title: New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis.
abstract: Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system, which is thought to be triggered by environmental factors in genetically susceptible individuals leading to activation of autoreactive T lymphocytes. Large multi-centre genome-wide association studies have identified multiple genetic risk loci in multiple sclerosis. In this study, we investigated T cell transcriptomic changes in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We correlated these findings with the multiple sclerosis risk genes postulated by the most recent Immunochip analysis and found that multiple sclerosis susceptibility genes were significantly regulated in experimental autoimmune encephalomyelitis. Our data indicate that nine distinct genes associated with multiple sclerosis risk, Bach2, Il2ra, Irf8, Mertk, Odf3b, Plek, Rgs1, Slc30a7 and Thada, can be confirmed to be differentially regulated in pathogenic CD4(+) T cells. During the effector phase within the inflamed CNS, CD4(+) T cells undergo comprehensive transformation and we identified key transcription factors and signalling networks involved in this process. The transformation was linked to metabolic changes with the involvement of liver X receptor/retinoid X receptor signalling and cholesterol biosynthesis, which might control the T cell effector function in the central nervous system. Thus, our study confirms the involvement of multiple sclerosis risk genes in the pathophysiology of the animal model and sheds light on additional disease-relevant inflammatory networks.
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Nicola
authors: N
authors: Hoppmann
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Christiane
authors: C
authors: Graetz
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Magdalena
authors: M
authors: Paterka
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Laura
authors: L
authors: Poisa-Beiro
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Catherine
authors: C
authors: Larochelle
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Maruf
authors: M
authors: Hasan
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany 2 Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany 3 Platform for Genome Analytics, Institutes for Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Maria-Goeppert-Str.1, 23562 Lübeck, Germany.
authors: Christina M
authors: CM
authors: Lill
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors: Frauke
authors: F
authors: Zipp
authors: 1 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany siffrinv@gmx.de.
authors: Volker
authors: V
authors: Siffrin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology
keywords: GWAS; experimental autoimmune encephalomyelitis; multiple sclerosis; plasticity; transcriptome analysis