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IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL-23R+ T cells are critical in driving T cell-mediated synovitis. We demonstrate, using knock-in IL-23R-GFP reporter (IL-23RGFP/+ ) mice, that CD4+ CCR6+ T cells and γδ T cells, but not CD8+ T cells, express the IL-23R(GFP). During early arthritis, IL-23R(GFP)+ CD4+ CCR6+ T cells, but not IL-23R(GFP)+ γδ T cells, were present in the inflamed joints. IL-23RGFP/+ mice were bred as homozygotes to obtain IL-23RGFP/GFP (IL-23R deficient/IL-23R-/- ) mice, which express GFP under the IL-23R promotor. Arthritis progression and joint damage were significantly milder in IL-23R-/- mice, which revealed less IL-17A+ cells in their lymphoid tissues. Surprisingly, IL-23R-/- mice had increased numbers of IL-23R(GFP)+ CD4+ CCR6+ and CCR7+ CD4+ CCR6+ T cells in their spleen compared to WT, and IL-23 suppressed CCR7 expression in vitro. However, IL-23R(GFP)+ CD4+ CCR6+ T cells were present in the synovium of IL-23R-/- mice at day 4. Finally, adoptive transfer experiments revealed that CD4+ CCR6+ T cells and not γδ T cells drive arthritis progression. These data suggest that IL-23R-dependent T cell-mediated synovitis is dependent on CD4+ CCR6+ T cells and not on γδ T cells.

OBJECTIVE Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan to kynurenine, is driven in part by type I and type II interferons (IFNs). Naive T cells are polarized into FoxP3+ Treg cells upon exposure to either IDO+ cells or kynurenine. Recent studies have suggested that the kynurenine pathway reflects a crucial interface between the immune and nervous system. The aims of the present study were to evaluate whether Treg cell levels are elevated, in conjunction with increased IDO activity, in patients with primary Sjogren's syndrome (SS) who are positive for the IFN gene expression signature, and to investigate the downstream kynurenine pathway in these patients. METHODS Serum from 71 healthy controls, 58 IFN-negative patients with primary SS, and 66 IFN-positive patients with primary SS was analyzed using high-performance liquid chromatography to measure the levels of tryptophan and kynurenine. Expression levels of messenger RNA (mRNA) for IDO and downstream enzymes in the kynurenine pathway were assessed in CD14+ monocytes using real-time quantitative polymerase chain reaction. CD4+CD45RO+ T helper memory cell populations were analyzed by flow cytometry. RESULTS Significantly increased levels of IDO activity (assessed as the kynurenine:tryptophan ratio) (P = 0.0054) and percentages of CD25(high) FoxP3+ Treg cells (P = 0.039) were observed in the serum from IFN-positive patients with primary SS, and these parameters were significantly correlated with one another (r = 0.511, P = 0.002). In circulating monocytes from IFN-positive patients with primary SS, the expression of IDO1 mRNA was up-regulated (P

Objective Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis. Methods Disease incidence and severity were scored in type II collagen–treated wild-type, IL-17RA–deficient, and IL-23p19–deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA). Results Comparable to the findings in IL-23p19–deficient mice, IL-17RA–deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA–deficient mice exhibited an increased number of IL-4–producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA–deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation. Conclusion These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint.

Objective To investigate the role of interleukin-4 (IL-4) and IL-10 in basal and IL-1– and IL-17–mediated inhibition of chondrocyte metabolism. Methods Cartilage explants of patellae from naive mice were incubated with IL-17 and/or IL-1 alone or were pretreated with IL-4 and IL-10. In addition, knee joints of naive mice were injected intraarticularly with IL-4 and IL-10 alone or were coinjected with IL-1. Chondrocyte proteoglycan (PG) synthesis was measured in intact murine articular cartilage. Levels of nitric oxide (NO) were measured using the Griess reagent. Results IL-17, a novel cytokine secreted by CD4+ activated memory T cells, inhibited chondrocyte PG synthesis in intact murine articular cartilage, although the suppressive effect was less potent than that of IL-1. The suppressive effect of IL-17 was completely abolished in the presence of L-NIO (L-N5-[1-iminoethyl]ornithine), an inhibitor of NO metabolism, and IL-17 only slightly induced inhibition of PG synthesis in cartilage explants of patellae from iNOS (inducible NO synthase) knockout mice. This indicates that the suppressive effect of IL-17 was mediated by NO. Pretreatment with IL-4, but not IL-10, significantly reduced the inhibition of chondrocyte PG synthesis induced by IL-1 or IL-17. The IL-4–induced reduction in the inhibitory effects of IL-1 and IL-17 on chondrocyte PG synthesis was accompanied by decreased NO formation in the culture supernatants. Conclusion IL-17 plays a role in the inhibition of chondrocyte PG synthesis. IL-4 and IL-10 have no effect on basal chondrocyte metabolism. However, IL-4–pretreated cartilage is less sensitive to the suppressive effect of IL-1 as well as IL-17. This suggests that IL-4 is protective in T cell–driven cartilage disturbances, probably through reduction of iNOS.

To the Editor: We would like to thank Dr. Leng and colleagues for their interest in our work. Our report focused on the modulation of T cell activity by 1,25(OH)2D3, with an emphasis on Th17 and T cell cytokine expression. Our findings demonstrated that 1,25(OH)2D3 has a suppressive effect on human IL-17A and IL-17F production. Importantly, we noted a direct (monocyte-independent) inhibitory effect of 1,25(OH)2D3, but not dexamethasone, on human Th17 polarization and human Th17 cytokine production in patients with early RA. We fully agree with Leng and colleagues that the precise molecular mechanism of how vitamin D modulates Th17 activity and corticosteroid-induced osteoporosis needs further investigation. Leng et al suggest that the vitamin D–induced IL-10 pathway may be critical and that 1,25(OH)2D3 treatment may be insufficient to prevent corticosteroid-induced osteoporosis in patients with early RA who have a defect in the IL-10/IL-10R pathway. The question is whether the 1,25(OH)2D3 effect is completely IL-10 dependent. We found an increase in IL-10 expression by 1,25(OH)2D3-treated peripheral blood mononuclear cells from healthy volunteers and patients with early RA. However, in fluorescence-activated cell sorted memory T cells from patients with early RA, 1,25(OH)2D3 did not up-regulate IL-10 expression although lower IL-17A levels were found (Lubberts E, et al: unpublished observations). This suggests that IL-10 can help in the suppressive effect of 1,25(OH)2D3 on human T cell activity, but that the suppressive effect on IL-17A is not completely IL-10 dependent and that other pathways may be involved as well. Further research is needed to unravel the precise molecular mechanism, including the role of the IL-10/IL-10R pathway in the suppressive behavior of 1,25(OH)2D3 on T cell biology and corticosteroid-induced osteoporosis, before it can be concluded that 1,25(OH)2D3 may be insufficient to prevent corticosteroid-induced osteoporosis in RA.

Objective. Human cartilage glycoprotein 39 (HC gp-39) was recently identified as a candidate autoantigen in the pathogenesis of rheumatoid arthritis, In the present studies, we investigated the capacity of HC gp-39 to interfere in clinical disease induced by an unrelated autoantigen, type II collagen (CII), by the induction of cross-tolerance. Methods, DBA-1j/Bom mice were immunized with bovine CII/complete Freund's adjuvant and were given intraperitoneal booster injections of CII on day 21, Tolerance was induced via the intranasal pathway with either the disease-inducing antigen (CII), a control antigen (ovalbumin), or HC gp-39 either before priming with CII or near the day of the booster injection. Arthritis was monitored visually, and joint pathology was examined histologically and radiologically, In addition, CII antibody levels in serum were analyzed by enzyme-linked immunosorbent assay. Results. In contrast to treatment before priming, intranasal application of HC gp-39 after immunization markedly suppressed disease activity and prevented joint destruction, whereas application of ovalbumin or CII was ineffective. Interference of HC gp-39 with the immune response to CII was demonstrated by decreased anti-CII antibody levels. The combined data indicate that intranasal treatment with HC gp-39 may trigger modulatory or regulatory mechanisms that interfere with the expression of disease in murine collagen-induced arthritis, Conclusion. HC gp-39 is the first cross-tolerance-inducing protein in arthritis that down-modulates a spectrum of disease features when given in a semitherapeutic protocol.