title: Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice.
abstract: Interleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice.
  
  
  
  Il21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset.
  
  
  
  Il21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA.
  
  
  
  IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.|Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakuraba
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.|Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Oyamada
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.|Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Fujimura
authors.affiliation: Laboratory of Molecular Immunology, National, Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.affiliation: Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Laboratory of Molecular Immunology, National, Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan. hisakata@bioreg.kyushu-u.ac.jp.|Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan. hisakata@bioreg.kyushu-u.ac.jp.
authors.forename: Hisakata
authors.identifier: 0000-0002-6329-7222
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21
keywords: B cell; Collagen-induced arthritis; Cytokine; Interleukin-21; Rheumatoid arthritis