Rheumatology Advance Access originally published online on August 22, 2007
Rheumatology 2008 47(1):8-12; doi:10.1093/rheumatology/kem203
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REVIEWS |
Cytokines in arthritis—the ‘big numbers’ move centre stage
Division of Rheumatology, Department of Medicine, University of Cambridge.
Correspondence to: Department of Medicine, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: jshg2{at}medschl.cam.ac.uk
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Abstract |
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Abstract
IntroductionMore than 20 yrs ago, T-helper lymphocytes were divided into Th1 and Th2 subsets on the basis of their cytokine production. The pro-inflammatory Th1 subset was considered predominant in inflammatory arthritis, but evidence for this notion was incomplete, and some called into question the role of helper T cells. The identification of a novel T cell subset, Th17 cells, which appears to be critical for several forms of autoimmune inflammation, including arthritis, requires a reconsideration of arthritis pathogenesis and the role of T cells. This review deals with several of the newly described (‘big number’) cytokines which are involved in the differentiation and action of Th17 cells, and pays particular attention to the pathogenesis of spondyloarthritis because of the implication of the same cytokine networks in psoriasis and inflammatory bowel disease. The role of dendritic cells as coordinators of T cell differentiation in response to pathogen-derived signals in also emphasized.
KEY WORDS: Cytokines, Spondyloarthritis, Th17, Dendritic cells
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Introduction |
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As the list of cytokines has grown inexorably over the last three decades, there has been a temptation to assume, naively, that cytokines would be discovered in approximate order of importance, and that the later arrivals—say anything after about IL-12—could be safely assumed to be a minor player in immune and pathological processes, and given less attention. Sadly, this strategy now looks flawed; there is increasing evidence that a satisfactory account of the pathogenesis of inflammatory arthritis may mainly involve interleukins with numbers between 15 and 35, rather that the hoped for 1 to 12, although ‘ancient’ cytokines such as TNF
and TGFβ still play major parts. Although this reassessment applies to current accounts of rheumatoid arthritis (RA), developments in spondyloarthritis (SpA) are particularly exciting with respect to ‘new’ cytokines. |
A new set of cytokines relevant to SpA pathogenesis |
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In distant uncomplicated times (i.e.1986 [1]), helper T cells were divided into two subsets, Th1 cells, with IFN
as their signature cytokine, and Th2 cells, making IL-4. The former were associated with inflammatory conditions and the latter with allergy. Since arthritis is clearly an inflammatory condition, Th1 cells have been assumed to be dominant. In SpA, however, several findings are discordant with this simple notion; IL-4 and IFN-secreting T cells have been demonstrated in SpA lesions [2], and SpA patients are less able to generate IFN-producing T cells than controls [3]. These discrepancies may now be resolved by the discovery of an additional T cell subset, Th17 cells, whose signature cytokine is IL-17 [4, 5]; they also make TNF, IL-6 and IL-22 [6, 7]. These cells were first shown to play an essential role in a number of murine experimental inflammatory conditions, including experimental allergic encephalomyelitis (EAE), and collagen-induced arthritis (CIA) [8, 9]. More recently, the arthritis seen in some strains of IL-1 receptor antagonist deficient mice [10], and the arthritis in the SKG mouse, which arises in the context of defective T cell signalling [11], have both been shown to depend critically on Th17 cells. Thus, IL-17 has been shown to be critical in arthritis models with very different proximate causes, suggesting a general association between this cytokine and pathological inflammation. This naturally leads to a focus on how and why IL-17 is produced. |
The IL-17:IL-23 cytokine axis |
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Human IL-17 was first cloned in 1995 [12] and shown to be produced by T lymphocytes, mainly CD4+ T cells but also CD8+ cells; more recently
T cells, Natural Killer (NK) cells and even neutrophils have been shown to make IL-17. Unhelpfully, there are six varieties of IL-17 (one doubles as IL-25), but IL-17A and IL-17F have similar properties and are the varieties made by Th17 cells—and often referred to loosely as ‘IL-17’ [13, 14]. As an indication of IL-17's likely importance, a herpesvirus genome encodes a homologue, presumably gained by the virus from a previous evolutionary host and maintained to combat anti-viral defence mechanisms. IL-17 also seems to be one of the most ancient cytokines—there is an IL-17 receptor homologue in lampreys.
What does IL-17 do? If Th1 cells are critical in coping with intracellular bacteria, whilst Th2 cells deal with extracellular parasites, Th17 cells defend against extracellular bacteria and fungi [15]. Thus, lack of IL-17 causes mice to be more sensitive to certain bacterial infections, including Klebsiella pneumoniae [16]. In addition to responses to specific infections, the physiological function of Th17 cells is exerted mainly at interfaces with commensal bacteria, particularly gut and skin. IL-17 is an important mediator of neutrophil recruitment and function, consistent with a role against extracellular bacteria. The principal receptor for IL-17 is expressed by very many kinds of cell, so that IL-17 is not merely an ‘interleukin’ but has influences on fibroblasts and epithelial cells relevant to its role in gut and skin. IL-17 induces epithelial cells to produce C-X-C chemokines such as IL-8, which are potent attractors of neutrophils. The properties of IL-17 are also directly relevant to joint inflammation and destruction. It induces production of both IL-1 and TNF from monocytic cells, influences metalloproteinase release, and is implicated in bony erosion through induction of RANKL [17–19]. Thus, from its first description, IL-17 had properties relevant to the hypothesis that T cell-mediated responses are critical to inflammatory arthritis. Its role in Klebsiella infection and neutrophil activation also rings bells for those interested in SpA pathogenesis. The increased titres of antibodies to Klebsiella in ankylosing spondylitis (AS) remain unexplained [20], despite simplistic attempts, as is the excessive neutrophil activation which has been documented in reactive arthritis (ReA) and AS [21].
Most of our knowledge of the factors controlling differentiation of the Th17 subset is derived from studies in the mouse, and this relates mainly to CD4+ T cells. Naïve T cells differentiate into Th17 cells under the influence of a combination of TGFβ and pro-inflammatory cytokines, particularly IL-6 but also IL-1 and TNF [22–25]. The cytokines required for Th17 differentiation in humans have not been fully defined, but IL-6 and TGFβ may not be required. In mouse, differentiation requires a specific transcription factor, RORt [26], whose expression is induced by IL-6 and TGFβ acting in concert. RORt is the counterpart to the transcription factors Tbet and GATA-3, used by Th1 and Th2 cells, respectively. In the adult mouse, RORt is expressed by both β and T cells in the lamina propria of the gut, and this seems to be a major site of IL-17-producing cells, possibly induced in response to commensal bacteria [26]. Both IFN and IL-4 inhibit differentiation of Th17 cells, just as Th1 and Th2 cells were previously found to be mutually antagonistic. Following differentiation, Th17 cells require IL-23 for their survival and expansion—this applies to both mouse and humans. This explains the resistance of mice deficient in IL-23 to induction of EAE or CIA—observations originally interpreted as showing a role for IL-23 in Th17 cell differentiation.
IL-23 is a member of the IL-12 family; both IL-12 and IL-23 are heterodimers with a common p40 subunit, combined with p35 (IL-12) or p19 (IL-23). The receptors for IL-12 and IL-23 are also heterodimers with a common IL-12Rβ1 subunit combined with IL-12Rβ2 or IL-23R, respectively. Dendritic cells are the principal source of IL-12 and IL-23 and determine the differentiation of Th1 vs Th17 cells. Therefore, based on murine studies, factors which increase dendritic cells (DC) production of IL-23, when present in a micro-environment containing TGFβ and IL-6/IL-1, should result in the production of increased numbers of Th17 cells. Conversely, factors increasing IL-12 production by DC inhibit production of IL-17 [27].
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IL-27 and IL-34 |
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Two additional members of the IL-12 family have been described: IL-27, which comprises two unique subunits, p28 and EBI3 [28, 29]; and IL-34, which combines p35 and EBI3 (data presented at Keystone conference, 2007). Information on IL-34 is still unpublished, but a recent communication suggested that it is a product of regulatory T cells (Treg) rather than DC, and has an inhibitory effect on effector cells, including those which produce IL-17. There are more data available on IL-27; despite initial lack of clarity about IL-27's function, the most recent experiments in mice lacking the IL-27 receptor strongly suggest that IL-27 is also predominantly anti-inflammatory. Experimental arthritis is worsened in IL-27 receptor deficient mice, whilst treatment with IL-27 is reported to alleviate it. One anti-inflammatory action of IL-27 may be to enhance Th2 responses, and thereby inhibit both Th17 and Th1 responses.
The situation can be summarized thus: naive T cells have the possibility of differentiating into Th1, Th2, Th17 and classical Treg (other subsets also exist but are less well defined). The differentiation pathway is controlled by the cytokine environment produced by accessory cells, predominantly DC. The end result reflects alterations in the production of IL-12, IL-23 and IL-27, in concert with other cytokines (TGFβ, IL-1, IL-6, IL-4, IFN), also produced by DC or present in the T cell's environment. There is also the possibility of one T cell affecting the differentiation of another by the cytokines it produces (IFN, IL-4, IL-34).
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The involvement of ‘new’ cytokines in inflammatory bowel disease (IBD) and psoriasis (Ps) |
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In view of the clear association between SpA and inflammation of both gut and skin, the implication of IL-17 and IL-23 in the pathogenesis of IBD and Ps is of particular interest. In IBD, increased levels of IL-17 and IL-23 have been noted in mucosal lesions, and very recently a polymorphism in the IL-23R has been strongly associated with CD and some cohorts of ulcerative colitis patients [30]. IL-23 is now emerging as a critical cytokine in CD [31–33], being absolutely required in several models of colitis. The normal function of IL-23 in the gut may be to induce IL-17 production, which in turn leads to increased mucosal integrity [34]. IL-23 also inhibits IL-12 production, and in one model of colitis in which a Th1 response predominates, IL-23 deficiency results in more severe disease [35]. Thus the ratio between Th1 and Th17 T cell responses to gut bacteria may be critical; in some models excessive Th17 cells drive inflammation, whilst in colitis driven by Th1 cells, IL-23/IL-17 ameliorates disease. In either case, increased differentiation or expansion of Th17 cells in the gut could, if the same cells find their way into joint, result in IL-17-driven joint inflammation. Mutations in the IL-23 receptor which have been seen in IBD and Ps, and is now known to be associated with AS, can be envisioned to influence generation of Th17 cells.
Other gene polymorphisms associated with CD are those in CARD15/NOD2, an intracellular sensor for the bacterial product Muramyl dipeptide (MDP). These may influence the relative amounts of IL-12 and IL-23 made by DC in response to gut bacteria. Interestingly, yet another ‘new’ cytokine IL-32 has been shown to synergize with ligands for CARD15/NOD2, and the related NOD1, to induce IL-1 and IL-6 [36]. IL-32 is present in large amounts in inflamed colon and significant quantities of IL-32 have also been noted in RA [37]. In fact, IL-32 mRNA was shown to be one of the most striking genes differentially expressed by RA vs OA synoviocytes [38]. Equivalent data for SpA are not yet available. An additional regulatory mechanism in the gut is contributed by the IL-17 family member IL-25 (IL-17E), which is made by gut CD4+ and CD8+ T cells. IL-25 induces a local Th2 response which in turn inhibits both Th17 and Th1 responses [39, 40].
The pathogenesis of Ps is still debated [41], but T cells are critical. Increased levels of IL-17 and IL-23 have been reported in psoriatic lesions, and an association with the IL-23R has also been described [42]. In a mouse model, intradermal IL-23 reproduces some features of the disease [43], whilst IL-17 may contribute to neutrophil infiltration and formation of psoriatic micro-abscesses. A recent trial has reported effective responses of human psoriatic plaques to an antibody to the p40 subunit shared by IL-12 and IL-23 [44], and it may be that the major effect of this antibody is via its action on IL-23 and downstream effects on IL-17 producing cells. Again, it is possible to envision Th17 cells, generated in skin as part of an exaggerated response to skin bacteria, trafficking to joints and driving inflammation. A recent paper has also suggested a major role for IL-22 in Ps pathogenesis; IL-22 in the skin may be made by Th17 cells, or possibly by T cells responding to IL-23 alone [45]. Again IL-22 has been described in RA synovium [46], but not yet examined in SpA.
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IL-17 and IL-23 in human SpA |
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Few data are available on human disease but IL-17 protein has been demonstrated in both SpA and RA synovial fluid [47–49]. Our laboratory has detected IL-17 mRNA in synovial fluid mononuclear cells (SFMC) but not peripheral blood mononuclear cells (PBMC) of some ReA patients, whilst in patients with ReA due to Chlamydia trachomatis (CT), IL-17 mRNA and protein were induced by co-culture of PBMC from with CT-infected monocytes. IL-17 mRNA was also demonstrated in both CD4+ and CD8+ cells from patients with genitourinary CT infection responding to CT-infected monocytes, but not to mock-infected cells. An SFMC-derived CD4+ T cell clone obtained from a patient with CT-induced ReA, specific for CT heat shock protein 60, produced substantial quantities of IL-17 in response to antigen. In general, T cell clones obtained from ReA SFMC produce IFN
in response to antigen stimulation, but it has been reported that prolonged culture of Th17 cells with IL-2 in the absence of IL-23 (as occurs in T cell cloning) can result in the loss of the Th17 phenotype and substitution of a Th1 phenotype [22]. We have also examined cytokine induction in DC and noted that infection with viable CT induced IL-23 p19 mRNA, whereas killed CT and LPS only induced IL-12 p40 and p35 mRNAs. This is consistent with CT activating DC through the toll-like receptor TLR2, which favours IL-23 p19 production [50]. Co-culture of CD8+ T cells from a CT-infected subject with CT-infected DC induced IL-17 and IL-6 mRNA. Thus, in human SpA, IL-17 is present at sites of disease, and is induced in T cells by bacteria-infected DC which elaborate IL-23.
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A relationship between regulatory T cells (Treg) and Th17 cells |
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A further twist in the Th17 story is their relationship with Treg, again with the caveat that this relationship has thus far only been demonstrated in murine studies. In mice, both Th17 and Treg differentiation require the same cytokine, TGFβ, but the presence of inflammatory cytokines, including IL-6, inhibits Treg activity and differentiation, whilst favouring Th17 differentiation [51]. In fact, Treg, by producing TGFβ, can themselves enhance Th17 generation in the presence of IL-6 [22, 52].
We have recently described a novel CD8+ Treg subset in SpA with many properties in common with the well-characterized CD4+CD25+ Treg subset, but also with important differences [53]. Like CD4+ Treg, they express CD25, CTLA-4 and Foxp3, the ‘signature’ transcription factor of Treg. Their inhibition of T cell proliferation and cytokine production requires cell:cell contact and they secrete TGFβ, but not IL-10. Unlike CD4+ Treg they are not anergic and have been cloned and characterized; they recognize self-peptides on class I HLA molecules, and again unlike CD4+ Treg, produce ‘Th2’ cytokines (IL-4,-5 and -13) but do not require these for their regulatory function. These cells were generated in vitro by co-culturing CD8+ T cells with LPS-activated autologous DC, and they are much more readily isolated from SpA patients’ peripheral blood than from healthy controls.
In relation to the role of IL-17 producing T cells in SpA pathogenesis, the CD8+ Treg which we have described might enhance Th17 differentiation in two ways. Firstly, they may act through production of TGFβ, if TGFβ does in fact play a role in Th17 differentiation in humans. Secondly, since they are potent inhibitors of IFN production by Th1 cells, this would favour differentiation of Th17 cells since IFN inhibits this. In relation to their effect on differentiated Th17 cells, they may inhibit IL-17 and lL-22 production in the same way that they affect IFN production by Th1 cells, through the contact dependent mechanisms which are used by ‘natural’ CD4+ Treg. However, as noted earlier, an additional inhibitory mechanism may be provided by Treg secretion of IL-34 (EBI3/p35); this has not yet been examined in CD8+ Treg.
The ready outgrowth of CD8+ Treg from co-cultures of SpA CD8+ T cells and autologous DC as compared with healthy control, implies that there are pre-existing differences in DC of SpA patients or their CD8+ T cell population, or both. In support of this idea, activation of SpA CD8+ T cells with anti-CD3 and anti-CD28 results in predominance of IFN-secreting CD8+ T cells, whereas co-culture with DC results in IL-4 producing cells (Zhang, Jarvis and Gaston, unpublished results). Possible differences in DC from SpA patients could include a propensity to produce IL-27, rather than IL-12 or IL-23, thus inhibiting generation of IFN and IL-17-producing cells.
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Conclusions and speculations |
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The new data concerning recently described cytokines can be brought together in a model (Fig. 1) which focuses on the DC as the determinant of T-cell differentiation and expansion, and therefore of the quality of the immune responses which they induce, including those which lead to joint inflammation. ‘New’ cytokines are mainly paired with ‘old’ ones in this process:
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Th1 cells
IFN and IL-12;
Th2 cells IL-4 and IL-25;
Th17 cells TGFβ, IL-6 and IL-23;
Treg cells TGFβ;
and these differentiation processes can be down-regulated both by mutual antagonism between the T-cell subsets, and by additional cytokines such as IL-27 and IL-34.
In relation to SpA pathogenesis, the new descriptions of the processes at work in IBD and Ps point to a loss of the normal control of responses to local bacteria, and the emergence of an excessive T cell-mediated response, particularly by Th17 cells. Genes which influence this loss of control are likely to be expressed in DC and affect their output (e.g. NOD2/CARD15; IL-12p40) or responses to their output (e.g. IL-23R). It is also tempting to postulate that HLA-B27 itself will act at this level, not as a classical presenter of peptides to autoreactive CD8+ T cells, but in altering the responses of DC to bacterial products. This could be brought about either through B27's ability to induce a stress response by its inefficient folding in the endoplasmic reticulum [54], or its expression as altered forms on the cell surface (e.g. homodimers). These forms interact with receptors on other cells (e.g. KIR on NK and T cells [55]) and allow DC to receive additional signals which would alter their output.
These new findings set the research agenda in SpA. Integrating the newly discovered cytokines into a plausible model of SpA will improve our understanding of pathogenesis, and holds the best hope of identifying new therapeutic targets. Ideally these would specifically ‘reset’ aberrant immune responses rather than dealing with their downstream effector molecules—in the way that TNF inhibitors have done so strikingly in SpA.
Disclosure statement: The author has declared no conflicts of interest.
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