ReviewRelationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis
Graphical Abstract
Research Highlights
► The balance between “Th1/Th2” or “Th17/Treg” cytokines is closely involved in the development of SSc. ► Several correlations have been shown between circulating or in situ cytokine levels and SSc severity, as assessed by the extent of skin fibrosis and organ involvement. ► Restoration of the Th1/Th2/Th17/Treg cytokine balance could be considered as a potential target while designing the therapeutic strategies.
Introduction
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations, progressive fibrosis of the skin and internal organs, as well as autoantibody production. Raynaud phenomenon due to vascular abnormalities is one of the hallmarks of the disease, but clinical features can be heterogeneous. Indeed, skin and organ manifestations of SSc can be slowly or rapidly progressive, leading to chronically disabling or fatal issues depending of patients. Two clinical subsets of SSc, namely the limited and the diffuse cutaneous forms, have been described contingent on fibrosis extent, autoantibody profile and patterns of organ involvement. The limited form, with slow progression, predominantly affects the skin distal to the elbows and knees, and is usually associated with anti-centromere antibodies. The diffuse form, with more rapid and generalized skin involvement, is characterized by earlier onset of internal organ (lung, heart, gastrointestinal tract and kidneys) involvement and frequently associated with anti-nuclear antibodies, such as anti-topoisomerase I (Scl-70) and anti-RNA polymerase III antibodies (ARA) [1], [2]. Rapidly progressive diffuse SSc, within the first 3 to 5 years after disease onset has a 35% to 45% survival rate, depending on the severity of major organs' involvement. The overall life expectancy in SSc patients, within 10 years after diagnosis, is 72 ± 8% with some improvement during the last years [3], [4].
Although the exact pathophysiology of SSc is still unknown, both antigen stimulation and genetic susceptibility may contribute to the autoimmunity process, with consequent B-cell and T-cell activation. Genetic associations have been observed between HLA types and autoantibody profiles in SSc patients [5]. Several genome-wide screening studies identified specific nucleotide polymorphisms (SNPs) in relevant genes related to SSc disease, such as genes coding for : vasomotor regulatory factors, B-cell markers, chemokines and chemokine receptors, cytokines (interleukin IL-1α, IL-4, tumor necrosis factor-α (TNF-α)), growth factors and their respective receptors (connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β)), extracellular matrix (ECM) proteins, CD247, IRF5, and STAT-4 [6]. More recently, use of microarray technology showed significant differences of gene patterns in skin biopsies from dSSc and lSSc patients, which also differed from normal controls [7]. In addition to this genetic background, environmental factors responsible for disease onset and progression have been identified such as exposure to various organic solvents and toxins [4]. The role of infectious agents and oxidative stress has also been questioned [8], [9]. Whatever the original stimulus, endothelial vascular damage leads to consequent activation of the immune response with various cytokine release, auto-antibody production, fibroblast activation and enhanced collagen synthesis [10], [11] (Fig. 1). Specifically, fibroblast activation by pro-fibrotic cytokines, such as TGF-β and CTGF, play a central role in SSc pathogenesis [11], [12]. Many other cell types are involved in the immune response activation, as shown by early T lymphocyte infiltrates in SSc skin and pulmonary specimen, B lymphocytes auto-antibody production, notably anticentromere and antitopoisomerase-I, presence of monocytes, macrophages and mast cells or altered endothelial cells, which all contribute to large amount of cytokine release and promote inflammation and fibrosis. We therefore aim to focus on the release of various cytokines and growth factors as specific pathogenic mediators of SSc. In this review, we highlight the interest of cytokine measurements to help for evaluation of SSc onset and development. T cell targeted strategy and treatment aiming to restore the Th1/Th2/Th17/Treg cytokine balance as a new therapeutic strategy.
Section snippets
Cytokines and functions
Originally, the cytokines were isolated and defined as several extracellular proteins, enabling interactions and communications between the various cell types involved in the immune response. Today, the word “cytokines” encompasses several proteins and peptides, all acting as humoral mediators during the immune response. Thus, cytokines modulate functional activities of cells or tissues during normal or pathological conditions. Contrary to hormones, cytokines act locally as autocrine, paracrine
Cytokine involvement in systemic sclerosis
In SSc, Th1 cytokines are known to be «inflammatory», whereas Th2 cytokines are «profibrotic». Th2 lymphocyte infiltration is observed in early stages of SSc [34]. These lymphocytes release mediators that are involved in the extracellular matrix remodeling by stimulating collagen production. Th2 «profibrotic» cytokines can be involved at several levels since they activate the fibroblast and their differentiation into myofibroblasts, and stimulate ECM production, leading to fibrosis. Fibroblasts
T-cell-targeted therapy with cytokines modulation and novel therapeutic strategies
Recently, significant advances have been made in SSc therapies, in particular with regard to the prevention of renal crisis, pulmonary hypertension and oesophageal involvement. However, despite widespread use of corticosteroids and immunosuppressive agents in these patients, no immunosuppressive or antifibrotic therapy has yet been shown to be significantly effective. All these treatments target the global immune response: corticosteroids inhibit cytokine production by macrophages (IL-1 and
Conclusion
In conclusion, measurement of circulating or in situ cytokine levels might provide further evidence for a balance between “Th1/Th2” or “Th17/Treg” cytokines in the onset and development of SSc. Thus, cytokine levels contribute to the evaluation of SSc patients, although no straightforward single correlation can be established between one cytokine and a clinical parameter. Nonetheless, cytokines levels do correlate with the extent of fibrosis, both in limited and in diffuse cutaneous SSc, and
Take-home messages
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The balance between ‘‘Th1/Th2’’ or ‘‘Th17/Treg’’ cytokines is closely involved in the development of SSc.
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Several correlations have been shown between circulating or in situ cytokine levels and SSc severity, as assessed by the extent of skin fibrosis and organ involvement.
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Restoration of the Th1/Th2/Th17/Treg cytokine balance could be considered as a potential target while designing the therapeutic strategies.
Acknowledgements
This work was supported by INSERM, the Association des Sclérodermiques de France (ASF, www.slerodermique.com), the Groupe Français de Recherche sur la Sclérodermie (GFRS, www.sclerodermie.org) and SRD “Société de Recherche en Dermatologie”.
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2018, Immunology LettersCitation Excerpt :Furthermore, the innate immunity seems to play an important role in early stages of the disease through the activation of NK/NKT-like cells [3]. Several studies have reported alterations in serum cytokine levels in SSc patients, with inconclusive results [1,4–7]. These discrepant results are explained by several aspects, including heterogeneity within SSc population, differences in disease duration, influence of systemic treatment, sample size, and various quantification methods used.