Background/Purpose: Rheumatoid arthritis is a very heterogeneous disease and distinct molecular mechanisms may underlie the disease process.  IL-23 is an important cytokine for the expansion of Th17 cells and in the development of a number of autoimmune diseases. IL-23 is a heterodimeric cytokine composed of p19 and p40 subunits.  IL-12, an important cytokine for differentiation of Th1 cells, is composed of p40 and p35. We have reported in proteoglycan-induced arthritis (PGIA) that the route of antigen exposure, intraperitoneal (i.p.) versus subcutaneous (s.c.), determines the Th1/Th17 phenotype respectively of the T cells involved in arthritis.  In this study, we assess the contribution of IL-23 to the development of PGIA induced by i.p. or s.c. immunization.

Methods: Wild type (WT), p19^-/- and p40^-/- female BALB/c mice (>3 months of age) were immunized i.p. or s.c. with 50 ug recombinant G1 domain of human PG in adjuvant dimethydioctadecy ammonium bromide (DDA) 3 times at 3-week intervals. Paws were examined every third day for arthritis assessed based on the intensity of erythema and swelling on a score of 1-4. ELISA measured cytokines from CD4⁺T cells and spleen cells re-stimulated in vitro with PG. T cell intracellarular cytokines were assessed by flow cytometry.

Results: In p19^-/- mice, arthritis severity was significantly reduced in s.c. immunized mice, but only mildly reduced in i.p. immunized mice.  In p40^-/- mice, arthritis was significantly reduced in both i.p. and s.c. immunized mice.  Levels of IL-17 were suppressed in splenocytes and inguinal lymph nodes (LN) from p19^-/- mice either s.c. or i.p. immunization.  However, IFN-γ levels were reduced only in p19^-/- mice after s.c. immunization.  To determine if suppression of IFN-γ was an early event after T cell priming we assess splenocyte responses early after immunization on day 9, IFN-γ was not suppressed in p19^-/- mice. In p40^-/-mice, IFN-γ and IL-17 responses were reduced after id or i.p. immunization.  

Conclusion: The present results demonstrate that IL-23 plays a critical role in the development of arthritis after s.c. immunization and a minor role after i.p. immunization. Since p40 is a shared subunit of IL-12 and IL-23 reduction in arthritis after i.p. or s.c. follows the requirement of IL-12 in Th1 responses after i.p. immunization and the requirement for IL-23 in Th17 responses after s.c. immunization.  These data suggest that activation of T cells in different compartments or routes of antigen exposure could affect the dominance of a Th1 versus a Th17 response.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-route-of-t-cell-priming-determines-the-requirement-for-il-23-in-the-development-of-arthritis/