Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.
Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.
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DOI：
10.1161/circresaha.110.221069
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发表时间：
2010-10-29
影响因子：
20.1
通讯作者：
Greenspan DS
中科院分区：
文献类型：
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作者：
Dart ML;Jankowska-Gan E;Huang G;Roenneburg DA;Keller MR;Torrealba JR;Rhoads A;Kim B;Bobadilla JL;Haynes LD;Wilkes DS;Burlingham WJ;Greenspan DS
大量证据表明动脉粥样硬化是一种慢性炎症性疾病，其中对自身抗原的免疫有助于疾病进展。我们最近发现胶原V [col(V)] α1(V)链是驱动th17依赖性细胞免疫的关键自身抗原，这是另一种慢性炎症性疾病，闭塞性细支气管炎的基础。由于α1(V)链的特异性诱导在人类动脉粥样硬化中已有报道，我们假设colv自身免疫参与动脉粥样硬化。目的：探讨冷(V)自身免疫是否参与动脉粥样硬化的发病机制。在这里，我们证明了th17依赖的抗col(V)免疫是人类冠状动脉疾病（CAD）患者和载脂蛋白E缺失（ApoE−/−）动脉粥样硬化小鼠动脉粥样硬化的特征。在参与可变Th1通路的CAD中，反应是α1(V)特异性的。在ApoE−/−小鼠的早期动脉粥样硬化中，抗col(V)免疫被il -10依赖机制调节。为了支持col(V)自身免疫在动脉粥样硬化发病中的因果作用，ApoE - / -小鼠的col(V)致敏克服了il -10介导的col(V)自身免疫抑制，导致这些小鼠的动脉粥样硬化负担增加和IL-17产生细胞的局部积累，特别是在动脉粥样硬化下层富含col(V)的外膜中。这些发现证实了col(V)在人类CAD中是一种自身抗原，并表明col(V)自身免疫在人类和小鼠动脉粥样硬化中是一致的特征。此外，数据与col(V)在动脉粥样硬化发病机制中的致病作用一致。
Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Since specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. Here we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E null (ApoE−/−) atherosclerotic mice. Responses were α1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE−/− mice, anti-col(V) immunity was tempered by an IL-10-dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V)-sensitization of ApoE−/− mice on a regular chow diet overcame IL-10-mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17 producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.