Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.
Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.
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DOI：
10.1038/nature10134
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发表时间：
2011-06-19
期刊：
影响因子：
64.8
通讯作者：
Ravetch JV
中科院分区：
文献类型：
--
作者：
Anthony RM;Kobayashi T;Wermeling F;Ravetch JV
高剂量静脉注射免疫球蛋白是一种广泛使用的高纯度免疫球蛋白G（IgG）抗体的治疗制剂。它以高剂量（1-2克/千克）给药，用于在各种临床环境中抑制自身抗体引发的炎症。静脉注射免疫球蛋白的这种抗炎活性是由少数IgG可结晶片段（Fc）触发的，其中聚糖终止于α 2，6唾液酸（sFc），靶向表达凝集素树突细胞特异性ICAM-3抓取非整联蛋白（DC-SIGN;也称为CD 209）的髓样调节细胞。在这里，为了详细表征这种应答，我们产生了人源化DC-SIGN小鼠（hDC-SIGN），并证明静脉内免疫球蛋白的抗炎活性可以通过将骨髓来源的sFc处理的hDC-SIGN+巨噬细胞或树突状细胞转移到幼稚受体中来重现。此外，sFc给药导致产生IL-33，进而诱导产生IL-4的嗜碱性粒细胞扩增，促进效应巨噬细胞上抑制性Fc受体FcγRIIB的表达增加。全身给予TH 2细胞因子IL-33或IL-4上调巨噬细胞上的FcγRIIB，并抑制血清诱导的关节炎。与这些结果一致，IL-33处理的嗜碱性粒细胞的转移抑制了诱导的关节炎炎症。这种由内源性配体sFc启动的新型DC-SIGN-TH 2通路提供了维持免疫稳态的内在机制，可操纵该机制以在自身免疫性疾病中提供治疗益处。
High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1–2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN+ macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the TH2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN–TH2 pathway initiated by an endogenous ligand, sFc, pro-vides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in auto-immune diseases.
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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
DOI：
10.4049/jimmunol.0802870
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ohmori K;Luo Y;Jia Y;Nishida J;Wang Z;Bunting KD;Wang D;Huang H
通讯作者：
Huang H
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0810163105
发表时间：
2008-12-16
影响因子：
11.1
作者：
Anthony, Robert M.;Wermeling, Fredrik;Ravetch, Jeffrey V.
通讯作者：
Ravetch, Jeffrey V.
影响因子：
4.4
作者：
Granelli-Piperno, A;Pritsker, A;Steinman, RM
通讯作者：
Steinman, RM