Related Experiment Videos
Cross-linking of Fc gamma receptor IIa and Fc gamma receptor IIIb induces different proadhesive phenotypes on human
M Kocher1, M E Siegel, J C Edberg
1Research Division, Hospital for Special Surgery, Cornell University Medical College, New York 10021, USA.
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.
Insights
Fc gamma receptor activation of polymorphonuclear leukocytes (PMN) can promote vascular injury. Fc gamma RIIIb activation leads to a pro-adhesion phenotype, increasing the risk of systemic vascular damage.
Area of Science:
- Immunology
- Cell Biology
- Vascular Biology
Background:
- Polymorphonuclear leukocytes (PMN) activation is crucial in vascular injury during systemic vasculitis and immune complex diseases.
- Intravascular PMN activation can be complex, as some stimuli induce L-selectin shedding, inhibiting endothelial attachment and potentially reducing inflammation.
Purpose of the Study:
- To investigate how Fc gamma receptor (Fc gamma R)-mediated activation influences the adhesive properties of PMN.
- To determine the specific roles of Fc gamma RIIa and Fc gamma RIIIb in PMN activation and adhesion molecule expression.
Main Methods:
- Targeting Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16) with specific reagents.
- Measuring the expression of L-selectin (for rolling) and CD11b/CD18 (for firm adhesion).
- Assessing PMN degranulation (CD66b upregulation) as a marker of activation.
Main Results:
- Engagement of Fc gamma RIIa or Fc gamma RIIIb induced PMN activation, evidenced by degranulation and increased CD11b/CD18 expression.
- Fc gamma RIIIb engagement resulted in minimal L-selectin shedding, unlike other stimuli.
- Fc gamma RIIa receptor polymorphisms influenced responses to anti-receptor IgG1, highlighting the role of allotypes.
Conclusions:
- Fc gamma RIIIb-mediated activation of circulating PMN promotes a pro-adhesive phenotype, potentially contributing to systemic vascular damage.
- The Fc gamma R-mediated adhesive phenotype is dependent on the specific receptors engaged and their allotypes.
- Host genetics and immune complex characteristics influence Fc gamma R allotypes and subsequent PMN behavior.