FcγRs on Human Neutrophils: Emerging Patho-Physiological Concerns pp. 123-152
Authors: (Louis Marois, Emmanuelle Rollet-Labelle, Paul H. Naccache, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ, Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University, Québec, Canada)
Abstract: In the immune system, phagocytes resolve a very large proportion of infections subsequently to the recognition and the destruction of pathogens. This crucial function is enhanced by the opsonisation of pathogens with immunoglobulins (mostly immunoglobulin G (IgG)). The latter are recognized by Fcγ receptors (FcγRs) through the Fc portion of IgGs. FcγRs also interact with IgG-containing immune complexes. Human neutrophils, the most abundant circulating phagocytes, constitutively express two types of FcγRs, FcγRIIa (CD32a) and FcγRIIIb (CD16b). This combination of isoforms is unique to human neutrophils. FcγRIIa possesses an Immunoreceptor Tyrosine-based Activation Motif (ITAM) in its cytoplasmic portion, whereas FcγRIIIb is a membrane-anchored receptor which does not possess any cytoplasmic sequence. Neutrophils are the only human phagocytes which do not express Immunoreceptor Tyrosine-based Inhibition Motif (ITIM)-bearing FcγR, i.e. FcγRIIb, which is thought to downregulate the signal of ITAM-bearing FcγRs. The absence of FcγRIIb on human neutrophils indicates that alternative negative regulatory processes may be at play. A recent study from our laboratory described a novel down-regulation mechanism of the activation of FcγRIIa mediated by a proteasomal degradation process. Little is known about the biological relevance of the co-expression of two FcγRs with overlapping ligand-binding specificity on human neutrophils. Cholesterol-rich and detergent-resistant plasma membrane micro-domains (DRMs or lipid rafts) appear to be required for the transmission of the appropriate signal leading to the functional responsiveness of neutrophils. Our previous studies provided evidence for a recruitment of both FcγR isoforms in these micro-domains. FcγRs recruitment in DRMs is a very early event observed following their cross-linking. These observations suggest that cooperation between FcγRIIa and FcγRIIIb, leading to an optimal neutrophil response, may take place in these domains. We are presently investigating this functional cooperation and our results indicate that both isoforms are essential for an optimal phagocytosis.
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