A regulatory role for the C5a anaphylatoxin in, type 2 immunity in asthma
A regulatory role for the C5a anaphylatoxin in, type 2 immunity in asthma
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DOI：
10.1172/jci26582
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发表时间：
2006-03-01
影响因子：
15.9
通讯作者：
Wills-Karp, M
中科院分区：
文献类型：
--
作者：
Köhl, J;Baelder, R;Wills-Karp, M
补体成分5（CS）被描述为促进或保护气道高反应性（AHR）：在实验性过敏性哮喘中，表明C5的多形性作用。在这里，我们报告说，在吸入耐受或过敏性哮喘小鼠模型中，在初始过敏原致敏之前，局部药物靶向C5 a受体（C5 aR）导致诱导或显著增强Th 2极化免疫应答、气道炎症和AHR。重要的是，C5 aR缺陷小鼠表现出相似的、增加的过敏表型。CSaR靶向小鼠的肺变应原暴露导致CD 4（+）CD 69（+）T细胞的致敏性和蓄积增加，与肺髓样DC数量显著增加相关，但与浆细胞样DC数量无关。来自C5 aR靶向小鼠的肺DC在体外产生大量CC趋化因子配体17（CCL 17）和CCL 22，表明C5 aR信号传导对Th 2细胞的肺归巢的负面影响。相反，C5 aR靶向致敏小鼠导致气道炎症和AHR抑制，但仍与Th 2效应细胞因子的产生增强有关。这些数据表明C5 a在过敏性哮喘中具有双重作用，即，在DC/T细胞界面的过敏原致敏过程中，保护不发生适应不良的2型免疫应答，但在已建立的炎症环境中增强气道炎症和AHR。
Complement component 5 (CS) has been described as either promoting or protecting against airway hyper-responsiveness (AHR):in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in CSaR-targeted mice resulted in increased sensitization and accumulation of CD4(+)CD69(+) T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.