A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases.
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.
Palacios
Ricardo
R
Department of Neurology, Clinica Universitaria de Navarra and Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Goni
Joaquin
J
Martinez-Forero
Ivan
I
Iranzo
Jaime
J
Sepulcre
Jorge
J
Melero
Ignacio
I
Villoslada
Pablo
P
D000818:Animals; D001499:Bayes Theorem; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D016022:Case-Control Studies; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D013601:T-Lymphocytes / Q000276:immunology*
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins