title: Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-β therapy in multiple sclerosis.
abstract: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4(+) T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. yuji@neurol.med.osaka-u.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakatsuji
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Moriya
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toyofuku
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Takata
authors.forename: Misa
authors.initials: M
authors.lastname: Nakano
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Sinobu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsui-Hasumi
authors.forename: Ayako
authors.initials: A
authors.lastname: Uto-Konomi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogata
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051381:Rats; D039961:Semaphorins / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: C574096:SEMA4A protein, human; C534721:Sema4A protein, mouse; D039961:Semaphorins; D016899:Interferon-beta