title: Tissue specific CD4+ T cell priming determines the requirement for interleukin-23 in experimental arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a chronic inflammatory disease with striking heterogeneity in (i) clinical presentation, (ii) autoantibody profiles and (iii) responses to treatment suggesting that distinct molecular mechanisms may underlie the disease process. Proteoglycan-induced arthritis (PGIA) is induced by two pathways either by intraperitoneal (i.p.) or subcutaneous (s.c.) exposure to PG. CD4+ T cells primed by the i.p. route are T helper (Th)1 cells expressing interferon gamma (IFN-γ) whereas CD4+ T cells primed by the s.c. route are Th17 cells expressing interleukin (IL)-17. IL-23 is necessary for maintaining the phenotype of Th17 cells; however, IL-23 is inflammatory independent of IL-17. The aim of this study was to determine if PGIA induced by different routes of immunization is dependent on IL-23.
  
  
  METHODS
  BALB/c wild type (WT), IL-12p40-/- and IL-23p19-/- littermate mice were immunized with recombinant G1 (rG1) domain of human PG in adjuvant either i.p. or s.c. and development of arthritis monitored. Joint histology was assessed. CD4+ T cell cytokines in spleen, lymph node (LN), and joint were assessed by intracellular staining and cytokine enzyme-linked immunosorbent assay. RNA transcripts for cytokines and transcription factors were examined.
  
  
  RESULTS
  PGIA was suppressed in the p40-/- and p19-/- mice immunized by the s.c. route but only inhibited in p40-/- mice by the i.p. route. The joints of s.c. but not i.p. sensitized mice contained a population of CD4+ T cells expressing single positive IFN-γ and IL-17 and double positive IFN-γ/IL-17 which were dependent on IL-23 expression. The IFN-γ and IL-17 response in spleen and inguinal LN was inhibited in p19-/- mice and p40-/- mice after s.c. immunization, whereas in i.p. immunized p19-/- mice, IL-17 but not IFN-γ was reduced. Inguinal LN CD11c+ dendritic cells (DC) from s.c. immunized, but not spleen DC from i.p. immunized mice, produced IL-23, IL-1β, and IL-6 and activated T cells to produce IL-17.
  
  
  CONCLUSIONS
  IL-23 is necessary for the activity of Th17 after s.c. immunization and does not play a role independent of IL-17 after i.p. immunization. These data demonstrate that the molecular pathways IL-23/17 and IL-12/IFN-γ may represent subtypes of arthritis determined by the mode of induction.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Olalekan
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Cao
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D039521:CD11c Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009928:Organ Specificity / Q000276:immunology*; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D011509:Proteoglycans; D007371:Interferon-gamma