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Review 10.1172/JCI130029

Functional diversification of IgGs through Fc glycosylation

Taia T. Wang1,2 and Jeffrey V. Ravetch3

1Department of Medicine, Division of Infectious Diseases, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.

2Chan Zuckerberg Biohub, San Francisco, California, USA.

3Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.

Address correspondence to: Jeffrey V. Ravetch, Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Email: ravetch@rockefeller.edu.

Find articles by Wang, T. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Infectious Diseases, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.

2Chan Zuckerberg Biohub, San Francisco, California, USA.

3Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.

Address correspondence to: Jeffrey V. Ravetch, Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. Email: ravetch@rockefeller.edu.

Find articles by Ravetch, J. in: JCI | PubMed | Google Scholar

First published September 3, 2019 - More info

Published in Volume 129, Issue 9 on September 3, 2019
J Clin Invest. 2019;129(9):3492–3498. https://doi.org/10.1172/JCI130029.
© 2019 American Society for Clinical Investigation
First published September 3, 2019 - Version history

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR–mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc’s affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.

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