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.
authors.affiliation: The Center for Individualized Medication, Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Sören
authors.initials: S
authors.lastname: Bruhn
authors.forename: Yu
authors.initials: Y
authors.lastname: Fang
authors.forename: Fredrik
authors.initials: F
authors.lastname: Barrenäs
authors.forename: Mika
authors.initials: M
authors.lastname: Gustafsson
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Aelita
authors.initials: A
authors.lastname: Konstantinell
authors.forename: Andrea
authors.initials: A
authors.lastname: Krönke
authors.forename: Birte
authors.initials: B
authors.lastname: Sönnichsen
authors.forename: Anne
authors.initials: A
authors.lastname: Bresnick
authors.forename: Natalya
authors.initials: N
authors.lastname: Dulyaninova
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yelin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jörg
authors.initials: J
authors.lastname: Klingelhöfer
authors.forename: Noona
authors.initials: N
authors.lastname: Ambartsumian
authors.forename: Mette K
authors.initials: MK
authors.lastname: Beck
authors.forename: Colm
authors.initials: C
authors.lastname: Nestor
authors.forename: Elsa
authors.initials: E
authors.lastname: Bona
authors.forename: Zou
authors.initials: Z
authors.lastname: Xiang
authors.forename: Mikael
authors.initials: M
authors.lastname: Benson
mesh_terms: D000328:Adult; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D016764:Cell Polarity; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D003872:Dermatitis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D000939:Epitopes / Q000187:drug effects; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D006967:Hypersensitivity / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D007156:Immunologic Memory / Q000187:drug effects; D018793:Interleukin-13 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D006255:Rhinitis, Allergic, Seasonal / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000172:deficiency / Q000235:genetics*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D057170:Translational Research, Biomedical
chemical_list: D019138:Antibodies, Blocking; D000939:Epitopes; D018793:Interleukin-13; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C077591:S100A4 protein, human