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Open Access Highly Accessed Research article

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

Moloud Rabieyousefi1, Pejman Soroosh27*, Kimio Satoh3, Fumiko Date1, Naoto Ishii26, Masahiro Yamashita1, Masahiko Oka4, Ivan F McMurtry4, Hiroaki Shimokawa3, Masato Nose5, Kazuo Sugamura2 and Masao Ono16*

Author Affiliations

1 Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai, Miyagi 980-8575 Japan

2 Department of Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai, Miyagi 980-8575 Japan

3 Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai, Miyagi 980-8575 Japan

4 Department of Pharmacology and Medicine and Center for Lung Biology, University of South Alabama, College of Medicine, 307 University Blvd N Mobile, AL 36688-0002 USA

5 Department of Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan

6 Japan Science and Technology Agency, CREST, Tokyo, Japan

7 Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA

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BMC Immunology 2011, 12:67  doi:10.1186/1471-2172-12-67

Published: 15 December 2011

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.

Conclusion

Present findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.