TY - JOUR
T1 - A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy
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
PY - 2014/1/8
Y1 - 2014/1/8
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 T H2 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 T H2 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.
UR - http://www.scopus.com/inward/record.url?scp=84892540269&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892540269&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3007410
DO - 10.1126/scitranslmed.3007410
M3 - Article
C2 - 24401939
AN - SCOPUS:84892540269
SN - 1946-6234
VL - 6
JO - Science translational medicine
JF - Science translational medicine
IS - 218
M1 - 218ra4
ER -
