Innate and acquired immune responses in human COPD

与吸烟有关的肺部疾病仍然是导致寿命缩短的最重要因素之一。 在我们退伍军人中的跨度和疾病。在过去的十年里，我们的研究已经确定了一些关键的 促进人类肺气肿病理生理学的炎症介质。我们最初的发现是 肺气肿前吸烟者肺内T和B细胞的激活，为寻求 获得性免疫的作用，可使易感吸烟者的肺部炎症持续存在。尽管 戒烟，我们和其他人已经确定了自身反应性的CD4T辅助细胞1(Th1)和Th17细胞 肺气肿吸烟者分泌针对肺基质蛋白的干扰素-和IL-17A。在临床前阶段 在烟雾诱导的肺气肿模型中，我们已经证明了吸烟能激活肺髓系树突状细胞(MDC)。 并降低外周免疫耐受性，部分是通过激活补体蛋白3(C3)。在这些人中 吸烟、烟雾衍生的颗粒物堆积所激活的最早病理性免疫事件 激活IL-1介导的炎症体通路，抑制抗炎介质(如PPAR-)，以及 扩增肺内Th1和Th17细胞。IL-17A与干扰素-(如CXCL10)诱导的趋化因子 在MDC中上调基质金属蛋白酶12(MMP12)和MMP9，从而破坏肺内的弹性蛋白纤维。 暴露在香烟烟雾中的小鼠激活了肺MDCs，刺激Th1/Th17细胞分化和 在肺气肿的发展中起着至关重要的作用。然而，烟雾介导的分子机制 MDCs的激活，以及促进肺气肿发展的下游途径仍不清楚。 我们对人肺MDCS的微阵列分析显示，补体蛋白的表达显著降低 1(C1q)基因在肺气肿中的表达及获得性C1q缺失与自身免疫性炎症 疾病。在这一应用中，将检验香烟烟雾导致C1q抑制的中心假设 协调导致肺气肿的失调的先天和后天免疫反应。的前提是 我们的研究基于我们的初步数据，即C1q促进抗炎T调节细胞(Tregs) 发育和C1q-/-小鼠对慢性吸烟的反应表现出夸大的肺部炎症。总而言之， 我们的发现指出了C1q在肺气肿中的免疫调节作用；我们的建议的意义 包括对推动吸烟引起的肺部炎症的机制的理解，这可能提供新的 以补体为基础的治疗肺气肿。我们的三个目标是：1)确定反- C1q在烟雾诱导的肺炎症和肺气肿中的炎症作用假设：香烟 烟雾抑制肺MDCs和/或肺泡巨噬细胞C1q，从而抑制Treg分化 和/或功能，并诱导自身反应性T细胞。2)确定负责的分子机制 香烟烟雾介导的C1q丢失和免疫耐受性降低。假设：香烟烟雾- 诱导IL-1、、IL-6和/或C3a的激活，抑制肺巨噬细胞和/或肺泡巨噬细胞的C1q 减少肺脏。3)确定T细胞中负责C1q介导的信号通路 促进Treg分化。假说：T细胞中C1q介导的信号通路对 维持免疫耐受性。

Cigarette smoke-related lung diseases remain one of the most significant contributors to the shortening of life span and illness among our veterans. Over the past decade, our research has identified some of the critical mediators of inflammation that promotes the pathophysiology of human emphysema. Our initial discovery of activated T and B cells in the lungs of former smokers with emphysema, provided the rationale for pursing the role of acquired immunity that can perpetuate inflammation in the lungs of susceptible smokers. Despite smoking cessation, we and others have identified autoreactive CD4 T helper 1 (Th1), and Th17 cells that secrete IFN- and IL-17A directed against lung matrix proteins in smokers with emphysema. In a pre-clinical model of smoke-induced emphysema, we have shown that smoke activates lung myeloid dendritic cells (mDC) and decreases peripheral immune tolerance, in part by activating complement protein 3 (C3). Among the earliest pathological immune events activated by smoking, accumulation of smoke-derived, particulate matter activates the IL-1-mediated inflammasome pathways, inhibits anti-inflammatory mediators (e.g., PPAR-), and expands lung Th1 and Th17 cells. IL-17A and chemokines induced by IFN- (e.g., CXCL10) strongly upregulate matrix metalloproteinase 12 (MMP12) and MMP9 in mDC, which destroy elastin fibrils in the lungs. Mice exposed to cigarette smoke have activated lung mDCs, which stimulate Th1/Th17 cell differentiation and are critical in emphysema development. However, the molecular mechanisms responsible for smoke-mediated activation of mDCs, and the downstream pathways that promote emphysema development remain unknown. Our microarray analysis of human lung mDCs showed significantly reduced expression of complement protein 1 (C1q) mRNA in emphysema, and acquired loss of C1q is associated with autoimmune inflammatory diseases. In this application will test the central hypothesis that cigarette smoke induced suppression of C1q coordinates the dysregulated innate and acquired immune responses that drive emphysema. The premise of our studies is based on our preliminary data that C1q promotes anti-inflammatory T regulatory cells (Tregs) development and C1q-/- mice show exaggerated lung inflammation in response to chronic smoke. Collectively, our findings point to an immune modulatory role for C1q in emphysema; the significance of our proposal includes understanding mechanism that drive smoke-induced lung inflammation that could provide novel complement-based therapeutics to treat emphysema. Our three Aims are: 1) Determine the anti- inflammatory role of C1q in smoke induced lung inflammation and emphysema. Hypothesis: Cigarette smoke suppresses C1q in lung mDCs and/or alveolar macrophages thereby inhibiting Treg differentiation and/or function, and inducing autoreactive T cells. 2) Determine the molecular mechanisms responsible for cigarette smoke-mediated loss of C1q, and reduction of immune tolerance. Hypothesis: Cigarette smoke- induced activation of IL-1 IL-6, and/or C3a, suppress C1q in lung mDCs and/or alveolar macrophages and reduce lung Tregs. 3) Determine the signaling pathways in T cells responsible for C1q-mediated enhancement of Treg differentiation. Hypotheses: C1q-mediated signaling pathways in T cells are critical for maintenance of immune tolerance.