New insights into CD4+ T cell abnormalities in systemic sclerosis

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New insights into CD4+ T cell abnormalities in systemic sclerosis Mengguo Liua,b , Wenyu Wua , Xinfen Suna , Ji Yangb , Jinhua Xua , Wenwen Fua,* , Ming Lib,* a b

Department of Dermatology, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, PR China Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, PR China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1 October 2015 Received in revised form 31 October 2015 Accepted 7 December 2015 Available online xxx

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by vasculopathy and excessive deposition of extracellular matrix, which causes fibrosis of the skin and internal organs and eventually leads to multiorgan dysfunction. Studies have shown that CD4+ T cell activation is a key factor in the pathogenesis of scleroderma because activated T cells can release various cytokines, resulting in inflammation, microvascular damage and fibrosis. T helper cell 17 (Th17) and regulatory T (Treg) cell activities are a hallmark SSc, as Th17-type cytokines can induce both inflammation and fibrosis. More recently, several studies have reported new T cell subsets, including Th9 and Th22 cells, along with their respective cytokines in the peripheral blood, serum and skin lesions of individuals with SSc. Herein, we review recent data on various CD4+ T helper cell subsets in SSc, and discuss potential roles of these cells in promoting inflammation and fibrosis. ã 2015 Elsevier Ltd. All rights reserved.

Keywords: Systemic Sclerosis Th17 cells Treg cells Th9 cells Th22 cells

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . An autoimmune abnormality: linking vascular dysregulation to fibrosis The Treg/Th17 dichotomy in SSc . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Th9 cells and SSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Th22 cells and SSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Hypothesis: T follicular helper (Tfh) cells may be involved in SSc 2.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

Abbreviations: ACA, anti-centromere antibodies; ACR, American College of Rheumatology; ANA, anti-nuclear antibodies; ARA, anti-RNA polymerase III antibodies; CCL-20, chemokine (C–C motif) ligand 20; CXCR-4, chemokine (C-XC motif) receptor 4; dcSSc, diffuse cutaneous subset; DVSMCs, dermal vascular smooth muscle cells; ET-1, endothelin-1; EULAR, European League Against Rheumatism; ICAM-1, intercellular adhesion molecule 1; ICOS, inducible costimulator; IL-17, interleukin-17; lcSSc, limited cutaneous subset; NKT, natural killer T cell; PD-1, programmed death-1; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, sjögren syndrome; SSc, systemic sclerosis; Tfh, T follicular helper cells; TGF-b, transforming growth factor-b; Th17, T helper cell 17; TNF, tumor necrosis factor; Treg, regulatory T cell; TSK-1, tight skin-1; VCAM-1, vascular adhesion molecule 1. * Corresponding authors. E-mail addresses: [email protected] (W. Fu), [email protected] (M. Li).

Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by inflammation and vascular abnormalities of the skin and internal organs, which lead to progressive fibrosis. The incidence of SSc is approximately 20 cases per million individuals per year and its prevalence is more than 250 patients per million individuals in the USA [1]. SSc mainly affects middle-aged women, in whom the average age of onset is 45 years old; however, it can also affect men, children, and the elderly [2]. Clinically, SSc is a heterogeneous disease, and its overall progression can vary from relatively benign to rapid changes, resulting in an extremely shortened life expectancy of patients. Based on the extent of skin involvement, autoantibody titers, and the pattern of organ involvement, SSc can be divided into the following two major

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Please cite this article in press as: M. Liu, et al., New insights into CD4+ T cell abnormalities in systemic sclerosis, Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.12.002

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clinical subgroups: the limited cutaneous subset (lcSSc) and the diffuse cutaneous subset (dcSSc). Because of the heterogeneity of clinical symptoms and signs, the American College of Rheumatology (ACR) and The European League Against Rheumatism (EULAR) recently developed a new classification criteria [3,4], which will improve sensitivity and lead to earlier diagnoses. No curative treatment yet exists for SSc, and current therapies are tailored to treat its clinical manifestations and SSc-related pathologies. Currently, there are limited therapeutic options for patients with SSc, so advances in understanding the pathogenesis of this disease will be critical to the development of novel treatments. In the past two decades, one important advance has been the characterization of aberrant CD4+ Tcell activation in SSc. In this review, we analyze the role of T cells and their associated cytokines in SSc based on experimental and clinical data. 2. An autoimmune abnormality: linking vascular dysregulation to fibrosis Vascular dysregulation is an important feature of SSc, which occurs at the earliest stage and exists throughout the course of the disease. In the early stages of scleroderma, endothelial cells are activated and adhesion molecules expressed on endothelial cells promote the perivascular infiltration of inflammatory cells, which ultimately leads to endothelial dysfunction and apoptosis [5]. Activated endothelial cells can also release endothelin-1 (ET1), a potent vasoconstrictor that promotes leukocyte adhesion, vascular smooth muscle cell proliferation, and fibroblast activation [6]. Abnormal vascular reactivity associated with structural fibrosis of blood vessels can result in severe tissue hypoxia, reduced capillary blood flow, intimal hyperplasia, and outer membrane fibrosis.Ultimately, these responses can result in corresponding clinical manifestations, such as Raynaud’s phenomenon, digital ulcers, pulmonary hypertension, and hypertensive renal crisis [7,8]. Fibrosis, another clinical hallmark of SSc [9], results from increased extracellular matrix (mainly types I and III collagen) synthesis and reduced degradation, which results from the dysfunction of fibroblasts, smooth muscle cells and stromal cells. The normal connective tissue is gradually replaced by abundant extracellular matrix, leading to affected organ dysfunction and causing pathological changes. In SSc, fibroblast or vascular smooth muscle cells can be converted into myofibroblasts or synthetic vascular smooth muscle cells, which can produce collagen, transforming growth factor-b (TGF-b), CTGF, IL-6, ET-1, or monocyte chemoattractant protein-1, which can promote cell proliferation and reduce apoptosis. In addition to vasculopathy and fibrosis, autoimmune abnormalities are another hallmark of SSc that can play crucial roles in the development of these aforementioned histopathological abnormalities [10]. Recently, it has become more accepted that the pathogenesis of SSc might be described by the autoimmune abnormality theory, which can link vasculopathy and fibrosis (see Graphical abstract). Innate and adaptive immune abnormalities can be observed in SSc, and immune cells may trigger the complex molecular and biochemical changes that occur in vasculopathy and fibrosis; however, the details of the underlying mechanism remain to be elucidated. Multiple studies have provided direct evidence that immunity is involved in the pathogenesis of SSc. Histological examinations of the skin of patients with SSc during the early edematous inflammatory phase have revealed the presence of mononuclear cell infiltrates that contain gdT cells with a perivascular distribution,which precedes the development of microangiopathy and fibrosis [11–15]. Notably, fibroblasts with increased expression of type I and III procollagen mRNA can frequently be detected in areas adjacent to the infiltrating

mononuclear cells, suggesting that inflammatory cells, particularly T cells, are responsible for the altered functional fibroblast phenotype [16]. T cell infiltration is more obvious in the edema stage than in the hardening stage. CD4+ T cell infiltration is significantly increased in skin lesions and peripheral blood of patients with SSc, and most of the T cell clones in skin lesions can express the CD4 co-receptor. Recently, it has been reported that CD4+CD8+ double-positive T cells exist in skin lesions of patients with scleroderma [17]. A TCR analysis of T cells infiltrating in skin lesions of SSc patients reveal oligoclonal T cell characteristics, suggesting that T cell proliferation and clonal expansion in response to unknown specific antigens may occur [18]. Activated T cells can activate adjacent fibroblasts via direct cell–cell contact or via paracrine cytokine and chemokine production. Furthermore, autoreactive T cells may interact with B cells to promote the production of characteristic autoantibodies. Antinuclear antibodies (ANAs) are present in approximately 95% of SSc patients and typically show speckled or nucleolar patterns in stains of cells, such as for anti-topoisomerase-I antibodies, anti-centromere antibodies (ACA) and anti-RNA polymerase III antibodies (ARA). The identification of different types of ANA is important for the diagnosis, classification and prognosis of SSc, but no definite evidence that such antibodies can promote tissue fibrosis has been reported [19]. Thus, T cell abnormalities may contribute to the initiation and/or promotion of pathological process, leading to vasculopathy or fibrosis in patients with SSc. However, the causative events that may trigger an altered immune reaction remain unknown. 2.1. The Treg/Th17 dichotomy in SSc Although the classic paradigm of Th1/Th2 polarization in the pathogenesis of SSc has long been appreciated, and recent evidence indicates that Th1/Th2-type cytokines often act in collaboration with cytokines that are elaborated by newly discovered CD4+T cell subsets. Evidence for functional and numerical changes of regulatory T (Treg) cells in SSc has been obtained in several studies, but the role of Treg cells in scleroderma is controversial. Some studies have shown that the number of CD4+ CD25+FoxP3+Treg cells in skin lesions and peripheral blood of patients with SSc increase significantly [20], especially in patients in the active stage or who are seriously ill [21]. Other studies have shown that, compared with healthy subjects, the number of Treg cells in patients with SSc are reduced and show an abnormal function [22–26]. Klein et al. [27] have shown that the absolute number of Treg cells in the peripheral blood was similar in SSc patients and healthy controls. Radstake et al. [28] found an increased overall number of Treg cells in SSc patients, but these cells had a diminished functional capacity to suppress effector CD4+ T cells, which was dependent upon an unidentified serum factor. Some studies have indicated that Treg cells can be transformed into Th17 cells in the presence of IL-1b, IL-2, IL23 or TGF-b [29]. Thus, conditions may exist that both favor fewer Treg cells and more Th17 cells in SSc patients [25]. Therefore, understanding the role of Treg cells in SSc will require further study. More recently, the importance of Th17 cells and interleukin (IL)17 in the pathology of human diseases have become apparent. Th17 cells are a novel subset of CD4+ T helper cells that primarily secrete IL-17A, IL–17 F and/or IL-22, and act as anti-bacterial and anti-fungal agents [30,31]. Th17 cells and their associated signature cytokines play pivotal roles in the pathogenesis of many autoimmune-mediated inflammatory diseases, including experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, and collagen-induced arthritis [32]. Previous studies have shown that

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the differentiation factors TGF-b and either IL-6 or IL-21, the growth and stabilization factor IL-23, and the transcription factors RORgt, RORa, and STAT-3 are involved in Th17 cell development. Notably, Th17 cells have been implicated in the pathogenesis of SSc. IL-17-producingTh17 cells are significantly increased in the peripheral blood, skin lesions and lung tissues of patients with SSc [33–36]. IL-17A levels are elevated in both the early and active stages of SSc [37,38]. Recently, Radstake found that activated CD4+ T cells that show high IL-23R expression are increased in SSc patients, which was related to IL-17. They also reported that levels of IL-6, IL-23 and IL-1a are elevated in SSc patients, which can induce the production of IL-17 [39]. Additionally, IL-21 is mainly secreted by activated CD4+ T cells and natural killer (NK) T cells, which mayenhance Th17 cell-mediated inflammatory responses by inducing IL-23 receptor expression and inhibiting regulatory T cells. IL-21 can also regulate Th1/Th2 cell responses and immunoglobulin production [40]. Studies have also shown that cell adhesion molecules, such as L-selectin and intercellular adhesion molecule 1 (ICAM-1), can regulate Th2 and Th17 cell infiltration in the skin and lungs, which leads to fibrosis. By contrast, P- and E-selectin may modulate Th1 cell infiltration, thereby inhibiting fibrosis [41]. Xing et al. [34] indicated that IL17A can stimulate the expression of ICAM-1, vascular adhesion molecule 1 (VCAM-1), chemokine (C-X-C motif) receptor 4 (CXCR4) and chemokine (C–C motif) ligand 20 (CCL-20) by vascular endothelial cells and promote collagen secretion from fibroblasts, which results in endothelial inflammation and fibrosis. Recently, Liu et al. [42,43] found that serum-derived IL-17A from SSc patients can promoteproliferation, migration, collagen synthesis and secretion of SSc patient-derived dermal vascular smooth muscle cells (DVSMCs), which likely further aggravates vasculopathy in SSc. Additionally, many other experimental studies have explored in detail the significance of Th17 cell abnormalities in the pathogenesis of SSc. IL-17A participates in bleomycin-induced lung and skin fibrosis in experimental animal models of scleroderma [44]. Furthermore, IL-17A deficiency can attenuate skin thickness in tight skin-1(TSK-1/+) mice. Additionally, IL-17 can promote the secretion of TGF-b, CTGF and collagen by mouse skin fibroblasts. IL-17 can facilitate collagen production in mouse alveolar epithelial cells in a TGF-b-dependent manner, and also induce epithelial-tomesenchymal transition. In humans, IL-17 significantly promote the secretion of IL-6 and IL-8 by adult human dermal fibroblasts [45,46], and induce IL-1, IL-6, adhesion molecule and chemokine expression in human vascular endothelial cells [47]. Thus, a positive feedback loop may exist in SSc whereby IL-17 can either directly or indirectly promote the activation of fibroblasts, vascular endothelial cellsand smooth muscle cells, and in turn the cytokines secreted by these cells can enhance Th17 cell differentiation. However, the role of Th17 cells in humans and mice remains controversial. Th17 cells and IL-17A might contribute to fibrosis in rodents, while inhibiting fibrosis in humans [48]. The reason for this discrepancy remains unclear, but may be associated with interspecies differences. Thus, further studies will be needed to unravel the role of Th17 cells and the interplay between IL-17A and other Th17-type cytokines in the pathogenesis of SSc. Another outstanding question iswhether the regulation of Th17 cell function will have effects that extend beyond neutralizing IL17A activity alone. 2.2. Th9 cells and SSc Whether Th1/Th2 or Treg/Th17 imbalances represent the key culprits of SSc has remained controversial. Indeed, recent studies have shown that Th9 cells, a newly described effector T cell subset, preferentially secrete interleukin-9 (IL-9) and are likely

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involved in SSc. IL-9, which was cloned more than 20 years ago, was initially thought to be a Th2-specific cytokine [49], which was predicted to contribute to the development of allergic and autoimmune diseases, such as asthma, lung fibrosis, experimental autoimmune encephalomyelitis and SLE [49–52]. In 2008, concurrent publications by Veldhoen et al. and Dardalhon et al. reported that IL-9 could be produced exclusively by a subpopulation of Th cells that was designated “Th9 cells” [53,54]. TGF-b and IL-4 have been shown to enhance IL-9 production from activated T cells. When naive CD4+ T cells are primed in the presence of TGFb and IL-4, or when differentiated Th2 cells are cultured in TGF-b, the cells are induced to produce high levels of IL-9, but show significantly lower expression of other lineage-specific cytokines and transcription factors. The discovery of Th9 prompted a new awareness of different CD4+ T cells in autoimmune diseases. Yanaba reported that Th9 and IL-9 might be related to the pathogenesis of SSc, which is the first report of elevated serum IL9 levels in patients with SSc [55]. IL-9 levels were raised not only in patients with dcSSc, but also in those with lcSSc, and were associated with a lower prevalence of pulmonary involvement and better pulmonary function. Thus, elevated IL-9 levels may be protective against the development of pulmonary fibrosis in SSc. It has also been demonstrated that IL-9 in combination with TGFb increases the production of Th17 cells. Although serum IL17 levels are increased in patients with SSc, elevated IL-17 levels tend to correlate with a lower frequency and severity of lung fibrosis, suggesting that IL-17 production in SSc serves as a protective factor. Interestingly, IL-9 also enhances the suppressive function of regulatory T cells. Thus increased IL-9 may induce IL17 production and regulatory T cell activation, thereby inhibiting the development of pulmonary fibrosis in SSc. It has also been shown that overexpression of IL-9 enhances the recruitment of B cells in the lung in murine silica-induced pulmonary fibrosis. Further, B cell deficiency abolishes the protective effect of IL-9. Therefore, IL-9 is likely to have a protective role in the development of lung fibrosis through the recruitment of B cells. Further studies examining the contribution of IL-9 to the regulation of interstitial lung disease and other organ involvement in SSc are required. Moreover, it is essential to examine the longitudinal changes of serum IL-9 levels in patients with SSc and to assess the association with disease activity. 2.3. Th22 cells and SSc In 2009, a new subset of Th cells that predominantly secrete interleukin-22 (IL-22) was identified and called Th22 cells [56,57]. Notably, Th22 cells appear to play an important role in inflammatory and autoimmune skin disorders. For example, the frequency of IL-22+ T cells in patients with psoriasis, atopic eczema, allergic contact dermatitis, Behcet’s disease and SLE is significantly higher than that of healthy controls [58,59]. Relatively little is known about the roles of Th22 cells and IL-22 in fibrosis. Recently, compared to Th1 cells, CD4+IL-22+IL-17 IFN-g IL4 T cells have been shown to be overrepresented in tissues of patients with SSc and to be linked to active disease, and this may occur in part because IL-22 has direct pro-fibrotic properties [13]. Studies have also shown that Th22 cells are increased in skin lesions and are not involved in the skin or peripheral blood of patients with SSc [60]. Additionally, Marie-Elise et al. identified a strong association between high numbers of Th22 cells and SSc-related interstitial lung disease [13]. Brembilla NC also reported that IL-22+ T cells were over-represented in the dermis and epidermis of morphea and in the epidermis of SSc compared with healthy controls [61]. Dermal fibroblasts expressed both IL-22 receptor subunits IL-10RB and IL-22RA, expression of which was enhanced by tumor necrosis factor (TNF) and reduced by TGF-b. IL-22 induced rapid

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phosphorylation of p38 and ERK1/2 in fibroblasts, but failed to induce the synthesis of chemokines and extracellular matrix components. However, IL-22 enhanced the production of monocyte chemotactic protein 1, IL-8 and matrix metalloproteinase 1 induced by TNF. Fibroblast responses were maximal in the presence of conditioned medium from keratinocytes activated by IL-22 in conjunction with TNF. Dermal thickness was maximal in mice injected simultaneously with IL-22 and TNF. IL-22 capacitates fibroblast responses to TNF and promotes a proinflammatory fibroblast phenotype by favoring TNF-induced keratinocyte activation. These results define a novel role for keratinocytefibroblast interactions in the context of skin fibrosis.

increased total CXCR5+, CXCR5+ICOShi or CXCR5+PD1hi Tfh cells have been observed in the peripheral blood of SS patients [71]. Subsequently increases in circulating CXCR5+, ICOS+, ICOShi, CXCR5+ICOShi, CXCR5+PD1+ and CXCR5+PD1hi CD4+ T cells have been reported in patients with RA [72–74], suggesting that Tfh cells are involved in the RA disease-process. The role of Tfh cells in SSc is not yet known. Considering the similarities between Scleroderma and other connective tissue diseases, such as SLE, SS, RA and juvenile dermatomyositis, we speculate that the development of SSc may be associated with the complex regulation of Tfh cells. Further studies will be required to confirm whether Tfh cells are involved in the pathogenesis of SSc.

2.4. Hypothesis: T follicular helper (Tfh) cells may be involved in SSc

3. Summary

Tfh cells, which are characterized by chemokine (C-X-C motif) receptor 5(CXCR5) expression, production of IL-21, and increased levels of many other molecules that include programmed death-1 (PD-1), inducible costimulator (ICOS), SLAM adapter protein and IL-4, were first described more than a decade ago as CD4+ T cells that reside in B cell areas of secondary lymphoid tissues in humans [62,63]. The ability of Tfh cells to leave the T cell area and localize in the B cell follicle is facilitated by their concurrent expression of the B cell zone homing chemokine receptor CXCR5 and downregulation of the T cell zone homing chemokine receptor CCR7. Recently Tfh cells have attracted a great amount of attention for their roles in providing critical help to B cells and contributing to autoimmunity. Dysregulation of Tfh cells has been associated with the development of several autoimmune diseases, including SLE [64,65], Sjögren syndrome (SS) [66], juvenile dermatomyositis [67], and rheumatoid arthritis (RA) [68]. Choi et al. reported that the subset of circulating Tfh-like T cells, identified as CXCR5+ICOS+PD-1+, are expanded in the blood of SLE patients compared with controls. Circulating Tfh-like cells are associated with the SLE Disease Activity Index (SLEDAI) [69]. Recently, increased amounts of CXCR5+CCR6+ Th17-like and CXCR5+CXCR3 CCR6 Th2-like Tfh cells have been detected in patients with juvenile dermatomyositis [70]. Additionally, disease scores and numbers of plasmablasts (CD19+CD20 CD27+CD38hi) correlated positively with Th2 and Th17-like Tfh cells in juvenile dermatomyositis. Consistently,

Although the pathogenesis of systemic sclerosis is complex and remains incompletely understood, understanding it will help us to develop more targeted treatment options and to learn more about the mechanisms underlying this devastating disease. Accumulating evidence has revealed a key role for CD4+ T cells in SSc (Fig. 1 Table 1). Recently, many studies have focused on the newly discovered T cell subsets, including Treg, Th17, Th9, Th22 and Tfh cells. If the functional activity of various types of T cells can be fullyanalyzed and the interactions between T cells and neighboring cells can be completely clarified, such studies will provide new molecular and cellular targets for the treatment of scleroderma. (Fig. 2)

Table 1 Polarized CD4+ T cells and their iconic cytokines in SSc. CD4+ T cells

Iconic cytokines

Expression

Th1 Th2 Th17 Treg Th9 Th22 Tfh

IFN-g IL-4, IL-5, IL-13 IL-17A, IL-17F TGF-b, IL-10 IL-9 IL-22 IL-21

Decreased Increased Increased Decreased Increased Increased Unclear

Fig. 1. CD4+ T cells interaction with vascular endothelial cells and vascular smooth muscle cells in SSc. Schematic representation of the influence of polarized CD4+ T cells and their signature cytokines on vascular endothelial cells and smooth muscle cells for pro-inflammatory and pro-fibrotic properties.

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Fig. 2. Schematic conspectus of SSc pathogenesis. Patients with systemic sclerosis display autoimmunity abnormality, vasculopathy and fibrosis.

Conflict of interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, this manuscript. Acknowledgements This work was supported by grants from National Natural Science Foundation of China (No. 81573043), Medical Guide Project from Shanghai Municipal Science and Technology (No. 134119a8400) and Shanghai Natural Science Foundation of China (No. 15ZR1406500). References [1] D. Pattanaik, M. Brown, B.C. Postlethwaite, A.E. Postlethwaite, Pathogenesis of systemic sclerosis, Front. Immunol. 6 (272) (2015) . [2] T.R. Katsumoto, M.L. Whitfield, M.K. Connolly, The pathogenesis of systemic sclerosis, Annu. Rev. Pathol. 6 (2011) 509–537. [3] F. van den Hoogen, D. Khanna, J. Fransen, et al., classification criteria for systemic sclerosis: an American College of Rheumatology/European league against Rheumatism collaborative initiative, Arthritis Rheum. 65 (2013) 2737–2747. [4] F. van den Hoogen, D. Khanna, J. Fransen, et al., classification criteria for systemic sclerosis: an American College of Rheumatology/European league against rheumatism collaborative initiative, Ann. Rheum. Dis. 72 (2013) 1747–1755. [5] S. Guiducci, O. Distler, J.H. Distler, M. Matucci-Cerinic, Mechanisms of vascular damage in SSc–implications for vascular treatment strategies, Rheumatology (Oxford) 47 (Suppl. 5) (2008) v18–v20. [6] S. Motegi, E. Okada, A. Uchiyama, et al., Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis, Exp. Dermatol. 23 (2014) 664–669. [7] M. Matucci-Cerinic, B. Kahaleh, F.M. Wigley, Review: evidence that systemic sclerosis is a vascular disease, Arthritis Rheum. 65 (2013) 1953–1962. [8] N. Kavian, F. Batteux, Macro- and microvascular disease in systemic sclerosis, Vascul. Pharmacol. (2015) . [9] S. Bhattacharyya, J. Wei, J. Varga, Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities, Nat. Rev. Rheumatol. 8 (2012) 42–54. [10] R. Manno, F. Boin, Immunotherapy of systemic sclerosis, Immunotherapy 2 (2010) 863–878. [11] P. Cipriani, A. Fulminis, E. Pingiotti, et al., Resistance to apoptosis in circulating alpha/beta and gamma/delta T lymphocytes from patients with systemic sclerosis, J. Rheumatol. 33 (2006) 2003–2014. [12] A.D. Roumm, T.L. Whiteside, T.J. Medsger, G.P. Rodnan, Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations, Arthritis Rheum. 27 (1984) 645–653. [13] M.E. Truchetet, N.C. Brembilla, E. Montanari, Y. Allanore, C. Chizzolini, Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease, Arthritis Res. Ther. 13 (2011) R166.

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Please cite this article in press as: M. Liu, et al., New insights into CD4+ T cell abnormalities in systemic sclerosis, Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.12.002