Severe angioproliferative PAH still today remains refractory to treatment, and PAH associated with scleroderma has a particularly dismal prognosis.A close link between idiopathic PAH and complex immune disorders has been recognized for decades and cells of the innate (macrophages, mast cells) and adaptive (T cells, B cells and dendritic cells) are present in and around the pulmonary vascular lesions; there are lymph follicles in close proximity to the lung vessel lesions. New animal models of severe PAH have recently improved our understanding of this link. In mice activated T lymphocytes appear to be involved in the muscularization of pulmonary arterioles and T cell deficient athymic rats treated with the VEGF receptor inhibitor Sugen 5416 (Su) develop lethal angioobliterative PAH that is rescued by transplantation of regulatory T cells. In human PAH high blood levels of IL-1 and IL-6 predict a shorter survival, there is a reduction of circulating T reg cell numbers and endothelial cell (EC) apoptosis, as in scleroderma. May be the initiating pathobiologically important event. Lung small vessel EC apoptosis may be triggered by high shear stress, impaired VEGF signaling, anti –endothelial cell antibodies and leukotriene B4 (LTB4). Hypoxia may, via HIF-1α and NFkappaB cause and amplify inflammation, alter the immune response and stimulate VEGF-dependent EC proliferation. The growth of apoptosis-resistant vascular cells may be driven and maintained by precursor/stem cells. Macrophage-derived LTB4 plays an important role in the athymic Su rat model of severe PAH and perhaps in patients with scleroderma-associated severe PAH who have elevated blood levels of the EC apoptosis – inducing LTB4.
In conclusion: both elements of the innate and adaptive immune system participate in the pathobiology of severe angioobliterative PAH. Specific treatments targeting critically important signaling nodes of inflammatory pathways need to be developed and tested.
Disclosure of Interest None declared