Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

Spontaneous onset of PAH was stably identified in mice with immune abnormality because of overexpression of the tumor necrosis factor (TNF) family molecule OX40 ligand (OX40L). Histopathological and physical examinations revealed the onset of PAH-like disorders in the C57BL/6 (B6) strain of OX40L transgenic mice (B6.TgL). Comparative analysis performed using different strains of transgenic mice showed that this onset depends on the presence of OX40L in the B6 genetic background. Genetic analyses demonstrated a susceptibility locus of a B6 allele to this onset on chromosome 5. Immunological analyses revealed that the excessive OX40 signals in TgL mice attenuates expansion of regulatory T cells the B6 genetic background, suggesting an impact of the B6 genetic background on the differentiation of regulatory T cells.Present findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.Pulmonary hypertension (PH) is a severe disease condition that can lead to progressive right ventricular failure and ultimately to death. Pulmonary arterial hypertension (PAH) is a major class of PH defined in the classification of the World Health Organization (WHO). The main histopathological manifestations of PAH are vasoconstriction, endothelial cell proliferation and fibrosis, smooth-muscle cell proliferation, and thrombosis in small pulmonary arteries. These changes result in elevation of pulmonary vascular resistance and, consequently, in pulmonary arterial pressure [1].PAH occurs as either a primary (idiopathic or familial) or a secondary disease. According to the WHO classification, inflammatory conditions, such as collagen vascular diseases, and viral infections are associated with the occurrence of PAH. Indeed, patients with a subset of idiopathic PAH have some inflammatory disturbances, presented as elevated circulating levels of TNF-α, interleukin (IL)-1, and IL-6 [2]. In the case of severe PAH in humans, infi