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Role of IL-13 in systemic sclerosis
Cytokine 56 (2011) 544–549
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Review Article
Role of IL-13 in systemic sclerosis Patrizia Fuschiotti ⇑ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Article history: Received 27 July 2011 Accepted 19 August 2011 Available online 14 September 2011 Keywords: IL-13 Human GATA-3 Autoimmunity Fibrosis
a b s t r a c t Systemic sclerosis (SSc) has the highest fatality rate among connective tissue diseases and is characterized by vascular damage, inflammation and fibrosis. Currently, no therapy has proven effective in modifying the course of SSc, a reflection of its complex pathogenesis. T cell-derived cytokines have been implicated in the induction of fibrosis. The role of the pro-fibrotic type 2 cytokine IL-13 and its regulation appear to be important in the pathogenesis of SSc and other fibrotic disorders. Recent work has shown that dysregulated production of IL-13 by effector CD8+ T cells is critical for predisposing patients to more severe forms of cutaneous disease and that this dysregulation is associated with defects in the molecular control of IL-13 production, such as increased expression of the transcription factor GATA-3. Silencing of GATA-3 with siRNA significantly reduces IL-13 production by CD8+ T cells from patients. We review these new insights into SSc pathogenesis that will enable establishment of highly relevant biomarkers of immune dysfunction in patients predisposed to develop SSc and open new possibilities for development of more specific diagnosis and treatment. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Systemic sclerosis (SSc, scleroderma) is an autoimmune disease of connective tissue characterized by vascular damage, inflammation and progressive fibrosis of the skin and other internal organs [1]. The etiology of SSc is unknown, although the role of genetic influences, environmental insults and abnormal immune function are subjects of active investigation [2,3]. Its prevalence is estimated as 276/1,000,000 in the USA [4] and susceptibility to the disease differs according to sex, age, and race [4]. SSc manifests a striking female predominance with a sex ratio ranging between 4 and 14:1 [4,5], occurring most frequently in the fourth and fifth decades of life, and more frequently in African–Americans than Caucasians [4]. The spectrum of clinical manifestations of SSc is wide and the overall rate of progression is variable. Two clinical subsets of SSc, namely the limited and the diffuse cutaneous forms, have been described on the basis of skin fibrosis extent, autoantibody profile and patterns of organ involvement [6]. The most prominent clinical features of the limited form (lcSSc) are vascular manifestations, with generally mild skin and internal organ fibrosis. In contrast, diffuse cutaneous (dc) SSc patients have rapidly progressive fibrosis of the skin, lungs, and other internal organs. SSc is associated with significant morbidity and mortality with the diffuse form of the disease having a worse prognosis (as high as 50% mortality at 10 years) than the limited form [7]. Tissue fibrosis is the most prominent clinical manifestation of SSc and is believed to result from fibroblast activation and ⇑ Tel.: +1 412 648 8804; fax: +1 412 383 8098. E-mail address: [email protected] 1043-4666/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2011.08.030
overproduction of extracellular matrix (ECM) components, mainly type I collagen [8]. This activation is likely a response to inflammation, autoimmune attack and vascular damage. T cells have been shown to play a significant role in the pathogenesis of SSc [2]. Activated a/b and c/d T lymphocytes [9–12] dominate the inflammatory infiltrates in the skin and involved tissues [9,10] of patients affected by SSc, show signs of antigen-driven expansion [12] and precede the development of vasculopathy and fibrosis [9,10,13]. Several studies suggest that activated T cells trigger activation of adjacent fibroblasts in such tissue by direct contact and by paracrine action of secreted cytokines [15–18] and provide important stimuli that drive collagen synthesis and fibrosis [14]. T cells were also found to be necessary for the production of anti-topoisomerase I antibodies in SSc [19], which together with other auto-antibodies, are a characteristic feature of patients with the disease [20]. Taken together, these observations strongly implicate T cells as initiators of SSc, that, in response to antigen-driven stimulation, produce cytokines that promote autoantibody secretion and overproduction of collagen by fibroblasts which results in excessive fibrosis [8]. 2. T cell-derived cytokines in systemic sclerosis Multiple studies have shown that T cell-derived cytokines are implicated in the inflammatory and fibrotic processes of SSc. Abnormal levels of these cytokines have been found in the serum and tissue of SSc patients. Th1 and Th17 cytokines are believed to be involved in the inflammatory processes in the early stage of the disease [21], whereas Th2 cytokines are considered pro-fibrotic [22]. These latter cytokines may be involved at several levels
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of the fibrotic process, since they activate the fibroblasts that differentiate into myofibroblasts, and they stimulate extracellular matrix (ECM) production and deposition [22]. Aberrant levels of specific T cell-derived cytokine in the serum of SSc patients have been considered as a potential diagnostic and prognostic marker for SSc progression and organ involvement. In general, analyses show increased levels of TGF-b [23], TNF-a [24], IL-6, IL-10 [25], IL-17 [26], IL-4 and IL-13 [27] in the serum of SSc patients as compared with healthy volunteers. However, conflicting results are also reported, likely reflecting patient heterogeneity, the complex network of cytokine interactions as well as the contribution of other cell types, including macrophages, neutrophils, mast cells, endothelial cells, and fibroblasts. Careful control of these factors will aid in understanding the precise roles of dysregulated serum cytokines in disease progression. Immunohistochemistry and gene expression studies have identified numerous T cell-derived cytokines that are selectively expressed in affected SSc tissues and are therefore believed to participate in SSc pathogenesis [23,28–31]. The role of TGF-b, a potent regulator of extracellular matrix formation and tissue remodeling [32], has been widely studied in SSc and its expression in situ is considered an important marker of skin and lung involvement during the early stage of SSc and subsequently of fibrotic extent [33,34]. Similarly, IL-4, IL-17 and IL-33 expression in the skin [21] and lung [35,36] of SSc patients has also been associated with the extent of fibrosis. Furthermore, other studies demonstrated increased in situ mRNA expression of IFN-a [37], IL-17 [26] and IL-21 [38] in SSc skin compared to healthy controls. Purified peripheral blood T-cell subsets from SSc patients were also found to produce abnormal levels of specific cytokines [2]. Indeed, a predominant pro-fibrotic type 2 cytokine profile [2,3], characterized by increased frequency of IL-4, IL-5 and IL-13-producing a/b T cells was observed in both CD4+ and CD8+ populations [39,40]. Despite this evidence, some results support Th1 activation [41] or a mixed type 1 and type 2 cytokine phenotype in SSc [17,42,43]. Similarly, we found that peripheral blood effector CD8+ T cells from SSc patients produce high levels of IL-13 while maintaining normal production of IFN-c, and potentially contributing to the development of sustained pro-fibrotic and inflammatory autoimmune responses [44]. This abnormality correlates with the extent of skin fibrosis, being more pronounced in SSc patients with dcSSc compared to lcSSc involvement [44]. Animal studies provide support for the role of a polarized immune response in the pathogenesis of fibrosis. Transcriptome analysis in animal models of inflammation has shown that genes involved in wound healing and fibrosis are associated with Th2 polarized responses [45,46] and IL-13 was shown to have an important role in the mouse model of bleomycin-induced fibrosis [47,48]. We will focus on IL-13 in the process of SSc pathogenesis for the reminder of this review.
3. IL-13 effector functions IL-13 is an immunoregulatory cytokine predominantly secreted by activated Th2 cells. IL-13 shares some functions with IL-4 and both play pivotal roles in the regulation of type 2 cytokine-mediated immune responses and as a counter-regulatory system for the type 1 immune response [49–51]. IL-13 binds to two primary receptor chains, IL-13Ra1 and IL-13Ra2 [52,53]. IL-13Ra1 is the functional IL-13 receptor that also recognizes IL-4, thus accounting for the functional overlap between the two cytokines [54]. Although it was thought that IL-13 was functionally redundant with IL-4, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrated that IL-13 possesses several unique effector functions that distinguish it from IL-4. The availability of both cytokines and the particular receptor
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combinations expressed on responding cells likely dictates the overall importance of IL-4 versus IL-13 in specific biological settings. IL-13 binds the IL-13Ra2 receptor with high affinity and specificity [55]. However, IL-13Ra2 is generally considered to be a decoy receptor for IL-13 since it has a short cytoplasmic tail, which is devoid of signaling activity [56]. IL-13Ra2 is believed to regulate IL-13 function by limiting its bioavailability and retarding signaling via IL-13Ra1 [57]. In vivo observations also suggest that IL-13Ra2 operates as a decoy receptor. Treating S. mansoni–infected mice with a soluble IL-13Ra2 fusion protein ameliorates fibrosis by binding IL-13 and preventing signaling [56]. Moreover, IL-13Ra2 knockout mice develop more severe liver fibrosis in the chronic phase of the disease apparently because the decoy receptor cannot sequester IL-13 [58]. IL-13 mediates a variety of different effects on various cell types including B cells, monocytes, natural killer cells, endothelial cells, and fibroblasts, but not T cells. Therefore, unlike IL-4, IL-13 does not have a direct effect on T cell priming. IL-13 may contribute to or perpetuate the type 2 response via several pathways, such as by inducing the expression of Th2-attracting chemokines [59], namely CCL17 (TARC) and CCL22 (MDC) [59]. Furthermore, it appears to promote its own production via regulation of several mediators, including adenosine and histamine, which in turn stimulate cells such as eosinophils, mast cells, basophils and smooth muscle cells to produce more IL-13. IL-13 mediates a diverse array of biological activities including regulation of gastrointestinal parasite expulsion, airway hyperresponsiveness (AHR), allergic inflammation, tissue eosinophilia, mastocytosis, IgE antibody production, goblet cell hyperplasia, tumor cell growth, intracellular parasitism, tissue remodeling, and fibrosis. As such, IL-13 plays a major role in various inflammatory diseases including cancer, asthma, allergy, parasitic infections and fibrosis [55].
4. IL-13 in the pathogenesis of SSc IL-13 is involved in the pathogenesis of many fibrotic diseases [22], including SSc, and appears to be necessary in the effector phase of inflammation and fibrosis. The profibrotic activities of IL-13 involve both direct fibroblast activation as well as indirect mechanisms due to stimulation of TGF-b [22], whereas the maintenance of the type-2 immune response and the activation of proinflammatory mediators are important contributors to the chronic nature of fibrotic disorders (Fig. 1). IL-13 stimulates macrophages to produce TGF-b by several distinct mechanisms, including the production of latent TGF-b and up-regulation of MMPs that cleave the LAP-TGF-b complex [60,61] as well as via an IL-13Ra2 signaling pathway. In fact, despite IL-13Ra2 being considered nonfunctional and only acting as a decoy receptor for IL-13, recent studies have shown that signaling is possible through IL-13Ra2 and that during prolonged inflammation, in the presence of TNF-a, this pathway leads to production of TGF-b by macrophages and, ultimately, fibrosis in various experimental inflammatory states [62,63]. Interestingly, a significant association between IL-13Ra2 gene polymorphisms and susceptibility to SSc has been found in a French cohort of Caucasian population [64]. The importance of IL-13 in SSc is supported by recent work from us [44] and other investigators [48,65,66]. We found that peripheral blood effector CD8+ T cells from SSc patients demonstrate a shift toward a type 2 phenotype characterized by up-regulation of IL-13, which correlates with the extent of skin fibrosis. Although IL-13 was previously associated with SSc through the observation of higher serum levels [27,67], we were able for the first time to associate dysregulated IL-13 production with a specific cell type in the peripheral blood of SSc patients and, furthermore, to suggest a direct role of this effector CD8+ T cell type in the pathogenesis of SSc
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Fig. 1. IL-13 in the pathogenesis of SSc. IL-13 is produced by type 2 cytokine-producing cells and participates in SSc pathogenesis by several different mechanisms as described below. (a) IL-13 binding to the IL-13Ra1 on fibroblasts induces their activation, differentiation into myofibroblasts, increased ECM deposition, and fibrosis; (b) IL-13 indirectly induces fibrosis by activating macrophages that produce TGF-b; (c) IL-13 contributes to SSc pathogenesis by regulating the activity of several other cell types such as smooth muscle cells, endothelium, epithelial and mucus-producing cells [57,109–111]; (d) B cells are activated by IL-13 and induced to differentiate into autoantibodyproducing cells [112,113].
[44,68]. Most studies to date have focused on CD4+ T cells because of the strong MHC class II HLA association with certain forms of the disease and the presence of distinct and specific autoantibodies [69,70]. Consequently, little is known of the role of CD8+ T cells in SSc. We found that CD4+ T cells from SSc patients show a lower and more variable level of IL-13 production compared to CD8+ T cells [44,68], suggesting that dysregulated IL-13 production is more a feature of CD8+ rather than CD4+ T cells in SSc. IL-13 dysregulation by SSc CD8+ T cells was found to be independent of disease duration and autoantibody expression but rather appears to be an intrinsic characteristic of SSc patients and predisposes them to more severe forms of scleroderma. Genetic studies implicate polymorphisms in the genes for IL-13 [65] and IL-13Ra2 [64] in increased susceptibility to SSc. Several single nucleotide polymorphisms in the IL-13 gene have been identified [71,72] and some of them have been associated with asthma and other atopic diseases in ethnically distinct populations [73]. Among these polymorphisms, the single nucleotide polymorphism (C to T exchange) in the promoter of the IL-13 gene immediately adjacent to the consensus NFAT site at position 1055, 13rs1800925C/T (IL-13-1055), has been reported to be associated with SSc in a cohort of Caucasian population [65] as well as with asthma [74] and also confers resistance to infection by Schistosoma haematobium in humans [75]. Interestingly, the IL-13-1055 TT genotype in allergic asthma correlates with altered regulation of IL-13 production and distinct patterns of DNA–protein interactions at the IL-13 promoter [74,76]. Thus, these findings support the hypothesis that defects in the molecular control of IL-13 production are likely to be an important factor in the pathogenesis of SSc and highlights mechanistic pathways that may link genetic variation in IL-13 and SSc. 5. Mechanisms of IL-13 regulation in SSc Transcriptional regulation of IL-13 has not been extensively studied. The regulation of IL-13 gene expression is coordinated with that of other Th2 cytokines, in part as a result of chromatin
remodeling at the Th2 locus [77,78]. Transcription factors such as STAT-6 and GATA-3 are essential for the establishment of the Th2 differentiation program [79–81]. In sharp contrast to IL-4 gene transcription, which is known to be regulated by the binding of numerous enhancing and repressing trans-acting factors to a complex proximal promoter [82–84], relatively few factors have been shown to regulate IL-13 transcription. GATA-3 is recognized to be the most important factor regulating IL-13 gene expression [81,85–88]. Kishikawa et al. recently reported that GATA-3 was able to activate the proximal IL-13 promoter and identified a putative GATA-3 binding site contained therein [89]. Upon IL-4 binding to its receptor, GATA-3 is induced through the action of STAT-6. GATA-3 regulates IL-13 expression not only at the transcription level, such as by directly binding to its promoter, but also by its involvement in the remodeling of the chromatin structure and opening the IL-4 locus. Furthermore, GATA-3 augments its own expression by a positive feedback autoregulation [87,90]. In a recent study [91], we found that defects in the molecular control of IL-13 production are likely to play an important role in the pathogenesis of diffuse cutaneous SSc [91]. We demonstrated that patient naïve peripheral blood CD8+ T cells are defective in polarizing and down-regulating their IL-13 production when cultured in type 1 conditions while maintaining adequate levels of IFN-c production. Furthermore, we observed that freshly isolated naïve CD8+ T cells from SSc patients express significantly higher levels of GATA-3 compared to controls, likely caused by an intrinsic defect in CD8+ T cells from SSc patients rather than an abnormality secondary to an ongoing immune response. This increase correlated with IL-13 production and disease severity. In addition, higher GATA-3+ cell frequencies were found in SSc patients with early, active inflammatory-fibrotic skin disease compared to those with inactive late stage skin disease. Transcriptional profiling of peripheral blood cells from early SSc patients also demonstrated upregulation of GATA-3 expression [92]. Silencing of GATA-3 with siRNA significantly reduced GATA-3 and IL-13, but not IFN-c levels in CD8+ T cells from SSc patients, further demonstrating a role for GATA-3 in regulating IL-13 expression [91].
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Several studies indicate that multiple factors control GATA-3 expression and function [93]. The Th1-specific transcription factor T-bet induces IFN-c production [94–96] and inhibits Th2 cytokines, including IL-13 [97,98], by antagonizing GATA-3 expression and/or function [99]. The mutually exclusive expression of T-bet and GATA-3 is believed to determine Th1/Th2 polarization [50]. We found that peripheral blood CD8+ T cells from SSc patients and normal donors express similar levels of IFN-c and T-bet [91]. However, SSc Tc1 cells failed to down-modulate GATA-3 expression while maintaining high levels of T-bet expression, suggesting that T-bet does not exert its regulatory, down-modulating activity on GATA-3, either because the interactions between these two factors are defective or because GATA-3 is present in excessive amounts in SSc patients. Interestingly, a recent report indicated that T-bet polymorphisms are associated with increased risk of SSc [100]. GATA-3 dysregulation could also result by excessive IL-4 production and STAT-6 activation [79]. Indeed, we found higher levels of STAT-6 phosphorylation in freshly isolated total CD8+ T cells from SSc patients compared to normal controls. Previous studies have shown increased levels of IL-4 in the serum of SSc patients [101]. While it appears from our studies that CD4 and/or CD8 T cells are the source of IL-4 in SSc patients, other cells such as basophiles and mast cells should be considered [102]. This initial burst of IL-4 is sufficient to stimulate GATA-3 activation, and once activated, positive feedback autoregulation maintains elevated levels of GATA-3 and is independent of both IL-4 and STAT-6 [85]. IL-33 was found to stimulate mouse bone marrow-derived eosinophils to secrete IL-13 and promote cutaneous fibrosis [66]. Previous studies have revealed an association between IL-33/ST2 and the development of fibrotic disorders, such as scleroderma and progressive systemic sclerosis [36,103]. These observations suggest that IL-13 overproduction in SSc may result from excess IL-33 stimulation. Taken together, these findings indicate that the molecular control of IL-13 production by CD8+ T cells is abnormal in SSc patients and is critical for predisposing patients to more severe forms of the disease, and that GATA-3 overexpression likely plays an important role in the pathogenesis of SSc.
6. Conclusions Systemic sclerosis has the highest case fatality rate among the connective tissue diseases. Although clinical outcomes have improved in recent years, no current therapy is able to reverse or slow the natural progression of this disease [104]. Thus, SSc is considered incurable, and so determining the mechanism(s) underlying the disease is a priority for research efforts. The profibrotic cytokine IL-13 and its regulation appear to be important in the pathogenesis of SSc and some other fibrotic disorders, and the recent work outlined above has provided new insights into potential pathogenic pathways in SSc by showing that peripheral blood effector CD8+ T cells from SSc patients demonstrate a shift toward a type 2 phenotype characterized by up-regulation of IL-13. This abnormality is critical for predisposing SSc patients to more severe forms of cutaneous disease and is associated with defects in the molecular control of IL-13 production, and abnormal expression of GATA-3 and STAT-6 nuclear proteins [91] that regulate this production. A molecular understanding of pathogenic pathways is expected to lead to the development of novel therapeutic strategies aimed at targeting these cells and the pathways governing abnormal expression of the cytokines they produce. There are currently two phase 2, double-blind, placebo-controlled randomized trials ongoing in SSc-related Interstitial Lung Disease (ILD) and Idiopathic Pulmonary Fibrosis (IPF) comparing a full human monoclonal antibody
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against human IL-13 (Clinical Trial Registration Numbers: NCT00581997 and NCT00532233). In addition, therapeutic strategies to interfere with the transcription factors that control the expression and function of IL-13 in the context of allergic diseases have been developed [105–108] and the central role played by STAT-6 and GATA-3 in regulating the expression and signaling of IL-13 suggests that they would be excellent therapeutic targets for SSc as well. Another particularly attractive strategy would be to exploit the natural suppressive mechanisms of the IL-13 decoy receptor [58]. However, a full understanding of its role in SSc needs to be detailed. As the underlying principles in normal and aberrant cytokine function become more fully understood, it is hoped that we will soon have the necessary information to develop targeted therapeutics for this devastating disorder and for other fibrotic diseases.
Acknowledgements This work has been financed in part by the Scleroderma Foundation. The author is grateful to Drs. Thomas A. Medsger Jr. and Penelope Morel for their support and on-going collaboration.
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Review Article
Role of IL-13 in systemic sclerosis Patrizia Fuschiotti ⇑ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Article history: Received 27 July 2011 Accepted 19 August 2011 Available online 14 September 2011 Keywords: IL-13 Human GATA-3 Autoimmunity Fibrosis
a b s t r a c t Systemic sclerosis (SSc) has the highest fatality rate among connective tissue diseases and is characterized by vascular damage, inflammation and fibrosis. Currently, no therapy has proven effective in modifying the course of SSc, a reflection of its complex pathogenesis. T cell-derived cytokines have been implicated in the induction of fibrosis. The role of the pro-fibrotic type 2 cytokine IL-13 and its regulation appear to be important in the pathogenesis of SSc and other fibrotic disorders. Recent work has shown that dysregulated production of IL-13 by effector CD8+ T cells is critical for predisposing patients to more severe forms of cutaneous disease and that this dysregulation is associated with defects in the molecular control of IL-13 production, such as increased expression of the transcription factor GATA-3. Silencing of GATA-3 with siRNA significantly reduces IL-13 production by CD8+ T cells from patients. We review these new insights into SSc pathogenesis that will enable establishment of highly relevant biomarkers of immune dysfunction in patients predisposed to develop SSc and open new possibilities for development of more specific diagnosis and treatment. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Systemic sclerosis (SSc, scleroderma) is an autoimmune disease of connective tissue characterized by vascular damage, inflammation and progressive fibrosis of the skin and other internal organs [1]. The etiology of SSc is unknown, although the role of genetic influences, environmental insults and abnormal immune function are subjects of active investigation [2,3]. Its prevalence is estimated as 276/1,000,000 in the USA [4] and susceptibility to the disease differs according to sex, age, and race [4]. SSc manifests a striking female predominance with a sex ratio ranging between 4 and 14:1 [4,5], occurring most frequently in the fourth and fifth decades of life, and more frequently in African–Americans than Caucasians [4]. The spectrum of clinical manifestations of SSc is wide and the overall rate of progression is variable. Two clinical subsets of SSc, namely the limited and the diffuse cutaneous forms, have been described on the basis of skin fibrosis extent, autoantibody profile and patterns of organ involvement [6]. The most prominent clinical features of the limited form (lcSSc) are vascular manifestations, with generally mild skin and internal organ fibrosis. In contrast, diffuse cutaneous (dc) SSc patients have rapidly progressive fibrosis of the skin, lungs, and other internal organs. SSc is associated with significant morbidity and mortality with the diffuse form of the disease having a worse prognosis (as high as 50% mortality at 10 years) than the limited form [7]. Tissue fibrosis is the most prominent clinical manifestation of SSc and is believed to result from fibroblast activation and ⇑ Tel.: +1 412 648 8804; fax: +1 412 383 8098. E-mail address: [email protected] 1043-4666/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2011.08.030
overproduction of extracellular matrix (ECM) components, mainly type I collagen [8]. This activation is likely a response to inflammation, autoimmune attack and vascular damage. T cells have been shown to play a significant role in the pathogenesis of SSc [2]. Activated a/b and c/d T lymphocytes [9–12] dominate the inflammatory infiltrates in the skin and involved tissues [9,10] of patients affected by SSc, show signs of antigen-driven expansion [12] and precede the development of vasculopathy and fibrosis [9,10,13]. Several studies suggest that activated T cells trigger activation of adjacent fibroblasts in such tissue by direct contact and by paracrine action of secreted cytokines [15–18] and provide important stimuli that drive collagen synthesis and fibrosis [14]. T cells were also found to be necessary for the production of anti-topoisomerase I antibodies in SSc [19], which together with other auto-antibodies, are a characteristic feature of patients with the disease [20]. Taken together, these observations strongly implicate T cells as initiators of SSc, that, in response to antigen-driven stimulation, produce cytokines that promote autoantibody secretion and overproduction of collagen by fibroblasts which results in excessive fibrosis [8]. 2. T cell-derived cytokines in systemic sclerosis Multiple studies have shown that T cell-derived cytokines are implicated in the inflammatory and fibrotic processes of SSc. Abnormal levels of these cytokines have been found in the serum and tissue of SSc patients. Th1 and Th17 cytokines are believed to be involved in the inflammatory processes in the early stage of the disease [21], whereas Th2 cytokines are considered pro-fibrotic [22]. These latter cytokines may be involved at several levels
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of the fibrotic process, since they activate the fibroblasts that differentiate into myofibroblasts, and they stimulate extracellular matrix (ECM) production and deposition [22]. Aberrant levels of specific T cell-derived cytokine in the serum of SSc patients have been considered as a potential diagnostic and prognostic marker for SSc progression and organ involvement. In general, analyses show increased levels of TGF-b [23], TNF-a [24], IL-6, IL-10 [25], IL-17 [26], IL-4 and IL-13 [27] in the serum of SSc patients as compared with healthy volunteers. However, conflicting results are also reported, likely reflecting patient heterogeneity, the complex network of cytokine interactions as well as the contribution of other cell types, including macrophages, neutrophils, mast cells, endothelial cells, and fibroblasts. Careful control of these factors will aid in understanding the precise roles of dysregulated serum cytokines in disease progression. Immunohistochemistry and gene expression studies have identified numerous T cell-derived cytokines that are selectively expressed in affected SSc tissues and are therefore believed to participate in SSc pathogenesis [23,28–31]. The role of TGF-b, a potent regulator of extracellular matrix formation and tissue remodeling [32], has been widely studied in SSc and its expression in situ is considered an important marker of skin and lung involvement during the early stage of SSc and subsequently of fibrotic extent [33,34]. Similarly, IL-4, IL-17 and IL-33 expression in the skin [21] and lung [35,36] of SSc patients has also been associated with the extent of fibrosis. Furthermore, other studies demonstrated increased in situ mRNA expression of IFN-a [37], IL-17 [26] and IL-21 [38] in SSc skin compared to healthy controls. Purified peripheral blood T-cell subsets from SSc patients were also found to produce abnormal levels of specific cytokines [2]. Indeed, a predominant pro-fibrotic type 2 cytokine profile [2,3], characterized by increased frequency of IL-4, IL-5 and IL-13-producing a/b T cells was observed in both CD4+ and CD8+ populations [39,40]. Despite this evidence, some results support Th1 activation [41] or a mixed type 1 and type 2 cytokine phenotype in SSc [17,42,43]. Similarly, we found that peripheral blood effector CD8+ T cells from SSc patients produce high levels of IL-13 while maintaining normal production of IFN-c, and potentially contributing to the development of sustained pro-fibrotic and inflammatory autoimmune responses [44]. This abnormality correlates with the extent of skin fibrosis, being more pronounced in SSc patients with dcSSc compared to lcSSc involvement [44]. Animal studies provide support for the role of a polarized immune response in the pathogenesis of fibrosis. Transcriptome analysis in animal models of inflammation has shown that genes involved in wound healing and fibrosis are associated with Th2 polarized responses [45,46] and IL-13 was shown to have an important role in the mouse model of bleomycin-induced fibrosis [47,48]. We will focus on IL-13 in the process of SSc pathogenesis for the reminder of this review.
3. IL-13 effector functions IL-13 is an immunoregulatory cytokine predominantly secreted by activated Th2 cells. IL-13 shares some functions with IL-4 and both play pivotal roles in the regulation of type 2 cytokine-mediated immune responses and as a counter-regulatory system for the type 1 immune response [49–51]. IL-13 binds to two primary receptor chains, IL-13Ra1 and IL-13Ra2 [52,53]. IL-13Ra1 is the functional IL-13 receptor that also recognizes IL-4, thus accounting for the functional overlap between the two cytokines [54]. Although it was thought that IL-13 was functionally redundant with IL-4, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrated that IL-13 possesses several unique effector functions that distinguish it from IL-4. The availability of both cytokines and the particular receptor
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combinations expressed on responding cells likely dictates the overall importance of IL-4 versus IL-13 in specific biological settings. IL-13 binds the IL-13Ra2 receptor with high affinity and specificity [55]. However, IL-13Ra2 is generally considered to be a decoy receptor for IL-13 since it has a short cytoplasmic tail, which is devoid of signaling activity [56]. IL-13Ra2 is believed to regulate IL-13 function by limiting its bioavailability and retarding signaling via IL-13Ra1 [57]. In vivo observations also suggest that IL-13Ra2 operates as a decoy receptor. Treating S. mansoni–infected mice with a soluble IL-13Ra2 fusion protein ameliorates fibrosis by binding IL-13 and preventing signaling [56]. Moreover, IL-13Ra2 knockout mice develop more severe liver fibrosis in the chronic phase of the disease apparently because the decoy receptor cannot sequester IL-13 [58]. IL-13 mediates a variety of different effects on various cell types including B cells, monocytes, natural killer cells, endothelial cells, and fibroblasts, but not T cells. Therefore, unlike IL-4, IL-13 does not have a direct effect on T cell priming. IL-13 may contribute to or perpetuate the type 2 response via several pathways, such as by inducing the expression of Th2-attracting chemokines [59], namely CCL17 (TARC) and CCL22 (MDC) [59]. Furthermore, it appears to promote its own production via regulation of several mediators, including adenosine and histamine, which in turn stimulate cells such as eosinophils, mast cells, basophils and smooth muscle cells to produce more IL-13. IL-13 mediates a diverse array of biological activities including regulation of gastrointestinal parasite expulsion, airway hyperresponsiveness (AHR), allergic inflammation, tissue eosinophilia, mastocytosis, IgE antibody production, goblet cell hyperplasia, tumor cell growth, intracellular parasitism, tissue remodeling, and fibrosis. As such, IL-13 plays a major role in various inflammatory diseases including cancer, asthma, allergy, parasitic infections and fibrosis [55].
4. IL-13 in the pathogenesis of SSc IL-13 is involved in the pathogenesis of many fibrotic diseases [22], including SSc, and appears to be necessary in the effector phase of inflammation and fibrosis. The profibrotic activities of IL-13 involve both direct fibroblast activation as well as indirect mechanisms due to stimulation of TGF-b [22], whereas the maintenance of the type-2 immune response and the activation of proinflammatory mediators are important contributors to the chronic nature of fibrotic disorders (Fig. 1). IL-13 stimulates macrophages to produce TGF-b by several distinct mechanisms, including the production of latent TGF-b and up-regulation of MMPs that cleave the LAP-TGF-b complex [60,61] as well as via an IL-13Ra2 signaling pathway. In fact, despite IL-13Ra2 being considered nonfunctional and only acting as a decoy receptor for IL-13, recent studies have shown that signaling is possible through IL-13Ra2 and that during prolonged inflammation, in the presence of TNF-a, this pathway leads to production of TGF-b by macrophages and, ultimately, fibrosis in various experimental inflammatory states [62,63]. Interestingly, a significant association between IL-13Ra2 gene polymorphisms and susceptibility to SSc has been found in a French cohort of Caucasian population [64]. The importance of IL-13 in SSc is supported by recent work from us [44] and other investigators [48,65,66]. We found that peripheral blood effector CD8+ T cells from SSc patients demonstrate a shift toward a type 2 phenotype characterized by up-regulation of IL-13, which correlates with the extent of skin fibrosis. Although IL-13 was previously associated with SSc through the observation of higher serum levels [27,67], we were able for the first time to associate dysregulated IL-13 production with a specific cell type in the peripheral blood of SSc patients and, furthermore, to suggest a direct role of this effector CD8+ T cell type in the pathogenesis of SSc
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Fig. 1. IL-13 in the pathogenesis of SSc. IL-13 is produced by type 2 cytokine-producing cells and participates in SSc pathogenesis by several different mechanisms as described below. (a) IL-13 binding to the IL-13Ra1 on fibroblasts induces their activation, differentiation into myofibroblasts, increased ECM deposition, and fibrosis; (b) IL-13 indirectly induces fibrosis by activating macrophages that produce TGF-b; (c) IL-13 contributes to SSc pathogenesis by regulating the activity of several other cell types such as smooth muscle cells, endothelium, epithelial and mucus-producing cells [57,109–111]; (d) B cells are activated by IL-13 and induced to differentiate into autoantibodyproducing cells [112,113].
[44,68]. Most studies to date have focused on CD4+ T cells because of the strong MHC class II HLA association with certain forms of the disease and the presence of distinct and specific autoantibodies [69,70]. Consequently, little is known of the role of CD8+ T cells in SSc. We found that CD4+ T cells from SSc patients show a lower and more variable level of IL-13 production compared to CD8+ T cells [44,68], suggesting that dysregulated IL-13 production is more a feature of CD8+ rather than CD4+ T cells in SSc. IL-13 dysregulation by SSc CD8+ T cells was found to be independent of disease duration and autoantibody expression but rather appears to be an intrinsic characteristic of SSc patients and predisposes them to more severe forms of scleroderma. Genetic studies implicate polymorphisms in the genes for IL-13 [65] and IL-13Ra2 [64] in increased susceptibility to SSc. Several single nucleotide polymorphisms in the IL-13 gene have been identified [71,72] and some of them have been associated with asthma and other atopic diseases in ethnically distinct populations [73]. Among these polymorphisms, the single nucleotide polymorphism (C to T exchange) in the promoter of the IL-13 gene immediately adjacent to the consensus NFAT site at position 1055, 13rs1800925C/T (IL-13-1055), has been reported to be associated with SSc in a cohort of Caucasian population [65] as well as with asthma [74] and also confers resistance to infection by Schistosoma haematobium in humans [75]. Interestingly, the IL-13-1055 TT genotype in allergic asthma correlates with altered regulation of IL-13 production and distinct patterns of DNA–protein interactions at the IL-13 promoter [74,76]. Thus, these findings support the hypothesis that defects in the molecular control of IL-13 production are likely to be an important factor in the pathogenesis of SSc and highlights mechanistic pathways that may link genetic variation in IL-13 and SSc. 5. Mechanisms of IL-13 regulation in SSc Transcriptional regulation of IL-13 has not been extensively studied. The regulation of IL-13 gene expression is coordinated with that of other Th2 cytokines, in part as a result of chromatin
remodeling at the Th2 locus [77,78]. Transcription factors such as STAT-6 and GATA-3 are essential for the establishment of the Th2 differentiation program [79–81]. In sharp contrast to IL-4 gene transcription, which is known to be regulated by the binding of numerous enhancing and repressing trans-acting factors to a complex proximal promoter [82–84], relatively few factors have been shown to regulate IL-13 transcription. GATA-3 is recognized to be the most important factor regulating IL-13 gene expression [81,85–88]. Kishikawa et al. recently reported that GATA-3 was able to activate the proximal IL-13 promoter and identified a putative GATA-3 binding site contained therein [89]. Upon IL-4 binding to its receptor, GATA-3 is induced through the action of STAT-6. GATA-3 regulates IL-13 expression not only at the transcription level, such as by directly binding to its promoter, but also by its involvement in the remodeling of the chromatin structure and opening the IL-4 locus. Furthermore, GATA-3 augments its own expression by a positive feedback autoregulation [87,90]. In a recent study [91], we found that defects in the molecular control of IL-13 production are likely to play an important role in the pathogenesis of diffuse cutaneous SSc [91]. We demonstrated that patient naïve peripheral blood CD8+ T cells are defective in polarizing and down-regulating their IL-13 production when cultured in type 1 conditions while maintaining adequate levels of IFN-c production. Furthermore, we observed that freshly isolated naïve CD8+ T cells from SSc patients express significantly higher levels of GATA-3 compared to controls, likely caused by an intrinsic defect in CD8+ T cells from SSc patients rather than an abnormality secondary to an ongoing immune response. This increase correlated with IL-13 production and disease severity. In addition, higher GATA-3+ cell frequencies were found in SSc patients with early, active inflammatory-fibrotic skin disease compared to those with inactive late stage skin disease. Transcriptional profiling of peripheral blood cells from early SSc patients also demonstrated upregulation of GATA-3 expression [92]. Silencing of GATA-3 with siRNA significantly reduced GATA-3 and IL-13, but not IFN-c levels in CD8+ T cells from SSc patients, further demonstrating a role for GATA-3 in regulating IL-13 expression [91].
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Several studies indicate that multiple factors control GATA-3 expression and function [93]. The Th1-specific transcription factor T-bet induces IFN-c production [94–96] and inhibits Th2 cytokines, including IL-13 [97,98], by antagonizing GATA-3 expression and/or function [99]. The mutually exclusive expression of T-bet and GATA-3 is believed to determine Th1/Th2 polarization [50]. We found that peripheral blood CD8+ T cells from SSc patients and normal donors express similar levels of IFN-c and T-bet [91]. However, SSc Tc1 cells failed to down-modulate GATA-3 expression while maintaining high levels of T-bet expression, suggesting that T-bet does not exert its regulatory, down-modulating activity on GATA-3, either because the interactions between these two factors are defective or because GATA-3 is present in excessive amounts in SSc patients. Interestingly, a recent report indicated that T-bet polymorphisms are associated with increased risk of SSc [100]. GATA-3 dysregulation could also result by excessive IL-4 production and STAT-6 activation [79]. Indeed, we found higher levels of STAT-6 phosphorylation in freshly isolated total CD8+ T cells from SSc patients compared to normal controls. Previous studies have shown increased levels of IL-4 in the serum of SSc patients [101]. While it appears from our studies that CD4 and/or CD8 T cells are the source of IL-4 in SSc patients, other cells such as basophiles and mast cells should be considered [102]. This initial burst of IL-4 is sufficient to stimulate GATA-3 activation, and once activated, positive feedback autoregulation maintains elevated levels of GATA-3 and is independent of both IL-4 and STAT-6 [85]. IL-33 was found to stimulate mouse bone marrow-derived eosinophils to secrete IL-13 and promote cutaneous fibrosis [66]. Previous studies have revealed an association between IL-33/ST2 and the development of fibrotic disorders, such as scleroderma and progressive systemic sclerosis [36,103]. These observations suggest that IL-13 overproduction in SSc may result from excess IL-33 stimulation. Taken together, these findings indicate that the molecular control of IL-13 production by CD8+ T cells is abnormal in SSc patients and is critical for predisposing patients to more severe forms of the disease, and that GATA-3 overexpression likely plays an important role in the pathogenesis of SSc.
6. Conclusions Systemic sclerosis has the highest case fatality rate among the connective tissue diseases. Although clinical outcomes have improved in recent years, no current therapy is able to reverse or slow the natural progression of this disease [104]. Thus, SSc is considered incurable, and so determining the mechanism(s) underlying the disease is a priority for research efforts. The profibrotic cytokine IL-13 and its regulation appear to be important in the pathogenesis of SSc and some other fibrotic disorders, and the recent work outlined above has provided new insights into potential pathogenic pathways in SSc by showing that peripheral blood effector CD8+ T cells from SSc patients demonstrate a shift toward a type 2 phenotype characterized by up-regulation of IL-13. This abnormality is critical for predisposing SSc patients to more severe forms of cutaneous disease and is associated with defects in the molecular control of IL-13 production, and abnormal expression of GATA-3 and STAT-6 nuclear proteins [91] that regulate this production. A molecular understanding of pathogenic pathways is expected to lead to the development of novel therapeutic strategies aimed at targeting these cells and the pathways governing abnormal expression of the cytokines they produce. There are currently two phase 2, double-blind, placebo-controlled randomized trials ongoing in SSc-related Interstitial Lung Disease (ILD) and Idiopathic Pulmonary Fibrosis (IPF) comparing a full human monoclonal antibody
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against human IL-13 (Clinical Trial Registration Numbers: NCT00581997 and NCT00532233). In addition, therapeutic strategies to interfere with the transcription factors that control the expression and function of IL-13 in the context of allergic diseases have been developed [105–108] and the central role played by STAT-6 and GATA-3 in regulating the expression and signaling of IL-13 suggests that they would be excellent therapeutic targets for SSc as well. Another particularly attractive strategy would be to exploit the natural suppressive mechanisms of the IL-13 decoy receptor [58]. However, a full understanding of its role in SSc needs to be detailed. As the underlying principles in normal and aberrant cytokine function become more fully understood, it is hoped that we will soon have the necessary information to develop targeted therapeutics for this devastating disorder and for other fibrotic diseases.
Acknowledgements This work has been financed in part by the Scleroderma Foundation. The author is grateful to Drs. Thomas A. Medsger Jr. and Penelope Morel for their support and on-going collaboration.
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