title: Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Present findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai, Miyagi 980-8575 Japan.
authors.forename: Moloud
authors.initials: M
authors.lastname: Rabieyousefi
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.forename: Fumiko
authors.initials: F
authors.lastname: Date
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamashita
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D001794:Blood Pressure; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D007156:Immunologic Memory; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053278:OX40 Ligand / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D053278:OX40 Ligand