Elsevier

Autoimmunity Reviews

Volume 10, Issue 2, December 2010, Pages 65-73
Autoimmunity Reviews

Review
Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis

https://doi.org/10.1016/j.autrev.2010.08.003Get rights and content

Abstract

Although the pathogenesis of systemic sclerosis (SSc) remains unknown, cytokine production and release are key events in this autoimmune disease, characterized by T cell activation and auto-antibodies production leading to microvascular damage, inflammation and fibrosis. We review herein experimental and clinical data, aiming to analyze the relationship between cytokine release and SSc pathogenesis. Measurement of circulating or in situ cytokine levels provides evidence for a balance between “Th1/Th2” or “Th17/Treg” cytokines in the development of SSc. Indeed, the Th2 cytokine response, with the production of IL-4, IL-10 and TGF-β, leads to tissue fibrosis, whereas Th1 and Th17 cytokines promote inflammation in SSc patients. Thus, cytokine levels have been assessed as diagnostic or prognostic markers in SSc patients. Restoration of the Th1/Th2/Th17/Treg balance is one of the hallmarks of treatment effectiveness and development of cytokine modulators could be considered for new therapeutic approaches in SSc patients.

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

  • 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.

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”.

References (58)

  • D. Pohlers et al.

    TGF-[beta] and fibrosis in different organs – molecular pathway imprints, Biochimica et Biophysica Acta (BBA)

    Mol Basis Dis

    (2009)
  • F. Verrecchia et al.

    Identification of novel TGF-β/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach

    J Biol Chem

    (2001)
  • Y.S. Gu et al.

    The immunobiology of systemic sclerosiS

    Semin Arthritis Rheum

    (2008)
  • N. Poulalhon et al.

    Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent?

    J Biol Chem

    (2006)
  • V.D. Steen et al.

    Severe organ involvement in systemic sclerosis with diffuse scleroderma

    Arthritis Rheum

    (2000)
  • B. Ranque et al.

    Geoepidemiology of systemic sclerosis

    Autoimmun Rev

    (2010)
  • S. Akimoto et al.

    HLA-DRB1 and DQB1 genes in anticentromere antibody positive patients with SSc and primary biliary cirrhosis

    Ann Rheum Dis

    (2001)
  • A. Milano et al.

    Molecular subsets in the gene expression signatures of scleroderma skin

    PLoS ONE

    (2008)
  • G.F. Mora

    Systemic sclerosis: environmental factors

    J Rheumatol

    (2009)
  • A. Gabrielli et al.

    Scleroderma

    (2009)
  • F. Verrecchia et al.

    Transforming growth factor-beta and fibrosis

    World J Gastroenterol

    (2007)
  • E. Bettelli et al.

    Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

    Nature

    (2006)
  • K. Yokota et al.

    Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis

    J Rheumatol

    (2006)
  • H. Jiang et al.

    Regulation of immune responses by T cells

    N Engl J Med

    (2006)
  • F. Fossiez et al.

    T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines

    J Exp Med

    (1996)
  • K. Kurasawa et al.

    Increased interleukin-17 production in patients with systemic sclerosis

    Arthritis Rheum

    (2000)
  • A.L. Wurster et al.

    Interleukin 21 Is a T Helper (Th) Cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon {gamma}-producing Th1 cells

    J Exp Med

    (2002)
  • S.K. Agarwal et al.

    Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis

    J Rheumatol

    (2009)
  • T.R. Radstake et al.

    The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes

    PLoS ONE

    (2009)
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