Novel collagen V-reactive natural Th17 cells in hypoxic pulmonary hypertension

缺氧性肺动脉高压(PH)是慢性肺的进行性后果，通常是致命的。 疾病、长期暴露在高海拔地区和急性肺损伤。我们已经证明了TH17 细胞是一种促炎T辅助细胞(CD4+)亚群，定位于血管周围区域。 肺动脉。这些细胞参与了CH诱导的PH。然而，是否对自我免疫 抗原对疾病进展的作用尚不清楚。V型胶原(Col V)正常情况下 被隔离在肺间质中，因此隐藏在免疫系统之外。缺氧可能会 导致暴露于Colol V，并成为抗原源。Col V细胞免疫有助于TH17- 肺移植后依赖性闭塞性毛细支气管炎、动脉粥样硬化和间质肺纤维化。 然而，目前尚不清楚COLV细胞免疫是否在TH17细胞依赖中发挥作用 血管周围炎症参与CH诱导的PH和TH17细胞归巢的机制。 这个TH17细胞是否属于自然发生的(NTH17)亚群也是未知的。因此，我们 提出nTH17介导的PH是由于COLV反应增加而发生的新假说 NTH17细胞和外周对COLV耐受性降低。我们还提出，这一机制需要 C-C基序趋化因子配体2引导nTH17细胞向血管周围区的迁移 (CCL2)/C-C趋化因子受体2型(CCR2)信号传导。我们将致力于实现以下目标： 特异性目的1：鉴定CH诱导或暴露的肺相关自身抗原。假设：第五列 是CH发现的一种肺相关自身抗原，可触发nTH17细胞介导的血管周围 发炎。 特异性目标2：确定nTH17细胞归巢至血管周围区域的反应机制 致CH.假设：CCL2/CCR2信号驱动nTH17细胞归巢到血管周围区域 对CH的回应 具体目标3：确定外周耐受性丧失对PH自身抗原的贡献。 假设：nTreg导致COLV反应性nTH17细胞和nTregs之间的正常平衡丧失 向nTH17表型的转变有助于PH的发展。 这些研究的完成将确定CH暴露的自身抗原或新抗原，确定 NTH17细胞归巢至肺血管周围区域的触发因素及外周血细胞的作用 这条途径的耐受性。这项开创性的研究也将促进治疗方法的发展 选择性地抑制自身反应性T细胞的产生及其运输到 炎症而不影响宿主对其进行适当炎症反应的能力 病原体。

Hypoxic pulmonary hypertension (PH) is a progressive and often fatal consequence of chronic lung diseases, chronic exposure to high altitude and acute lung injury. We have demonstrated that TH17 cells, a pro-inflammatory T helper (TH) cell (CD4+) subset, are localized in the perivascular region of pulmonary arteries. These cells contribute to CH-induced PH. However, whether immunity to self- antigens contributes to disease progression is unknown. Type V collagen (col V) is normally sequestered within the lung interstitium and therefore, hidden from the immune system. Hypoxia could lead to exposure of col V and be a source of antigen. Col V cellular immunity contributes to TH17- dependent obliterative bronchiolitis post-lung transplant, atherosclerosis and interstitial lung fibrosis. However, it is unknown whether colV cellular immunity plays a role in the TH17 cell-dependent perivascular inflammation that contributes to CH-induced PH and the mechanism of TH17 cells homing. It is also unknown if this TH17 cells belong to the natural occurring (nTH17) subset. Therefore, we propose the novel hypothesis that nTH17-mediated PH develops as a result of increased col V-reactive nTH17 cells and reduced peripheral tolerance to col V. We also propose that this mechanism requires nTH17 cell trafficking to the perivascular region under the guidance of C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling. We will pursue the following aims: Specific Aim 1: To identify lung-associated self-antigens induced or exposed by CH. Hypothesis: Col V is a lung-associated self-antigen uncovered by CH that triggers nTH17 cell-mediated perivascular inflammation. Specific Aim 2: To identify the mechanism of nTH17 cell homing to the perivascular region in response to CH. Hypothesis: CCL2/CCR2 signaling drives nTH17 cell homing to the perivascular region in response to CH. Specific Aim 3: To determine the contribution of loss of peripheral tolerance to self-antigens in PH. Hypothesis: A loss in the normal balance between col V-reactive nTH17 cells and nTregs due to nTreg transition to an nTH17 phenotype contributes to the development of PH. Completion of these studies will identify the self-antigens or neo-antigens exposed by CH, determine triggers for nTH17 cell-homing to the pulmonary perivascular region, and the role of peripheral tolerance in this pathway. This groundbreaking study will also facilitate the development of therapies to selectively inhibit the generation of autoreactive T cells and their trafficking to the site of inflammation without affecting the capacity of the host to mount a proper inflammatory response to pathogens.