Abstract
IntroductionRheumatoid 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.MethodsBALB/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.ResultsPGIA 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.ConclusionIL-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0440-1) contains supplementary material, which is available to authorized users.
Highlights
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
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
IL-23 is critical for the development of Proteoglycan-induced arthritis (PGIA) after subcutaneous but not intraperitoneal induction We have reported that PGIA is induced by immunization with PG in adjuvant by either the i.p. or the s.c. route [38]
Summary
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. The clinical presentation of RA reveals striking heterogeneity; patients with apparently identical clinical involvement may have very dissimilar patterns of leukocyte infiltration and activation of genes associated with inflammation [1,2] This heterogeneity extends to therapy, where even with the advent of highly effective biologically based therapeutics such as tumor necrosis factor blockade [3,4], anti-CD20 monoclonal antibodies [5], CTLA-4 co-stimulation inhibition [6], and interleukin (IL)-6 inhibition [7] at best 40 to 50% of subjects achieve an American College of Rheumatology 50% improvement criteria response with any specific agent [8]. Systemic induction of IL-23 induces entheseal inflammation in a model of ankylosing spondylitis that is independent of IL-17 [32]
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