title: Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.
abstract: Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4(+) Th cells. IL-12-polarized Th1 cells, IL-23-polarized Th17 cells, and Th17 cells that acquire Th1 characteristics were each implicated in autoimmune pathogenesis. It is debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study, we assessed the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFN-γ- or IL-17-skewed responses to myelin basic protein over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFN-γ and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of experimental autoimmune encephalomyelitis. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th-polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS.
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Carbajal
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Mironova
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ulrich-Lewis
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Deven
authors.initials: D
authors.lastname: Kulkarni
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Heather M
authors.initials: HM
authors.lastname: Grifka-Walk
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Huber
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Shrager
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Giger
authors.affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109; Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105 bmsegal@umich.edu.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Segal
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001921:Brain / Q000000981:diagnostic imaging; D002454:Cell Differentiation / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D009900:Optic Nerve / Q000276:immunology / Q000473:pathology; D011859:Radiography; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D004676:Myelin Basic Protein; D018664:Interleukin-12; D007371:Interferon-gamma