Abstract
Psoriatic arthritis and spondyloarthritis (SpA) are complex immune-mediated diseases affecting peripheral and axial joints. T cells have been considered fundamental in triggering the disease and maintaining the process in the chronic phase. The recent discovery of the CD4+ Th17 lymphocyte subset and the interleukin 23/interleukin 17 axis has further contributed to the definition of unknown pathways, challenging previous models and the role of Th1/Th2 T cells in immune mediated diseases, including SpA.
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement that strongly affects the daily life of patients1. Apart from skin inflammation and peripheral or axial arthritis, the main clinical manifestations are enthesitis, dactylitis, and other extraarticular features common to the spectrum of the spondyloarthropathies (SpA), including uveitis and inflammatory bowel diseases (IBD)2. The early events in PsA pathogenesis as well as in other SpA conditions are believed to occur in predisposed subjects3 and to be mediated by T cells4 interacting with other cells such as antigen-presenting cells (APC)5. This process gives rise to the inflammatory cascade that then activates a wide range of effector mechanisms, leading ultimately to joint damage and repair mechanisms. Recently, increasing evidence has linked a new subset of T lymphocyte, Th17, according to its signature cytokine, to the pathogenesis of PsA and SpA.
INTERLEUKIN 17 AND THE Th17 SUBSET
Interleukin 17 (IL-17) is the signature cytokine of a recently described CD3+/CD4+ T lymphocyte subset, Th17. IL-17 is an inflammatory cytokine involved in host defense against bacteria, fungi, and protozoa6. IL-17 secretion by CD4 T cells was described in 19957, but only later was it determined that CD4+ T cells producing IL-17 represent a separate T cell lineage termed Th178,9, similarly to the first described Th1 and Th2 subsets. Before the definition of the Th17 subset it was believed that antigenic stimulation of naive CD4+ T cells could give rise to either Th1 lymphocytes secreting interferon γ (IFN-γ), defending against intracellular pathogens and involved in autoimmunity, or Th2 lymphocytes secreting IL-4, IL-5, IL-6, and IL-13, defending against extracellular organisms and involved in humoral immunity and allergy.
Th1 development is mainly driven by the cytokine IL-12; an initial innate immune response, possibly driven by activated natural killer (NK) cells, may activate the T-bet transcription factor through STAT1, enhancing responsiveness to IL-1210. On the other hand, Th2 development is mainly driven by the cytokine IL-4 and by activation of STAT3 and GATA-310. IL-23, together with IL-1, tumor necrosis factor (TNF)-α, and IL-6, plays a key role in polarizing naive CD4+ T cells toward the Th17 subset. The role of transforming growth factor (TGF)-ß, primarily in mice, is still under debate in humans, showing contrasting results in its ability to induce Th17 differentiation11,12. It is noteworthy that TGF-ß and IL-6 are able to induce retinoic acid orphan receptors (RORgt and RORa) in naive T lymphocytes, causing the upregulation of IL-23 receptor (IL-23R)13, thus facilitating Th17 polarization. IL-23 is part of the IL-12 family and is a dimeric molecule composed of the subunits IL-12p40 and IL-23p19, while IL-12 is composed of IL-12p35 and IL-12p40 subunits (IL-12p70). This has important implications when targeting these cytokine subunits for therapeutic purposes. Further, similarly to IL-12 and IL-23 cytokines, IL-12 and IL-23 receptors also share a common subunit. IL-23R is a heterodimeric molecule composed of IL-12Rb1 and IL-23R; on the other hand, IL-12R is composed of IL-12Rb1 in association with the IL-12Rb2 subunit. IL-23 therefore appears to be the primary cytokine involved in the amplification and differentiation of the Th17 subset and in the induction of IL-17 secretion14.
The balance between the Th17 subset and regulatory T cells (Treg) is regulated by several mechanisms: IFN-γ and IL-4 inhibit IL-17 production8,9,15, IL-2 inhibits Th17 cell differentiation by downregulating RORγδ16, and IL-27 (a cytokine belonging to the IL-12 family mainly produced by APC) inhibits IL-17 production by T cells inducing IL-10 secretion from Treg cells17. Human Th17 cells secrete IL-17A and IL-17F, but other leukocytes are able to produce IL-17. Among them, NK cells, CD8+ lymphocytes, γδ T cells, and neutrophils can produce other IL-17 family cytokines18. In the already complex inflammatory milieu, CD4+ T lymphocytes secreting IL-17 may also produce other cytokines including TNF-α, IL-619, and IL-2220. It is noteworthy for implications in the pathogenesis of psoriasis that IL-22 has been reported to stimulate epidermal hyperplasia and dermal inflammation21. The biological effects of IL-17 are diverse and directed to different cell populations, such as monocytes and macrophages, osteoblasts, fibroblasts, and endothelial and epithelial cells. IL-17 is able to induce the production of proinflammatory cytokines such as IL-6, TNF-α, IL-1ß, and IL-8, the expression of homing receptors and chemokines, colony stimulating factors, and matrix metalloprotease18.
Th17 IN PsA AND SpA
In the last decade, Th17 cells and IL-17 have been implicated in the pathogenesis of chronic arthritis conditions such as rheumatoid arthritis (RA), PsA, and SpA in general, including IBD and skin psoriasis. These diseases were previously considered Th1-mediated diseases, with IFN-γ and IL-2 playing important roles in the generation of the inflammatory cascade.
Susceptibility to both skin psoriasis and PsA is associated with alleles of the IL-12B and IL-23R genes22,23. Similarly, IL23R alleles predispose genes also to other SpA such as ankylosing spondylitis and Crohn’s disease24,25. This shared association suggests common inflammatory pathways involving IL-23R in all SpA. Further, IL23p19 and p40 (shared by IL-12p70 and IL-23 cytokines) subunits, but not IL-12p35 (only present in IL-12), are increased in lesional psoriatic skin compared to nonlesional skin26. Notably, serum levels of IL12/23 p40 subunit are significantly higher in patients with PsA compared to controls27. Given the importance of IL-23R and IL-23 stimulation for the Th17 subset, this experimental evidence suggests a primary role of the Th17 subset in PsA and SpA. This is confirmed by a randomized controlled trial by Gottlieb, et al28 that showed that treatment with human IL-12/23 p40 monoclonal antibody reduces the signs and symptoms of joint inflammation in PsA.
In RA, IL-17 and IL-23 have been found in synovial membrane, synovial fluid, and serum samples29; further, a correlation of messenger RNA expression of the receptor activator of nuclear factor-κB ligand (RANK ligand; RANKL) with IL-23 expression has been shown30. RANKL may be induced by IL-17 and also by TNF-α, and may interact with osteoclasts to activate their erosive capabilities at sites of inflammation18. This may support the concept that the IL-23/IL-17 axis takes part in the mechanisms leading to bone destruction. IBD are part of the SpA spectrum. It is therefore noteworthy that IL-17 has been found overexpressed in the sera and colon of these patients31 and that an increased number of Th17 cells were found in the gut tissue from patients with Crohn’s disease32.
Recently, Bowness and colleagues provided an explanation that links the well-known associations found in axial SpA patients with HLA-B27, and the association with IL-23R and the Th17 subset33. HLA-B27 is an heterotrimeric molecule that tends to dissociate from bound peptide and ß2-microglobulin (ß2m), giving rise to free heavy chains which aggregate in ß2m-free heavy chain homodimers (B272). Bowness, et al have shown that B272-expressing APC stimulate the survival, proliferation, and IL-17 production of KIR3DL2+ CD4+ Th-17 cells, demonstrating that this is mediated by the KIR3DL2/B272 pair interaction. The B272 responsive IL-17 producing CD4+ T cells expressed IL-23R, and were also able to produce TNF-α and/or IFN-γ. T lymphocyte with an overlapping Th17 and Th1 phenotype (plasticity) are found in SpA and may therefore be involved in the disease process.
The precise immune mechanisms that determine and drive PsA and SpA and the role of the Th17 subset need further research. In particular, the complex network of the different T cell subsets and cytokines in the inflammatory milieu of PsA and SpA (Figure 1) at an early stage as well as at established stages of disease will be fundamental to understanding the precise pathogenesis of SpA and the opportunity for treatment. Modulation of the Th17 pathway, with or without TNF-α antagonism, appears to be a promising approach in the attempt to achieve satisfactory control of disease activity and to block disease progression and damage.
Acknowledgments
The authors thank Dr. Grazia Dessole for her scientific and artistic contribution in creating Figure 1.