Immunobiology of systemic sclerosis
The Immunobiology of Systemic Sclerosis

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Objectives

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by vascular damage, autoimmunity, and excessive collagen deposition. Despite advances in disease-specific treatment of other rheumatologic diseases, disease-targeted treatment in SSc continues to be elusive. In this review, our goal was to place the contemporary immunobiology of SSc in the perspective of clinical medicine.

Methods

We performed a PubMed search for the period from 1989 to 2007, using the keyword, “systemic sclerosis,” resulting in a total of 9099 publications, including 1252 reviews. Articles were then selected based on their discussion of recent advances in the elusive pathogenesis of SSc. A final total of 259 articles were chosen for the review.

Results

The SSc hallmarks of vascular damage, immunologic activation, and collagen deposition can be traced to 4 major factors: T-cells, fibroblasts, B-cells, and cytokines/chemokines. T-cells are a major component of the infiltrate in skin and lung, exhibiting increased expression of activation markers and showing signs of antigen-driven expansion. Preliminary data indicate that induction of oral tolerance with collagen, a target of SSc T-cell responses, is associated with clinical benefits. Although this suggests that T-cells participate in the pathogenesis of SSc, their precise role and antigen specificity largely remain to be elucidated. Defective numbers and functions of certain T-cell subsets, such as natural killer and γδ T-cells, may be involved in the failure to maintain tolerance. Other data suggest that γδ T-cells may themselves be effector cells in endothelial cell cytotoxicity. There are several lines of evidence for a pathogenic role of B-cells in SSc, in particular, through the production of autoantibodies. Antibody-dependent cell-mediated cytotoxicity is a primary pathogenic event in an animal model of SSc and is likely to be involved in human SSc. Nonetheless, there is as yet no convincing evidence for the pathogenicity of SSc-specific antibodies. SSc fibroblasts exhibit a specific phenotype characterized not only by excessive collagen production but also by increased responsiveness to and production of cytokines and chemokines. This phenotype is induced by a complex network of cytokines and chemokines but appears to be maintained in the absence of exogenous stimuli via the autocrine production of some of these factors by SSc fibroblasts themselves, particularly transforming growth factor, platelet-derived growth factor, monocyte chemoattractant protein 1, and interleukin-1.

Conclusions

Significant variations in laboratory data among patients suggest that the pathology reflects a heterogeneous disease. Nonetheless, the possibility of achieving clinical benefits by inducing oral tolerance highlights the importance of characterizing SSc T-cell antigens. It is hoped that the identification of some of the key players in the induction and maintenance of the SSc fibroblast phenotype may yield new disease-targeted treatment regimens for patients with SSc.

Section snippets

Methods

We performed a PubMed search using the terms “systemic sclerosis” in the period of 1989 to 2007, restricted to the English Language. This yielded a total of 9099 publications, including 1252 reviews. From this list and based on the abstracts, a total of 328 articles were initially chosen that appeared to highlight recent progress in the pathogenesis of SSc as well as in the use of diagnostic tools and therapeutic approaches. A final review of the data in 262 articles regarding the current

Discussion

Recent human studies, animal models, and gene analyses have provided much deeper insight into the molecular mechanisms behind the development of SSc. In review of these collective data, the hallmarks of vascular damage, immunologic activation, and collagen deposition can be traced to 4 major factors: T-cells, fibroblasts, B-cells, and cytokines/chemokines.

T-cells are the major component of the infiltrate in both the lung and the skin of SSc patients, frequently exhibit an activated phenotype,

References (262)

  • S. Sato et al.

    Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis

    J Invest Dermatol

    (2003)
  • S. Svegliati et al.

    Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2Amplification of ROS and Ras in systemic sclerosis fibroblasts

    J Biol Chem

    (2005)
  • A. Servettaz et al.

    Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B)

    Clin Immunol

    (2006)
  • V.A. Nguyen et al.

    Endothelial injury in internal organs of University of California at Davis line 200 (UCD 200) chickens, an animal model for systemic sclerosis (Scleroderma)

    J Autoimmun

    (2000)
  • N. Asano et al.

    B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse

    Am J Pathol

    (2004)
  • M. Hasegawa et al.

    B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis

    Am J Pathol

    (2006)
  • K.N. Kasturi et al.

    B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene

    J Autoimmun

    (1997)
  • F. Ingegnoli et al.

    Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis

    Clin Immunol

    (2003)
  • S.A. Jimenez et al.

    Murine animal models of systemic sclerosis

    Curr Opin Rheumatol

    (2002)
  • J. Van de Water et al.

    Animal models of scleroderma: contrasts and comparisons

    Int Rev Immunol

    (1995)
  • R.J. Prescott et al.

    Sequential dermal microvascular and perivascular changes in the development of scleroderma

    J Pathol

    (1992)
  • R. Sgonc et al.

    Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95

    Arthritis Rheum

    (2000)
  • R. Sgonc et al.

    Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma

    J Clin Invest

    (1996)
  • A. Kalogerou et al.

    Early T-cell activation in the skin from patients with systemic sclerosis

    Ann Rheum Dis

    (2005)
  • C. Mavilia et al.

    Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis

    Am J Pathol

    (1997)
  • R. Giacomelli et al.

    Circulating Vδ1+ T-cells are activated and accumulate in the skin of systemic sclerosis patients

    Arthritis Rheum

    (1998)
  • B.M. Kräling et al.

    Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages

    Pathobiology

    (1995)
  • J.R. Seibold et al.

    Dermal mast cell degranulation in systemic sclerosis

    Arthritis Rheum

    (1990)
  • M.K. Ozbilgin et al.

    The roles of transforming growth factor type β3 (TGF-β3) and mast cells in the pathogenesis of scleroderma

    Clin Rheumatol

    (2003)
  • H.N. Claman et al.

    Endothelial and fibroblastic activation in sclerodermaThe myth of the “uninvolved skin”

    Arthritis Rheum

    (1991)
  • A.E. Koch et al.

    In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosisTheir role in early and late disease

    Pathobiology

    (1993)
  • M.S. Gruschwitz et al.

    Up-regulation of class II major histocompatibility complex and intercellular adhesion molecule 1 expression on scleroderma fibroblasts and endothelial cells by interferon-γ and tumor necrosis factor α in the early disease stage

    Arthritis Rheum

    (1997)
  • E. Scala et al.

    α4β1 and α4β7 CD4+ T-cell numbers increase and CLA+ CD4+ T-cell numbers decrease in systemic sclerosis

    Clin Exp Immunol

    (2005)
  • F.K. Tan et al.

    Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients

    Rheumatology (Oxford)

    (2006)
  • H. Ihn et al.

    Circulating intercellular adhesion molecule-1 in the sera of patients with systemic sclerosis: enhancement by inflammatory cytokines

    Br J Rheumatol

    (1997)
  • K. Scharffetter et al.

    Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization

    Eur J Clin Invest

    (1988)
  • M.L. Whitfield et al.

    Systemic and cell type-specific gene expression patterns in scleroderma skin

    Proc Natl Acad Sci USA

    (2003)
  • D. Kessler-Becker et al.

    Expression of pro-inflammatory markers by human dermal fibroblasts in a three-dimensional culture model is mediated by an autocrine interleukin-1 loop

    Biochem J

    (2004)
  • N.K. Harrison et al.

    Structural features of interstitial lung disease in systemic sclerosis

    Am Rev Respir Dis

    (1991)
  • A.U. Wells et al.

    Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium

    Eur Respir J

    (1995)
  • M.R. Hussein et al.

    Alterations of mononuclear inflammatory cellsCD4/CD8+ T-cells, interleukin 1β, and tumour necrosis factor α in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis

    J Clin Pathol

    (2005)
  • I.G. Luzina et al.

    Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T-cells from scleroderma patients

    Arthritis Rheum

    (2003)
  • G.H. Stummvoll et al.

    Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis

    Rheumatology (Oxford)

    (2000)
  • L.P. Ercole et al.

    Analysis of lymphocyte subpopulations in systemic sclerosis

    J Investig Allergol Clin Immunol

    (2003)
  • V. Riccieri et al.

    Reduced circulating natural killer T-cells and γ/δ T-cells in patients with systemic sclerosis

    J Rheumatol

    (2005)
  • R.F. Holcombe et al.

    Natural killer cells and γδ T-cells in scleroderma: relationship to disease duration and anti-Scl-70 antibodies

    Ann Rheum Dis

    (1995)
  • S. Kojo et al.

    Dysfunction of T-cell receptor AV24AJ18+BV11+ double-negative regulatory natural killer T-cells in autoimmune diseases

    Arthritis Rheum

    (2001)
  • A. Mitsuo et al.

    Decreased CD161+CD8+T-cells in the peripheral blood of patients suffering from rheumatic diseases

    Rheumatology (Oxford)

    (2006)
  • S.R. Carding et al.

    γδ T-cells: functional plasticity and heterogeneity

    Nat Rev Immunol

    (2002)
  • J.D. Reveille et al.

    Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies

    Arthritis Rheum

    (2003)
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