Rheumatology 2006 45(Supplement 3):iii23-iii25; doi:10.1093/rheumatology/kel285
© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Immunological basis of systemic sclerosis
J.-P. Zuber and
F. Spertini
Division of Immunology and Allergy, Département de médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Correspondence to: Dr Jean-Philippe Zuber, Division of Immunology and Allergy, CHUV, BH 18/707, 1011 Lausanne, Switzerland. E-mail: jean-philippe.zuber{at}chuv.ch
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Abstract
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Systemic sclerosis (SSc) is a disease of unknown aetiology characterized
by excessive and often progressive fibrosis in skin and multiple
internal organs, an aberrant immune activation marked by multiple
humoral and cellular immunological abnormalities and pronounced
alterations in the microvasculature. The pathogenesis of SSc
is complex and, although progress in the understanding of the
multiple processes underlying SSc has been made in recent years,
no single unifying hypothesis explaining all aspects of this
disease exists. Recent studies have suggested that the activation
of the immune system is a key stimulus to vascular abnormalities
and fibrosis. Once T-cells are activated, they infiltrate the
skin lesions early, and produce the profibrotic cytokine IL-4.
They are also required for autoantibody production. B-cells
may contribute to fibrosis, as deficiency of CD19, a B-cell
signal transduction molecule, results in decreased fibrosis
in animal models. In recent years, clinical advances have occurred
in parallel with a better understanding of the underlying disease
mechanisms. In this article, the immunological aspects and multiple
altered immunological processes found in SSc are discussed.
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Introduction
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The exact mechanisms involved in the pathogenesis of systemic
sclerosis (SSc) are still unknown, but there are fundamental
abnormalities in at least three types of cells responsible for
the clinical and pathological manifestations of this disease:
(i) fibroblasts; (ii) cells of the immune system, in particular
T- and B-lymphocytes; and (iii) endothelial cells. The functional
alterations in these cells result in the characteristic triad
of pathological changes: progressive cutaneous and visceral
fibrosis, a functional and structural vasculopathy and cellular
immunological abnormalities, which include the production of
autoantibodies, chronic mononuclear cell infiltration of affected
tissues (mainly T-lymphocytes and macrophages), and the dysregulation
of lymphokine and growth factor production [
1]. In recent years,
there have been major advances in our understanding of the biology
of SSc, and further progress in the understanding of the pathogenesis
of this difficult-to-treat disease is necessary to develop targeted
therapy. This article focuses on the various immunological processes
involved in the pathogenesis of SSc.
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Cellular immunology in SSc
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Immune activation is an early event in SSc. However, it is not
known whether it is the initiating event or whether it is secondary
to other disease processes. Some of the earliest evidence suggesting
that chronic and persistent inflammation may play a role in
the pathogenesis of SSc was provided by the demonstration of
infiltrates of T-cells, macrophages, mast cells and, rarely,
B-lymphocytes in affected skin from patients with disease of
recent onset [
2]. In fact, inflammation may appear in the skin
before any histological evidence of fibrosis [
2]. Progressively,
as fibrosis increases, the inflammatory infiltrates tend to
decrease.
The mononuclear cells within the skin infiltrates are predominantly CD4+ T-cells (which outnumber CD8+ T-cells) and macrophages. Natural killer (NK) cells are present in reduced number in the skin of patients with SSc. CD4+ T-cells in cutaneous infiltrates are activated, as indicated by the increased proportion of T-cells bearing activation markers such as IL-2 receptor and class II MHC antigen DR. The data available on the characteristics of T-cells infiltrating organs in patients with SSc are heterogeneous. Most data support a role for pathogenic T-cells from tissues undergoing fibrosis in SSc by outlining the preferential production of IL-4, a Th2 cytokine [3]. Accordingly, increased levels of the Th2 cell-derived cytokines IL-4, IL-10, IL-13 and IL-17 were observed in SSc [3, 4]. IL-4 and TGF-ß are the major fibrogenic cytokines in SSc. IL-4 increases collagen production in fibroblasts in patients with SSc and induces the production of TGF-ß. TGF-ß stimulates the synthesis of various collagens, proteoglycans and fibronectin, and inhibits extracellular matrix degradation by decreasing the synthesis of matrix metalloproteinases (MMP) and by increasing the synthesis of the tissue inhibitor of MMP. IL-17, a T-cell cytokine that can be produced by both Th1 and Th2 cells, is overexpressed in peripheral blood and skin of patients with SSc. It enhances the proliferation of fibroblasts, promotes macrophage production of TNF-
and IL-1 (which in turn induces fibroblast production of collagen, IL-6 and PDGF), and induces endothelial cell production of IL-1, IL-6 and adhesion molecules ICAM-1 and VCAM-1 [5]. Most authors consider that Th2 cells (producing IL-4) stimulates collagen synthesis and Th1 cells (producing IFN-
) inhibits collagen synthesis, but some authors report that Th2 cells can reduce type I collagen synthesis by dermal fibroblasts [6] and that an increased percentage of IFN- positive cells can be observed in peripheral T-cells from SSc patients [7]. Therefore, it is possible that Th1 cytokines, in addition to Th2 cytokines, also play a role in the development of SSc. Other cytokines that are at increased levels in the sera and tissues of patients with SSc include IL-1, IL-6 and CTGF (connective tissue growth factor). All these mediators are implicated in the pathogenesis of SSc and affect fibroblasts, endothelial cells and macrophages (Fig. 1). Expansion of CD4+ T-cells within the tissue appears to be oligoclonal, as shown in studies of T-cell receptor transcripts in the skin of patients with SSc [8]. These results suggest an antigen-driven T-cell response, although at present the putative antigen or antigens that may involved are not known. T-cells may induce fibrosis through cytokines or through direct contact with fibroblasts. However, whether the alterations observed in T-lymphocytes and various cytokines are secondary to disease activity or reflect a more fundamental pathogenic event is unknown. As immunological activity in SSc is considered to be a key stimulus to vascular abnormalities and fibrosis, existing (i.e. steroids, azathioprine, methotrexate and cyclophosphamide) and novel therapies (i.e. autologous stem cell transplantation, antithymocyte globulins and induction of tolerance to type I collagen) are targeting immunological activation.
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Humoral immunology in SSc
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B-cells are activated in SSc, as indicated by hypergammaglobulinaemia,
the presence of autoantibodies, the overexpression of the B-cell
transduction molecule CD19 in peripheral blood, expanded naive
B-cells and activated, but diminished, memory B-cells [
9]. Furthermore,
in animal models of fibrosis, deficiency of CD19 results in
decreased fibrosis, suggesting that B-cells may also contribute
to fibrosis. Activated B-cells are known to produce IL-6 and
IL-10, and both these may promote a predominant Th2 immune response
that induces collagen synthesis. The production of IL-6, as
well as the production of TGF-ß by activated B-cells,
may also induce directly tissue fibrosis in SSc patients.
More than 90% of patients with SSc harbour antinuclear antibodies in their serum. Anti-Scl-70 antibodies have been shown to react with DNA topoisomerase I and are almost exclusively present in patients with the diffuse forme of SSc, although only about 30–40% of these patients harbour these autoantibodies. Anticentromere antibodies are present in 80–90% of patients with the limited form of SSc but are found in fewer than 10% of patients with diffuse SSc. Other autoantibodies include anti-RNA polymerase I and III antibodies, antifibrillarin antibodies and anti-PM-Scl antibodies. Antiendothelial cell autoantibodies are also detected in SSc and can induce apoptosis of endothelial cells [10]. Antifibroblast antibodies reacting with fibroblast surface molecules have been demonstrated in the sera from patients with SSc [11] and have the potential to activate fibroblasts (Fig. 1). For the synthesis of anti-DNA topoisomerase I and very likely of other autoantibodies in SSc, B-cells appear to require T-cells. The accumulation of B-cells in skin lesions may also depend on T-cells. One can support the hypothesis that the T–B interaction is essential for the pathogenesis of SSc. Although autoantibodies are common in SSc, their significance in the pathogenesis of SSc is not known. However, owing to their high frequency and their specificity for certain clinical disease subsets, their presence is very helpful in establishing the diagnosis and predicting a probable pattern of organ involvement, severity and disease progression.
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FIG. 1. Schematic diagram of the involvement of different cell types (T-cell, B-cell, fibroblast, macrophage and endothelial cell) in the pathogenesis of SS. IL, interleukin; TGF-ß, transforming growth factor-ß; CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; ANA, anti-nuclear antibodies.
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SSc and microchimerism
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A novel hypothesis has been proposed, suggesting that allogeneic
fetal and maternal cells, which cross the placenta during pregnancy
in bidirectional traffic, may be involved in the pathogenesis
of SSc. Fetal or maternal cells persist in the circulation and
tissues of the mother or child as a result of HLA II (DRB1)
compatibility between the mother and the fetus. These engrafted
foreign cells may become activated by a second event and may
initiate a graft-
vs-host (GVH) reaction towards the mother or
offspring, which manifests as SSc. It has been shown that the
foreign T-cells can react with patient's major histocompatibility
complex molecules and produce IL-4. The remarkable clinical,
histopathological and serological similarities between GVH disease
(GVHD) and SSc support this hypothesis. The identification of
Y-chromosome sequences in the DNA obtained from skin biopsy
from female SSc patients who had previously given birth to a
male offspring provides further support for this hypothesis
[
12]. Microchimeric cells of maternal origin have also been
identified in the circulation of offspring, which might explain
the occurrence of SSc in nulliparous women and in men.
J.-P.Z. received speaker's honorarium for participation at Actelion Winter School.
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References
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- Worda M, Sgonc R, Dietrich H, et al. (2003) In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorioallantonic membrane assay. Arthritis Rheum 48:2605–14.[CrossRef][ISI][Medline]
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Abstract
Introduction