A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy

Sören Bruhn; Yu Fang; Fredrik Barrenäs; Mika Gustafsson; Huan Zhang; Aelita Konstantinell; Andrea Krönke; Birte Sönnichsen; Anne Bresnick; Natalya Dulyaninova; Hui Wang; Yelin Zhao; Jörg Klingelhöfer; Noona Ambartsumian; Mette K Beck; Colm Nestor; Elsa Bona; Zou Xiang; Mikael Benson

doi:10.1126/scitranslmed.3007410

A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy

Sören Bruhn, Yu Fang, Fredrik Barrenäs, Mika Gustafsson, Huan Zhang, Aelita Konstantinell, Andrea Krönke, Birte Sönnichsen, Anne Bresnick, Natalya Dulyaninova, Hui Wang, Yelin Zhao, Jörg Klingelhöfer, Noona Ambartsumian, Mette K Beck, Colm Nestor, Elsa Bona, Zou Xiang, Mikael Benson

30 Citations (Scopus)

Abstract

The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

Original language	English
Journal	Science Translational Medicine
Volume	6
Issue number	218
Pages (from-to)	218ra4
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3007410
Publication status	Published - 8 Jan 2014

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Bruhn, S., Fang, Y., Barrenäs, F., Gustafsson, M., Zhang, H., Konstantinell, A., Krönke, A., Sönnichsen, B., Bresnick, A., Dulyaninova, N., Wang, H., Zhao, Y., Klingelhöfer, J., Ambartsumian, N., Beck, M. K., Nestor, C., Bona, E., Xiang, Z., & Benson, M. (2014). A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy. Science Translational Medicine, 6(218), 218ra4. https://doi.org/10.1126/scitranslmed.3007410

Bruhn, S, Fang, Y, Barrenäs, F, Gustafsson, M, Zhang, H, Konstantinell, A, Krönke, A, Sönnichsen, B, Bresnick, A, Dulyaninova, N, Wang, H, Zhao, Y, Klingelhöfer, J, Ambartsumian, N, Beck, MK, Nestor, C, Bona, E, Xiang, Z & Benson, M 2014, 'A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy', Science Translational Medicine, vol. 6, no. 218, pp. 218ra4. https://doi.org/10.1126/scitranslmed.3007410

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title = "A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy",

abstract = "The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.",

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AU - Bruhn, Sören

AU - Fang, Yu

AU - Barrenäs, Fredrik

AU - Gustafsson, Mika

AU - Zhang, Huan

AU - Konstantinell, Aelita

AU - Krönke, Andrea

AU - Sönnichsen, Birte

AU - Bresnick, Anne

AU - Dulyaninova, Natalya

AU - Wang, Hui

AU - Zhao, Yelin

AU - Klingelhöfer, Jörg

AU - Ambartsumian, Noona

AU - Beck, Mette K

AU - Nestor, Colm

AU - Bona, Elsa

AU - Xiang, Zou

AU - Benson, Mikael

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N2 - The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

AB - The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

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DO - 10.1126/scitranslmed.3007410

M3 - Journal article

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SN - 1946-6234

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SP - 218ra4

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 218

ER -

A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy

Abstract

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