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

被引：370

作者：

Karsten, Christian M. ^{[1
]}

Pandey, Manoj K. ^{[2
]}

Figge, Julia ^{[1
]}

Kilchenstein, Regina ^{[1
]}

Taylor, Philip R. ^{[3
]}

Rosas, Marcela ^{[3
]}

McDonald, Jacqueline U. ^{[3
]}

Orr, Selinda J. ^{[3
]}

Berger, Markus ^{[4
]}

Petzold, Dominique ^{[4
]}

Blanchard, Veronique ^{[4
]}

Winkler, Andre ^{[5
]}

Hess, Constanze ^{[5
]}

Reid, Delyth M. ^{[6
]}

Majoul, Irina V. ^{[7
]}

Strait, Richard T. ^{[8
]}

Harris, Nathaniel L. ^{[2
]}

Koehl, Gabriele ^{[1
]}

Wex, Eva ^{[9
]}

Ludwig, Ralf ^{[10
]}

Zillikens, Detlef ^{[10
]}

Nimmerjahn, Falk ^{[11
]}

Finkelman, Fred D. ^{[2
,12
,13
]}

Brown, Gordon D. ^{[6
]}

Ehlers, Marc ^{[1
,5
]}

Koehl, Joerg ^{[1
,2
]}

机构：

[1] Med Univ Lubeck, Inst System Inflammat Res, D-23538 Lubeck, Germany

[2] Univ Cincinnati, Coll Med, Div Cellular & Mol Immunol, Cincinnati, OH USA

[3] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff, S Glam, Wales

[4] Charite, Cent Inst Lab Med & Pathobiochem, D-13353 Berlin, Germany

[5] German Rheumatism Res Ctr, Lab Tolerance & Autoimmun, Berlin, Germany

[6] Univ Aberdeen, Sect Infect & Immun, Aberdeen, Scotland

[7] Med Univ Lubeck, Ctr Struct & Cell Biol Med, Inst Biol, D-23538 Lubeck, Germany

[8] Univ Cincinnati, Coll Med, Div Emergency Med, Cincinnati, OH USA

[9] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Resp Dis Res, Biberach, Germany

[10] Med Univ Lubeck, Dept Dermatol, D-23538 Lubeck, Germany

[11] Univ Erlangen Nurnberg, Dept Biol, Chair Genet, D-91054 Erlangen, Germany

[12] Univ Cincinnati, Coll Med, Div Immunol, Cincinnati, OH USA

[13] Cincinnati Vet Affairs Med Ctr Cincinnati, Dept Med, Cincinnati, OH USA

来源：

NATURE MEDICINE | 2012年 / 18卷 / 09期

基金：

英国惠康基金;

关键词：

IN-VIVO; AUTOIMMUNE ARTHRITIS; RECEPTOR DECTIN-1; C5A ANAPHYLATOXIN; IMMUNE-RESPONSES; COMPLEMENT; INDUCTION; MICE; NEUTROPHILS; DISEASE;

D O I：

10.1038/nm.2862

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis(1). C5a and its G protein-coupled receptor mediate many of the proinflammatory properties of complement(2). Despite the key role of C5a in allergic asthma(3), autoimmune arthritis(4), sepsis(5) and cancer(6), knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor Fc gamma RIIB and the C-type lectin-like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of Fc gamma RIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain-containing inositol phosphatase (SHIP) downstream of Fc gamma RIIB 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 Fc gamma RIIB and dectin-1. Thus, galactosylated IgG1 and Fc gamma RIIB exert anti-inflammatory properties beyond their impact on activating Fc gamma Rs.

引用

页码：1401 / +

页数：9

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