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Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1 [Letter]

Karsten, Christian M., Pandey, Manoj K., Figge, Julia, Kilchenstein, Regina, Taylor, Philip Russel, Rosas, Marcela, McDonald, Jacqueline U., Orr, Selinda Jane, Berger, Markus, Petzold, Dominique, Blanchard, Veroniqué, Winkler, André, Hess, Constanze, Reid, Delyth M., Majoul, Irina V., Strait, Richard T., Harris, Nathaniel L., Köhl, Gabriele, Wex, Eva, Ludwig, Ralf, Zillikens, Detlef, Nimmerjahn, Falk, Finkelman, Fred D., Brown, Gordon D., Ehlers, Marc and Köhl, Jörg 2012. Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1 [Letter]. Nature Medicine 18 (9) , pp. 1401-1406. 10.1038/nm.2862

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Abstract

Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis1. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement2. Despite the key role of C5a in allergic asthma3, autoimmune arthritis4, sepsis5 and cancer6, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 1078-8956
Last Modified: 03 Mar 2020 02:52
URI: http://orca.cf.ac.uk/id/eprint/41573

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