A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy

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 (T H 2) 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 H 2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4 , resulted in decreased signs of allergy including T H 2 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.