Galactosylated IgG1 links FcγRIIB and Dectin-1 to block complement-mediated inflammation

Christian M Karsten, Manoj K Pandey, Julia Figge, Regina Kilchenstein, Philip R Taylor, Marcela Rosas, Jacqueline U McDonald, Selinda J Orr, Markus Berger, Dominique Petzold, Veroniqué Blanchard, André Winkler, Constanze Hess, Delyth M Reid, Irina V Majoul, Richard T Strait, Nathaniel L Harris, Gabriele Köhl, Eva Wex, Ralf LudwigDetlef Zillikens, Falk Nimmerjahn, Fred D Finkelman, Gordon D Brown, Marc Ehlers, Jörg Köhl


Complement is an ancient danger sensing system playing critical roles in host defense, immune surveillance and homeostasis(). C5a and its G-Protein-coupled receptor mediate many of the pro-inflammatory properties of complement(). Despite its critical role in allergic asthma(), autoimmune arthritis(), sepsis() and cancer(), our knowledge about C5a regulation is limited. Here we demonstrate an unexpected link through which IgG1 immune complexes (IC), the inhibitory IgG receptor FcγRIIB and the C-type lectin-like receptor Dectin-1 suppress C5a receptor (C5aR) functions. Specifically, we found that IgG1 IC associate FcγRIIB with Dectin-1, resulting in phosphorylation of spleen tyrosine kinase (Syk) downstream of Dectin-1 and Src homology 2 domain containing inositol phosphatase (SHIP) downstream of FcγRIIB. This pathway blocks C5a receptor-mediated ERK1/2 phosphorylation and C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo including the development of skin blisters in experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disorder. Notably, high galactosylation of IgG N-glycan is critical for this inhibitory property of IgG1 IC as it promotes the association between FcγRIIB and Dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert immunoregulatory properties beyond their impact on activating FcγRs that may control allergy, autoimmunity and cancer.
Original languageEnglish
JournalNature Medicine
Issue number9
Pages (from-to)1401-1406
Number of pages6
Publication statusPublished - 2012


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