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.
Hypoxic pulmonary hypertension (World Health Organization [WHO]; group III) is caused by a variety of chronic respiratory diseases including chronic obstructive pulmonary disease (COPD) but also by living at high-altitude. Pulmonary hypertension occurs when blood pressure within the lungs increases above normal, making the heart pump harder and eventually fail. Chronic respiratory diseases are the third leading cause of death in the United States (Federal Centers for Disease Control and Prevention) and pulmonary hypertension increases the risk of mortality. Unfortunately, there is no cure for pulmonary hypertension and medical regimens are limited. Of all the mechanisms involved in the pathogenesis of pulmonary hypertension, inflammation remains the core of the etiology of this disease. The scientific premise of our research is that immunity against self contributes to development of pulmonary hypertension.
