Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension.
Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension.
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DOI：
10.1186/1471-2172-12-67
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发表时间：
2011-12-15
期刊：
影响因子：
3
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Rabieyousefi M;Soroosh P;Satoh K;Date F;Ishii N;Yamashita M;Oka M;McMurtry IF;Shimokawa H;Nose M;Sugamura K;Ono M
肺动脉高压（Pulmonary hypertension， PH）是指肺动脉压升高引起的一系列疾病。肺动脉高压（PAH）是一种临床表现为严重PH的疾病，其组织病理学特征为肺小动脉闭塞、内侧肌肉肥大和/或内膜纤维化。多环芳烃可继发性发病，也可原发性发病。继发性多环芳烃已知会并发免疫功能紊乱。本研究的目的是对一种新的PAH动物模型进行组织病理学和遗传学表征，并阐明OX40配体在PAH发病机制中的作用。在肿瘤坏死因子（TNF）家族分子OX40配体（OX40L）过度表达导致免疫异常的小鼠中，PAH的自发性发作得到了稳定的鉴定。组织病理学和体格检查显示，OX40L转基因小鼠（B6. tgl） C57BL/6 （B6）株出现多环芳烃样疾病。使用不同转基因小鼠品系进行的比较分析表明，这种发病取决于B6遗传背景中OX40L的存在。遗传分析表明，5号染色体上有一个B6等位基因易感位点。免疫学分析显示，过量的OX40信号在TgL小鼠中减弱了B6遗传背景下调节性T细胞的扩增，提示B6遗传背景对调节性T细胞的分化有影响。目前的研究结果表明，ox40l衍生的免疫应答和上位遗传效应在免疫介导的多环芳烃发病机制中起作用。
Pulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 ligand in the pathogenesis of PAH. 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.
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影响因子：
4.4
作者：
Marzo, AL;Vezys, V;Lefrançois, L
通讯作者：
Lefrançois, L
影响因子：
15.3
作者：
Daley, Eleen;Emson, Claire;Guignabert, Christophe;Malefyt, Rene de Waal;Louten, Jennifer;Kurup, Viswanath P.;Hogaboam, Cory;Taraseviciene-Stewart, Laimute;Voelkel, Norbert F.;Rabinovitch, Marlene;Grunig, Ekkehard;Grunig, Gabriele
通讯作者：
Grunig, Gabriele
影响因子：
--
作者：
MORRIS, JA;GARDNER, MJ
通讯作者：
GARDNER, MJ
影响因子：
5.4
作者：
Hoshino, A;Tanaka, Y;Okumura, K
通讯作者：
Okumura, K
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M