title: Characterization of Multiple Sclerosis candidate gene expression kinetics in rat experimental autoimmune encephalomyelitis.
abstract: The immunological mechanisms underlying autoimmunity are being elucidated through genetic and functional analyses in both humans and rodent models. However, acceptance of models as valid equivalents of human disease is variable, and the validation of defined human candidate molecules in experimental models is hitherto limited. We thus aimed to determine the kinetic expression of several Multiple Sclerosis (MS) candidate genes in the myelin oligodendrocyte glycoprotein (MOG)-induced rat experimental autoimmune encephalomyelitis (EAE) model using susceptible DA and resistant PVG inbred strains. Increased expression of MS candidate genes IL2RA and IL7RA associated with disease susceptibility. Higher expression of these candidate genes and IL18R1 in susceptible rats may lead to enhancement of the disease-driving T(H)1 and T(H)17 pathways. Susceptible DA rats had augmented marker molecules of these pathways and upon restimulation with autoantigen produced increased effector molecules including IFN-gamma, IL-17F and IL-22. The altered T helper cell differentiation pathways led to differences in a MOG-specific proliferative and autoantibody response, which ultimately results in infiltration in the central nervous system and EAE induction. Our results validate the MOG-induced EAE model as having similar mechanisms to human MS and determined the kinetics of several disease mechanisms in relevant tissues.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thessen Hedreul
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D007700:Kinetics; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011919:Rats, Inbred Strains; D020395:Receptors, Interleukin-7 / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D006023:Glycoproteins; C508573:Il18r1 protein, mouse; C508018:Il2ra protein, mouse; D053727:Interleukin-18 Receptor alpha Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020395:Receptors, Interleukin-7; C445081:myelin oligodendrocyte glycoprotein (35-55)