Complement regulates inhalation tolerance at the dendritic cell/T cell interface
Complement regulates inhalation tolerance at the dendritic cell/T cell interface
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DOI：
10.1016/j.molimm.2006.06.016
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Wills-Karp, Marsha
中科院分区：
文献类型：
--
作者：
Kohl, Jorg;Wills-Karp, Marsha
肺部接触无害的气源性过敏原是导致吸入耐受的常见事件。肺树突状细胞 (DC) 和调节性 T 细胞 (T(Reg)) 的不同亚群在介导和维持这种耐受性方面发挥着关键作用。对于哮喘患者，相同的空气过敏原会引发适应不良、偏向 Th2 的免疫反应，导致气道炎症和气道高反应性。吸入耐受性崩溃导致越来越多的工业化国家哮喘患者出现 Th2 驱动的炎症，其机制仍然难以捉摸。最近人们对先天免疫介质在调节适应性免疫反应中的作用重新产生兴趣，引发了旨在确定补体在过敏性哮喘中的作用的研究。在此背景下，发现了过敏毒素 C5a 受体在过敏致敏中的意想不到的作用。在实验性过敏性哮喘模型中，初始过敏原暴露期间 C5aR 信号传导的消除会诱导或增强 Th2 致敏。从机制上讲，C5aR 信号传导直接影响不同肺 DC 亚群的功能，这些亚群诱导或控制过敏原诱导的适应性免疫反应。 C5 下游的信号通路也可能影响 T(Reg) 的功能，因为来自 C5 的 T(Reg) 足以抑制 DC 激活和随后 Th2 驱动的炎症的发展，但来自 C5 缺陷小鼠的 T(Reg) 则不然。新兴的范例是，气道树突状细胞中 C5a 和 C5aR 信号的局部生成直接控制吸入耐受性，并通过气道树突状细胞对 T(Reg) 介导的免疫抑制的敏化来间接控制吸入耐受性。 (C) 2006 Elsevier Ltd. 保留所有权利。
Pulmonary exposure to innocuous aeroallergens is a common event leading to inhalation tolerance. Distinct subsets of pulmonary dendritic cells (DC) and regulatory T cells (T(Reg)) play critical roles in mediating and maintaining such tolerance. In asthmatics, the same aeroallergens drive a maladaptive, Th2-biased immune response resulting in airway inflammation and airway hyper-reactivity. The mechanisms underlying the breakdown of inhalation tolerance, leading to the Th2-driven inflammation in rising numbers of asthmatic patients from industrialized countries remain elusive. The recent resurgence of interest in the role of the innate immune mediators in regulating adaptive immune response has sparked studies aimed at identifying the role of complement in allergic asthma. In this context, an unexpected role for the anaphylatoxin C5a receptor in allergic sensitization has been found. In models of experimental allergic asthma, ablation of C5aR signaling during initial allergen exposure either induced or enhanced Th2 sensitization. Mechanistically, C5aR signaling directly affected the function of distinct pulmonary DC subsets that induce or control allergen-induced adaptive immune responses. Signaling pathways downstream of C5 may also impact the function of T(Reg), as T(Reg) from C5 sufficient, but not from C5 deficient mice, suppress DC activation and subsequent development of Th2-driven inflammation. The emerging paradigm is that constitutive local generation of C5a and C5aR signaling in airway DCs controls inhalation tolerance directly as well as indirectly through sensitization of airway DCs for T(Reg)-mediated immunosuppression. (C) 2006 Elsevier Ltd. All rights reserved.