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Review
. 2015 Aug 24;212(9):1361-9.
doi: 10.1084/jem.20151267. Epub 2015 Aug 17.

The role of Fc-FcγR interactions in IgG-mediated microbial neutralization

Stylianos Bournazos  1 , David J DiLillo  1 , Jeffrey V Ravetch  2
Affiliations
Review

The role of Fc-FcγR interactions in IgG-mediated microbial neutralization

Stylianos Bournazos et al. J Exp Med. .

Abstract

Antibodies are bifunctional molecules, containing a variable Fab domain that mediates binding specificity and a constant Fc domain that bridges antibody-coated targets with FcγR-expressing cells that mediate effector functions. Although traditional mechanisms of antibody-mediated neutralization of microbes have been largely thought to result from Fab-antigen interactions, recent studies suggest that recruitment of FcγR-expressing effector cells by antibodies is a major in vivo mechanism of antibody-mediated protection from infection. In this article, we review FcγR biology, compare mammalian FcγR families, and summarize recent evidence demonstrating the crucial role that Fc-FcγR interactions play during in vivo protection from infection.

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Figures

Figure 1.
Figure 1.
Overview of the FcγR family. (A) Schematic representation of the different FcγR classes. FcγRs are broadly categorized as activating or inhibitory, based on the presence of an intracellular ITAM (red) or ITIM (blue) that transduces activating or inhibitory signals upon receptor cross-linking by IgG complexes. The extracellular domain of FcγRs consists of two (three for FcγRI) Ig domains that mediate IgG binding. (B) Genomic organization of the FcγR locus in the indicated species. With the exception of FcγRI, all FcγR genes are mapped at a common, highly conserved locus. The unique organization of the human FcγR locus is the result of nonhomologous recombination that gave rise to additional FcγR genes (FCGR2C and FCGR3B). (C) Human IgG1 binding affinities (Kd [M]) to the low-affinity FcγRs of human, rhesus, guinea pig, and mouse. FcγRs among different species are grouped based on sequence homology and named after the corresponding human orthologue.
Figure 2.
Figure 2.
FcγR-mediated effector pathways during viral infection. Interactions of the IgG Fc domain have pleiotropic effects that contribute to the in vivo protective activity of antibodies during infection. (A) IgG-opsonized viral particles are cleared by FcγR-expressing effector leukocytes, like neutrophils, macrophages, and NK cells. (B) Additionally, IgG binding to infected cells expressing viral proteins on their surface recruits effector leukocytes, such as macrophages and NK cells, through Fc–FcγR interactions. Infected cells are thereby cleared by FcγR-expressing leukocytes, limiting the viral reservoir and preventing further viral spreading. (C) Lastly, IgG–antigen immune complexes generated during these steps have the capacity to stimulate host immune responses through FcγR engagement on DCs, inducing cellular maturation and enhancing antigen presentation to T cells.
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