title: Pathological mechanism of secondary-progressive multiples sclerosis and its animal model.
abstract: Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2, which we have previously reported to be upregulated in peripheral blood T cells from patients of multiple sclerosis (MS). EAE induced in mice lacking NR4A2 in T cells showed a great reduction in Th17-mediated acute symptoms, whereas a late-onset disease independent of NR4A2 was still inducible. We identified cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes) as a pathogenic component for the development of the late-onset disease. Furthermore, T cell-specific deletion of the Eomes gene or Eomes-specific RNA interference in vivo remarkably ameliorated the late-onset EAE. Intriguingly, similar Eomes-expressing CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid only from patients with secondary-progressive MS accompanied by neurodegenerative symptoms, but not in relapsing-remitting MS. Mechanistic analysis revealed that granzyme B was secreted by Eomes-expressing CD4+ T cells and the activation of protease-activated receptor-1 by granzyme B is involved in the neuroinflammation observed in the late-onset EAE.
authors.affiliation: Department of Immunology, National Institute of Neuroscience, NCNP.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D053804:Granzymes / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020528:Multiple Sclerosis, Chronic Progressive / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000502:physiology; D044463:Receptor, PAR-1 / Q000502:physiology; D020825:T-Box Domain Proteins; D006377:T-Lymphocytes, Helper-Inducer; D058504:Th17 Cells
chemical_list: C491198:Eomes protein, mouse; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D044463:Receptor, PAR-1; D020825:T-Box Domain Proteins; D053804:Granzymes