title: Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine.
abstract: The intestinal microbiota is involved in the pathogenesis of arthritis. Altered microbiota composition has been demonstrated in patients with rheumatoid arthritis (RA). However, it remains unclear how dysbiosis contributes to the development of arthritis. The aim of this study was to investigate whether altered composition of human intestinal microbiota in RA patients contributes to the development of arthritis.
  
  
  
  We analyzed the fecal microbiota of patients with early RA and healthy controls, using 16S ribosomal RNA-based deep sequencing. We inoculated fecal samples from RA patients and healthy controls into germ-free arthritis-prone SKG mice and evaluated the immune responses. We also analyzed whether the lymphocytes of SKG mice harboring microbiota from RA patients react with the arthritis-related autoantigen 60S ribosomal protein L23a (RPL23A).
  
  
  
  A subpopulation of patients with early RA harbored intestinal microbiota dominated by Prevotella copri; SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis when treated with zymosan. Lymphocytes in regional lymph nodes and the colon, but not the spleen, of these mice showed enhanced interleukin-17 (IL-17) responses to RPL23A. Naive SKG mouse T cells cocultured with P copri-stimulated dendritic cells produced IL-17 in response to RPL23A and rapidly induced arthritis.
  
  
  
  We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurakawa
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Umemoto
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Motooka
authors.affiliation: Kyoto University, Kyoto, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Osaka University, Osaka, Japan, and Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Kyoto University, Kyoto, Japan, and Osaka University, Osaka, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.affiliation: National Hospital Organization Osaka Minami Medical Center, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Yoki
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narazaki
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakaguchi
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iida
authors.affiliation: National Hospital Organization Osaka Minami Medical Center, Osaka, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Japan Agency for Medical Research and Development, Tokyo, Japan, Kyoto University, Kyoto, Japan, and Osaka University, Osaka, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan. ktakeda@ongene.med.osaka-u.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000382:microbiology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D016022:Case-Control Studies; D003106:Colon / Q000276:immunology; D004269:DNA, Bacterial / Q000235:genetics; D064806:Dysbiosis / Q000276:immunology*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D012269:Ribosomal Proteins / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D015054:Zymosan / Q000633:toxicity
chemical_list: D001324:Autoantigens; D004269:DNA, Bacterial; D020381:Interleukin-17; D012336:RNA, Ribosomal, 16S; D012269:Ribosomal Proteins; C000621189:Rpl23a protein, mouse; D015054:Zymosan