Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Raffi Tachdjian; Clinton Mathias; Shadi Al Khatib; Paul J. Bryce; Hong S. Kim; Frank Blaeser; Brian D. O'Connor; Danuta Rzymkiewicz; Andrew Chen; Michael J. Holtzman; Gurjit K. Hershey; Holger Garn; Hani Harb; Harald Renz; Hans C. Oettgen; Talal A. Chatila

doi:10.1084/jem.20091480

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Raffi Tachdjian, Clinton Mathias, Shadi Al Khatib, Paul J. Bryce, Hong S. Kim, Frank Blaeser, Brian D. O'Connor, Danuta Rzymkiewicz, Andrew Chen, Michael J. Holtzman, Gurjit K. Hershey, Holger Garn, Hani Harb, Harald Renz, Hans C. Oettgen, Talal A. Chatila

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

Abstract

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα-dependent signaling.

Original language	English (US)
Pages (from-to)	2191-2204
Number of pages	14
Journal	Journal of Experimental Medicine
Volume	206
Issue number	10
DOIs	https://doi.org/10.1084/jem.20091480
State	Published - Sep 28 2009

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1084/jem.20091480

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Tachdjian, R., Mathias, C., Khatib, S. A., Bryce, P. J., Kim, H. S., Blaeser, F., O'Connor, B. D., Rzymkiewicz, D., Chen, A., Holtzman, M. J., Hershey, G. K., Garn, H., Harb, H., Renz, H., Oettgen, H. C., & Chatila, T. A. (2009). Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. Journal of Experimental Medicine, 206(10), 2191-2204. https://doi.org/10.1084/jem.20091480

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title = "Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma",

abstract = "Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα-dependent signaling.",

author = "Raffi Tachdjian and Clinton Mathias and Khatib, {Shadi Al} and Bryce, {Paul J.} and Kim, {Hong S.} and Frank Blaeser and O'Connor, {Brian D.} and Danuta Rzymkiewicz and Andrew Chen and Holtzman, {Michael J.} and Hershey, {Gurjit K.} and Holger Garn and Hani Harb and Harald Renz and Oettgen, {Hans C.} and Chatila, {Talal A.}",

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Tachdjian, R, Mathias, C, Khatib, SA, Bryce, PJ, Kim, HS, Blaeser, F, O'Connor, BD, Rzymkiewicz, D, Chen, A, Holtzman, MJ, Hershey, GK, Garn, H, Harb, H, Renz, H, Oettgen, HC & Chatila, TA 2009, 'Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma', Journal of Experimental Medicine, vol. 206, no. 10, pp. 2191-2204. https://doi.org/10.1084/jem.20091480

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AU - Tachdjian, Raffi

AU - Mathias, Clinton

AU - Khatib, Shadi Al

AU - Bryce, Paul J.

AU - Kim, Hong S.

AU - Blaeser, Frank

AU - O'Connor, Brian D.

AU - Rzymkiewicz, Danuta

AU - Chen, Andrew

AU - Holtzman, Michael J.

AU - Hershey, Gurjit K.

AU - Garn, Holger

AU - Harb, Hani

AU - Renz, Harald

AU - Oettgen, Hans C.

AU - Chatila, Talal A.

PY - 2009/9/28

Y1 - 2009/9/28

N2 - Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα-dependent signaling.

AB - Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target- and tissue-specific manner to mediate heightened expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα-dependent signaling.

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Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Abstract

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UN SDGs

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