Mechanisms driving airway inflammation in chronic lung disease

在目前的资助期内，我们发现小气道获得性粘膜免疫缺陷是一个重要的免疫学指标。 慢性阻塞性肺疾病（COPD）的中心特征。我们现在建议调查 宿主第一道防线的受损会导致后续宿主防线的持续激活 防御（先天免疫和适应性免疫），从而推动COPD进展。虽然很明显， 几年来，COPD病理学开始于小阻力气道，连接小阻力气道的机制， 气道和实质病理学一直不清楚。小气道上皮产生粘膜宿主 通过多种机制进行防御，包括将免疫球蛋白转运到气道表面。向下- 调节多聚免疫球蛋白受体（pIgR）的表达，这是转运二聚免疫球蛋白所必需的。 伊加从气道的基底外侧到管腔表面，在COPD中选择性降低， 在气道表面上产生分泌型伊加（SIgA）屏障。COPD个体小气道 患者中，SIgA减少与细菌侵入上皮层、NF-κB活化和 炎症/免疫细胞的流入。这些致病特征可以在pIgR缺陷型（pIgR-/-） 小鼠，其粘膜表面缺乏SIgA。像COPD患者一样，这些小鼠发展为进行性 肺气肿和小气道重塑，沿着气道上皮层内细菌的证据， 上皮NF-κB活化和炎性/免疫细胞的流入。无菌饲养pIgR-/-小鼠 条件下，用广谱口服抗生素治疗和中性粒细胞耗竭减少肺病理学。在 此外，pIgR-/-小鼠发生淋巴细胞蓄积，包括增加的CD 4+和Th 17 + T细胞，以及 肺中的三级淋巴结构，特别是高龄患者（与患有严重COPD的人相似）， 沿着树突状细胞群向单核细胞衍生的树突状细胞增加的转变。 淋巴细胞耗竭减少了pIgR-/-小鼠中的COPD样病理学和用广谱免疫球蛋白治疗 抗生素使DC群体正常化，减少T细胞流入，消除三级淋巴细胞的积累， 结构，从而暗示先天性和适应性免疫在该模型中的COPD样病理学。 总之，现有的数据表明，多层气道宿主防御结构的每一层， 进化为保护脆弱的粘膜表面，在COPD中变得功能失调。因此，我们假设 小气道中SIgA免疫屏障的破坏导致上皮细胞中的炎症信号， 导致先天性免疫细胞的持续募集和激活以及适应性免疫细胞的病理性激活。 免疫力，协同作用导致气道重塑和肺气肿。具体目标是：1）调查 上皮细胞NF-κB在黏膜免疫小鼠天然免疫和适应性免疫激活中作用 2）鉴定T淋巴细胞在患有C 0 PD的小鼠中的COPD样病理学发展中的作用， 粘膜免疫缺陷，以及3）确定肺中改变的树突状细胞亚群是否介导 适应性免疫激活和持续性炎症。详细了解 需要驱动COPD进展的粘膜、先天和适应性免疫，以开发新的方法来限制 进行性组织损伤，同时在肺中保持足够的宿主防御。

In the current funding period, we showed that acquired defects in mucosal immunity in small airways are a central feature of chronic obstructive pulmonary disease (COPD). We now propose to investigate mechanisms by which impairment of this first line of host defense leads to persistent activation of subsequent lines of host defense (innate and adaptive immunity), thus driving COPD progression. Although it has been clear for several years that COPD pathology begins in the small resistance airways, the mechanisms linking small airway and parenchymal pathology have been obscure. The small airway epithelium generates mucosal host defense by a variety of mechanisms, including transporting immunoglobulins to the airway surface. Down- regulation of polymeric immunoglobulin receptor (pIgR) expression, which is required for transport of dimeric IgA from the basolateral to luminal surface of the airway, is selectively reduced in COPD and impairs generation of the secretory IgA (SIgA) barrier on the airway surface. In individual small airways of COPD patients, reduced SIgA is associated with bacterial invasion into the epithelial layer, activation of NF-κB, and influx of inflammatory/immune cells. These pathogenic features can be modeled in pIgR deficient (pIgR-/-) mice, which lack SIgA on mucosal surfaces. Like COPD patients, these mice develop progressive emphysema and small airways remodeling, along with evidence of bacteria within the airway epithelial layer, epithelial NF-κB activation, and an influx of inflammatory/immune cells. Raising pIgR-/- mice in germ-free conditions, treatment with broad spectrum oral antibiotics, and neutrophil depletion reduce lung pathology. In addition, pIgR-/- mice develop lymphocyte accumulation, including increased CD4+ and Th17+ T cells, and tertiary lymphoid structures in the lungs, particularly with advanced age (similar to humans with severe COPD), along with a shift in the dendritic cell population towards increased monocyte-derived dendritic cells. Lymphocyte depletion reduces COPD-like pathology in pIgR-/- mice and treatment with broad spectrum antibiotics normalizes DC populations, reduces T cell influx, and eliminates accumulation of tertiary lymphoid structures, thus implicating both innate and adaptive immunity in the COPD-like pathology in this model. Together, available data suggests that each layer of the multi-layered airway host defense structure, which evolved to protect vulnerable mucosal surfaces, becomes dysfunctional in COPD. Therefore, we hypothesize that disruption of the SIgA immune barrier in small airways results in inflammatory signaling in epithelial cells, leading to persistent recruitment and activation of innate immune cells and pathologic activation of adaptive immunity, which synergize to drive airway remodeling and emphysema. Specific Aims are: 1) to investigate the role of epithelial NF-κB in driving innate and adaptive immune activation in mice with mucosal immune deficiency, 2) to identify the role of T lymphocytes in development of COPD-like pathology in mice with mucosal immune deficiency, and 3) to determine whether altered dendritic cell subsets in the lungs mediate adaptive immune activation and sustained inflammation in COPD. Detailed knowledge of interactions between mucosal, innate, and adaptive immunity that drive COPD progression is required to develop new ways to limit progressive tissue injury while maintaining adequate host defense in the lungs.