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Harvard Medical School

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J. Allergy Clin. Immunol., published online 13 May 2013 | doi:10.1016/j.jaci.2013.03.025 T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death

Abstract

Hye Young Kim, PhD^a,*, Ya-Jen Chang, PhD^a,*‡, Ya-Ting Chuang, PhD^a, Hyun-Hee Lee, PhD^a, David I. Kasahara, PhD^b, Thomas Martin, MD, PhD^c, Joyce T. Hsu, MD^a, Paul B. Savage, PhD^d, Stephanie A. Shore, PhD^b, Gordon J. Freeman, PhD^e, Rosemarie H. DeKruyff, PhD^a, Dale T. Umetsu, MD, PhD^a

^aDivision of Immunology and Allergy, Children's Hospital, Harvard Medical School, Boston, Mass
^bMolecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, Mass
^cDivision of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, Mass
^dDivision of Immunology and Allergy, Children's Hospital, Harvard Medical School, Boston, Mass
Brigham Young University, Provo, Utah
^eDepartment of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Mass

Corresponding author: Dale T. Umetsu, MD, PhD, Division of Immunology, Karp Laboratories, Rm 10127, Children's Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115.

^*These authors contributed equally to this work.
^‡Ya-Jen Chang is currently affiliated with the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Background
Studies of asthma have been limited by a poor understanding of how nonallergic environmental exposures, such as air pollution and infection, are translated in the lung into inflammation and wheezing.

Objective
Our goal was to understand the mechanism of nonallergic asthma that leads to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity.

Method
We examined mouse models of experimental asthma in which AHR was induced by respiratory syncytial virus infection or ozone exposure using mice deficient in T-cell immunoglobulin and mucin domain 1 (TIM1/HAVCR1), an important asthma susceptibility gene.

Results
TIM1^-/- mice did not have airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1^-/- mice had allergen-induced experimental asthma, as previously shown. The RSV- and ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of AHR.

Conclusion
We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells.

Key words: TIM-1, natural killer T, apoptosis, asthma

논문정보

형식Research article
게재일2013년 05월 (BRIC 등록일 2013-05-15)
연구진국외 연구진
분야 의약학 > 면역의학

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