Pathways for interleukin‐1–driven arthritis (2008)

T cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) on the basis of an observed genetic association with MHC class II alleles, the high numbers of T cells in the inflamed synovial tissues in RA, and the requirement for T cells in rodent models of RA. The effector functions of CD4+ T cells are, in general, carried out by the production of cytokines. Synovial CD4+ T cells could contribute directly to synovitis by the production of inflammatory cytokines. Originally, CD4+ effector T cells were divided into two subsets based on their preferential production of cytokines (Figure 1). Th1 cells are potent activators of cell-mediated immunity and produce interferon-γ (IFN-γ), lymphotoxinβ (LTβ), and tumor necrosis factor (TNF) whereas Th2 cells are potent activators of B cell IgE production, eosiniphil recruitment and secretion of interleukin (IL)-4, IL-5, and IL-13 (1). More recently, T cells expressing IL-17 have been recognized as a distinct T cell subset, Th17, which produce IL-17, IL-17F, IL-21, and IL-22 (2). In several animal models of RA, IL-17 has been implicated in promoting disease based on the observation that arthritis is ameliorated by neutralizing IL-17 or in IL-17-deficient mice. Innate immune signals from dendritic cells and macrophages drive the differentiation of T cell subsets. Differentiation of Th17 cells is determined by the production of several cytokines, most predominantly transforming growth factor β-1 (TGFβ-1), IL-6 and IL-1β, although there is some disagreement about the requirement for IL-1β (3). Evidence in support of IL-1β as a Th17 differentiation factor showed that IL-1β alone induced CD4+ differentiation into Th17 cells and that blocking IL-1β disables Th17 T cells differentiation mediated by TGFβ-1 and IL-6 (4). Also IL-1β enhances Th17 cell differentiation in autoimmune encephalomyelitis (5) and in Bordetella infection (6). Furthermore, spontaneous arthritis develops in the interleukin-1 receptor antagonist (IL-1ra)-deficient mice that is IL-17-dependent (7).



Figure 1

Overview of T helper cell differentiation and cytokine produced. Mechanisms by which IL-1 and IL-17 reciprocally activate each others function.



IL-1 is a major mediator of inflammation and is produced by monocytes, macrophages, and synovial lining cells. Members of the IL-1 family IL-1α, IL-1β, and IL-1ra bind to the IL-1 receptor. IL-1α and IL-1β are pro-inflammatory cytokines whereas IL-1receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 and competes with IL-1α and IL-1β for binding to the IL-1R. IL-1 is a central mediator of the inflammatory process in RA acting to stimulate monocytes, recruit inflammatory cells into the joint and induce secretion of factors that degrade cartilage (8). Inhibition of IL-1 with IL-1ra in RA is moderately efficacious. In IL-1ra-deficient mice on the BALB/c background, inflammatory and erosive arthritis develops spontaneously due to induction of autoimmunity. Autoimmunity in these mice is characterized by excess production of pro-inflammatory cytokines IL-1, IL-6, TNF and IL-17 and autoantibodies; IgG rheumatoid factor, anti-type II collagen and anti-DNA (7, 9). Further studies show that arthritis is T cell dependent and that arthritis does not develop in IL-1ra-deficient mice also deficient in either IL-17 or TNF highlighting the importance of these cytokines in the development of disease (10).

In this issue of Arthritis & Rheumatism, Koenders and colleagues report new findings regarding the role of cytokines in IL-1ra-deficient mice. The objective of this study was to use the IL-1ra-deficient mice to assess the importance of TNF and IL-17 in chronic progression of arthritis that is IL-1-dependent. After arthritis was established in IL-1ra-deficient mice, IL-1, IL-17 and TNF were neutralized. The results from these studies were quite different from those in which IL-1ra-deficient mice were also deficient in either TNF or IL-17. In the Koenders study, TNF blockade had no effect on arthritis severity. These results are contrary to those observed for the IL-1ra and TNF double-deficient mice in which arthritis is significantly suppressed (10). At face value the data indicate that TNF is critical for the development of arthritis but not for the chronic phase of disease. It would have been helpful in the Koenders study to test TNF blocked with the soluble TNFRI before the development of arthritis to more directly recapitulate the Horai study in the TNF/IL-1ra double-deficient mice. There may be some differences between complete ablation of TNF at the gene level and neutralization of TNF with soluble TNFRI. The IL-1ra-deficient mice may be analogous to the group of RA patients refractory to anti-TNF therapy where IL-1 may dominate the drive toward joint inflammation

What is most interesting about the Koenders study is the relationship between IL-1 and IL-17 in this model of spontaneous arthritis. Inhibition of IL-1 had a dramatic effect on all aspects of arthritis pathology. There was almost complete suppression of the macroscopic arthritis score, cellular infiltration into the joint, proteoglycan-depletion, and bone erosion. In addition, blockade of IL-1 reduced the number of IL-17+ cells in the lymph nodes. In comparison, the effect of IL-17 blockade was modest. Progression of disease was reduced but not arrested and cellular infiltration and bone erosion were suppressed although not as dramatically as IL-1 blockade. Interestingly, staining for IL-1 in the joint was reduced with anti-IL-17 antibody treatment.

In the chronic progression of arthritis in the IL-1ra-deficient mice, IL-1 appears to drive the disease through at least two interrelated mechanisms. The primary mechanism is inflammation driven by excess IL-1 completely independent of TNF and partially independent of IL-17. A secondary mechanism is the IL-1 induced differentiation of Th17 cells. Although it is not apparent if other cytokines such as TGF-β1 are upregulated in IL-1ra deficient mice and act in concert with IL-1, clearly IL-1 plays a pivotal role. The Koenders study is in agreement with studies in autoimmune encephalomyelitis, an IL-17-dependent autoimmune disease, where disease is suppressed and IL-17 production reduced in IL-1 receptor-1-deficient mice (5). The reduced efficacy of IL-17 blockade in comparison to gene ablation of IL-17 in the IL-1ra-deficient mice may indicate that IL-17 is acting at the induction phase. Once Th17 cells are activated, IL-17 can induce the secretion of TNF and IL-1 having both additive and synergistic effects on cytokine production, neutrophil recruitment and tissue destruction in particular bone erosion (11). Thus, in the chronic phase of arthritis in IL-1ra-deficient mice, IL-1 and IL-17 form an inflammatory loop enhancing tissue damage.

It is important to point out, although several models of rodent arthritis are IL-17-dependent and considered Th17-autoimmune diseases, proteoglycan-induced arthritis (PGIA) is Th1-dependent requiring IFN-γ but not IL-17 for arthritis development. In PGIA, a deficiency in IL-17 neither inhibits arthritis, neutrophil recruitment nor bone erosion indicating that other inflammatory mediators such as IL-1, IL-6, and TNF are sufficient to induce disease (12, 13). It is clear from the rodent models of RA that very similar pathology can be induced by completely different mechanisms.

Despite evidence for IL-17 in some models of arthritis, data supporting a role for IL-17 in RA is inconclusive. Evidence can be cited for the expression of both IL-17 and IFN-γ in RA synovial fluids and in the T cell areas of RA synovial tissue (14-17). Since RA is a very a heterogeneous disease it is possible the Th1/Th17 spectrum represents different subtypes of RA. Another possibility is that Th1/Th17 cells may act at different stages of disease or synergistically to induce pathogenesis. The role of IFN-γ and IL-17 in RA remains the subject of intense research.