties of the immune complex and the genetics of the host.
authors.affiliation: Research Division, Hospital for Special Surgery, Cornell University Medical College, New York 10021, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kocher
authors.forename: M E
authors.initials: ME
authors.lastname: Siegel
authors.forename: J C
authors.initials: JC
authors.lastname: Edberg
authors.forename: R P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D000483:Alleles; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000494:pharmacology; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D003432:Cross-Linking Reagents; D000242:Cyclic AMP / Q000097:blood; D015536:Down-Regulation / Q000276:immunology; D000939:Epitopes / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D019041:L-Selectin / Q000096:biosynthesis / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D018821:CD18 Antigens; D003432:Cross-Linking Reagents; D000939:Epitopes; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D019041:L-Selectin; D000242:Cyclic AMP