a network analysis of the human t-cell activation gene network identifies jagged1 as a therapeutic target for autoimmune diseases网络分析人类t细胞激活的基因网络标识jagged1作为自身免疫性疾病的治疗目标.pdfVIP

A Network Analysis of the Human T-Cell Activation Gene Network Identifies Jagged1 as a Therapeutic Target for Autoimmune Diseases 1 1,2 1,2 1 1 3 1 Ricardo Palacios , Joaquin Goni , Ivan Martinez-Forero , Jaime Iranzo , Jorge Sepulcre , Ignacio Melero , Pablo Villoslada * 1 Department of Neurology, Clinica Universitaria de Navarra and Center for Applied Medical Research, University of Navarra, Pamplona, Spain, 2 Department of Physics and Applied Mathematics, University of Navarra, Pamplona, Spain, 3 Hepathology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS). The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions) identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-ß therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differ