Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1.
Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1.
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DOI：
10.1038/nm.2862
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发表时间：
2012-09
期刊：
影响因子：
82.9
通讯作者：
Koehl, Joerg
中科院分区：
文献类型：
--
作者：
Karsten, Christian M.;Pandey, Manoj K.;Figge, Julia;Kilchenstein, Regina;Taylor, Philip R.;Rosas, Marcela;McDonald, Jacqueline U.;Orr, Selinda J.;Berger, Markus;Petzold, Dominique;Blanchard, Veronique;Winkler, Andre;Hess, Constanze;Reid, Delyth M.;Majoul, Irina V.;Strait, Richard T.;Harris, Nathaniel L.;Koehl, Gabriele;Wex, Eva;Ludwig, Ralf;Zillikens, Detlef;Nimmerjahn, Falk;Finkelman, Fred D.;Brown, Gordon D.;Ehlers, Marc;Koehl, Joerg
补体是一种古老的危险感知系统，在宿主防御、免疫监视和体内平衡中起着重要作用。C5 a及其G蛋白偶联受体介导补体的许多促炎特性。尽管C5 a在过敏性哮喘、自身免疫性关节炎、败血症和癌症中起着关键作用，但我们对C5 a调节的了解有限。在这里，我们证明了IgG 1免疫复合物（IC），抑制性IgG受体FcγRIIB和C型凝集素样受体Dectin-1抑制C5 a受体（C5 aR）功能的意外联系。具体而言，我们发现IgG 1 IC将FcγRIIB与Dectin-1结合，导致Dectin-1下游的脾酪氨酸激酶（Syk）和FcγRIIB下游的含Src同源2结构域的肌醇磷酸酶（SHIP）磷酸化。该途径阻断C5 a受体介导的ERK 1/2磷酸化和体外C5 a效应子功能以及体内C5 a依赖性炎症反应，包括实验性获得性大疱性表皮病（EBA）（一种自身免疫性皮肤病）中皮肤水疱的发展。值得注意的是，IgG N-聚糖的高半乳糖基化对于IgG 1 IC的这种抑制特性至关重要，因为它促进FcγRIIB和Dectin-1之间的结合。因此，半乳糖基化IgG 1和FcγRIIB发挥免疫调节特性，其影响超出了可能控制过敏、自身免疫和癌症的激活Fcγ R。
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.
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DOI：
10.1038/nri2569
发表时间：
2009-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Geijtenbeek TB;Gringhuis SI
通讯作者：
Gringhuis SI
影响因子：
7.8
作者：
Graham, I L;Anderson, D C;Holers, V M;Brown, E J
通讯作者：
Brown, E J
影响因子：
4.4
作者：
Godau, J;Heller, T;Köhl, J
通讯作者：
Köhl, J
影响因子：
15.9
作者：
Köhl, J;Baelder, R;Wills-Karp, M
通讯作者：
Wills-Karp, M
影响因子：
15.9
作者：
Shushakova, N;Skokowa, J;Gessner, JE
通讯作者：
Gessner, JE