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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Inmunología terapia génica > DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista >

A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases
Authors: Palacios, R. (Ricardo)
Goñi, J. (Joaquín)
Martinez-Forero, I. (Iván)
Iranzo, J. (Jaime)
Sepulcre, J. (Jorge)
Melero, I. (Ignacio)
Villoslada, P. (Pablo)
Keywords: Calcium-Binding proteins/antagonists and inhibitors
Encephalomyelitis, autoimmune, experimental/therapy
Lymphocyte activation/genetics
Membrane proteins/antagonists and inhibitors
Multiple sclerosis/therapy
T-Lymphocytes/immunology
Issue Date: 2007
Publisher: Public Library of Science
Publisher version: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001222
ISSN: 1932-6203
Citation: Palacios R, Goni J, Martinez-Forero I, Iranzo J, Sepulcre J, Melero I, et al. A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases. PLoS One 2007 Nov 21;2(11):e1222.
Abstract
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 differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases.
Permanent link: http://hdl.handle.net/10171/21775
Appears in Collections:DA - Ciencias - Física - Artículos de Revista
DA - CUN - Neurología - Artículos de revista
DA - Medicina - Medicina Interna - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista

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