J Mol Med (2014) 92:913–924 DOI 10.1007/s00109-014-1190-x
REVIEW
Molecular and cellular basis of scleroderma Beate Eckes & Pia Moinzadeh & Gerhard Sengle & Nico Hunzelmann & Thomas Krieg
Received: 19 February 2014 / Revised: 2 June 2014 / Accepted: 5 June 2014 / Published online: 18 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Systemic sclerosis (scleroderma) is a chronic inflammatory disease that leads to fibrosis of the skin and involved internal organs. No efficient therapy is currently available. This review summarizes recent progress made in basic as well as clinical science and concludes with a concept that therapy targeting fibrosis in scleroderma needs to take into account the global microenvironment in the skin with its diverse cellular players interacting with a complex extracellular matrix environment and matrix-associated growth factors. Keywords Systemic sclerosis . Scleroderma . Extracellular microenvironment . Pathophysiology . Signaling
the mechanisms leading to the fibrotic response are similar in all these processes. Systemic sclerosis (scleroderma) is a slowly progressing chronic inflammatory disease, which leads to fibrosis of the skin and the involved internal organs [2] (Fig. 1). Clinically, systemic sclerosis is a heterogeneous disease with different subsets, which are characterized by the extent of skin fibrosis, presence of distinct circulating autoantibodies, and by the involvement of internal organs [3, 4]. It is a rare disease with a prevalence ranging from 50 to 300 cases per million. As in many other autoimmune diseases, women are at higher risk than men [4–6].
Genetic background The term “scleroderma” is descriptive and is currently used for a broad variety of diseases (Table 1). In localized scleroderma, the fibrotic reaction is exclusively found in the skin; the overlap syndromes have similar clinical features as scleroderma but show additional symptoms usually found in other inflammatory connective tissue diseases (for review, see [1]). This review will focus on systemic sclerosis (SSc) although B. Eckes : P. Moinzadeh : N. Hunzelmann : T. Krieg (*) Department of Dermatology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany e-mail: [email protected] G. Sengle Center for Biochemistry, University of Cologne, Cologne, Germany G. Sengle : T. Krieg Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany T. Krieg Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Scleroderma is not an inherited disease and does not follow Mendelian inheritance; however, several independent investigations suggest that a genetic background predisposes to the development of the disease. Family studies indicate an increased probability to develop scleroderma in families with other autoimmune diseases [7]. Moreover, inbred populations exist with a very high frequency of certain subsets of scleroderma [8–11]. More recently, genetic linkage studies and genome-wide association studies (GWAS) have identified polymorphisms associated with the predisposition of patients to develop systemic sclerosis [11–16]. Some of those have identified genes associated with the metabolism of extracellular matrix (ECM) molecules [11, 17, 18]. As for other autoimmune diseases, most investigations provide evidence for an association with genes coding for proteins involved in the control of innate immunity, macrophage activation, and T-cell functions [13, 14, 19–21]. For further improvement, several large registries have been developed worldwide [22, 23], which provide a detailed characterization of patients, defining subsets and allowing controlled follow-up clinical studies. These networks enable additional validation in large well-
914 Table 1 The clinical spectrum of sclerodermatous disease Localized scleroderma Overlap syndromes Systemic sclerosis (scleroderma) Pseudoscleroderma
characterized patient cohorts and provide the basis for mechanistic molecular studies.
Environmental risk factors and trigger mechanisms In addition to a predisposing genetic background, an early trigger is likely required to initiate the disease process. Various reports have correlated environmental factors with the incidence of scleroderma or related diseases [24–26]. These include environmental challenges such as vinyl chloride, silica, viral (e.g., cytomegalovirus and EBV) or bacterial infections, or certain drugs and chemicals. Since some aspects in the pathophysiology of scleroderma resemble the changes occurring in graft-versus-host disease, the hypothesis was raised that fetal and maternal lymphocytes can cross the placenta barrier during pregnancy, thereby initiating a chronic inflammatory reaction leading to fibrosis [27, 28]. These studies will require further validation.
J Mol Med (2014) 92:913–924
Microvascular damage as an early step in the pathophysiology Clinical symptoms and also the histological investigation of early disease stages clearly indicate that microvascular damage is an important feature in the early phases of the disease [29, 30]. Although this is more pronounced in certain subsets (limited disease), similar alterations are found in all other forms (e.g., diffuse scleroderma). For clinical routine alterations of the nail fold, capillaries can be visualized by capillaroscopy (for review, see [31]). Vascular damage includes swelling and morphological alterations in endothelial cells as well as the presence of endothelial cell toxic factors in the circulation [32–34]. More recently, circulating autoantibodies targeting vascular receptors have been detected [35]. At the ultrastructural level, gaps between adjacent endothelial cells and vacuolization as well as duplications of the basement membrane have been reported [32]. Hypoxia and reactive oxygen radicals contribute to endothelial cell damage [2]. Endothelial cells were found to induce vascular cell adhesion molecule (VCAM)-1 expression, secrete a number of cytokines and chemokines, release potent factors such as the vasoconstrictor endothelin-1, and to participate in the remodeling of vascular structures [30]. Progressive thickening of the vessel wall with duplications of the basement membrane results in a narrowing of the lumen of the capillaries and finally in the loss of the microvasculature, which is a specific feature detected by capillaroscopy. Interestingly, a recent report initially based on extensive genome-wide association studies describes elevated CXCL4 levels in the circulation of SSc patients. CXCL4 is a chemokine (also known as platelet factor 4) with anti-angiogenic activities secreted by plasmacytoid dendritic cells [23].
The inflammatory response
Fig. 1 The clinical and histological features of systemic sclerosis (scleroderma). a Edematous swelling of the fingers with fibrosis in a patient with early scleroderma. b Digital ulcerations developing in a patient with diffuse cutaneous systemic sclerosis and severe fibrosis of the digits and hand. c Histology of a skin biopsy from a patient with an early phase of SSc. Intense deposition of collagenous extracellular matrix throughout the entire dermis and the subcutaneous fat layer in diffuse SSc. Lymphohistiocytic infiltrations are seen around blood vessels. d Lymphohistiocytic infiltrations around blood vessels consisting of mononuclear cells in a patient with early diffuse SSc
Histologically, endothelial cell damage is accompanied by the presence of perivascular lymphohistiocytic infiltrates [29, 32, 36] (Fig. 1d). These consist mainly of activated CD3- and CD4-positive mononuclear cells, which release proinflammatory and fibrogenic cytokines. Mast cells and eosinophils have also been discussed to contribute to the fibrotic reaction, however, recent studies show that the early work, based mainly on electron microscopy studies, has led to an overinterpretation and indicate that mast cells are dispensable for the development of fibrosis [37, 38]. Also eosinophils, which play an important role in combating parasite infections, are probably not directly responsible for the fibrotic reaction often arising subsequently to infection and severe tissue damage. More recently, the shift from Th1 to Th2 lymphocytes and a concomitant modulation of macrophage subsets has been highlighted (for review see [39]). This is supported by
J Mol Med (2014) 92:913–924
increased serum levels of cytokines released from these inflammatory cells. More recently, activation of macrophages was identified as a major factor for the development of SScrelated progressive lung fibrosis [21]. By immunohistochemistry, B cells have further been detected in the inflammatory infiltrates, and an activated B cell signature was found by microarray analysis [40, 41]. Interestingly, depletion of B cells in a mouse model of scleroderma was reported to lead to
915
reduced fibrosis [42], yet clinical studies in patients using rituximab led to conflicting results [43–49]. From several studies based on in situ hybridization and gene expression analysis, it is believed that transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), interleukins, and connective-tissue growth factor (CTGF) are released from these early inflammatory infiltrates (Table 2); these are factors crucial for the activation of
Table 2 Cytokines and growth factors in systemic sclerosis Cellular source
Biological activity
IFNγ
Th1 cells, memory T CD8+ cells, dendritic and NK cells
TNFα
Macrophages, APC, skin mast cells and keratinocytes
Interleukin-1
Th1 cells, monocytes, macrophages, dendritic, and endothelial cells
Interleukin-2
T lymphocytes
Interleukin-4
Th2 cells, macrophages, mast cells, and NK cells
Interleukin-5 Interleukin-6
Th2 cells, as well as mast cells and eosinophils Th2 cells, macrophages, and B lymphocytes as well as epithelial cells and fibroblasts
Interleukin-8
Alveolar macrophages, lung fibroblasts and skin fibroblasts
Interleukin-10 Interleukin-13
Activated B cells and monocytes Th2 cells, NK and mast cells
Interleukin-12
Monocytes, macrophages, dendritic cells as well as B lymphocytes Th17 cells and NK cells Th17 cells and NK cells Mature Th17 cells and Th2 and NK cells Keratinocytes, macrophages, fibroblasts, T and B cells, platelets and endothelial cells
Th1 differentiation, activation of B cells Th2 cytokine inhibition Neutrophil/lymphocyte recruitment Pro-inflammatory and pro-apoptotic Pro-inflammatory, production of IL-6 and PDGFα Th1 (together with IL-1β, IL-23) and Th17 (together with IL-1β, IL-6, and IL-23) differentiation Stimulates NK and T CD8+ cells Lymphocyte proliferation and differentiation to Th1 cells in the presence of IL-12 and IFNγ as well as Th2 cells together with IL-4 Anti-inflammatory response associated with Th17 inhibition and Treg activation Th2 differentiation, Th1 cytokine inhibition as well as Treg differentiation Fibroblast proliferation, chemotaxis, and collagen production Production of TGFβ, CTGF, and TIMP-1 B cell differentiation Th2 differentiation, Th17 differentiation (together with TGFβ and IL-21) Inhibition of Treg differentiation Stimulation of collagen production and inhibition of collagenase production Stimulates fibroblast chemotaxis, chemoattractant and activator of neutrophils Induces Th2 immune response and collagen synthesis B cell proliferation and differentiation, anti-inflammatory response and fibrosis Th1 differentiation, inhibits Th17 differentiation Pro-inflammatory Pro-inflammatory and pro-fibrotic Th17 response expansion Pro-inflammatory Stimulates fibroblast proliferation and expression of TGFβ and PDGF receptors, production of CTGF and endothelin-1 Stimulates synthesis of collagen, fibronectin, proteoglycans, and TIMP (inhibition of ECM degradation) Induced by TGFβ, IL-4, and VEGF Induces fibroblast proliferation and chemotaxis of fibroblasts, stimulates ECM production Mitogen/chemoattractant for fibroblasts, synthesis of collagen, fibronectin, and proteoglycans Stimulates secretion of TGFβ, MCP-1, and IL-6 Dose-dependent vasoconstrictor and dose dependent inducer of fibroblast proliferation and collagen synthesis
Interleukin-17 Interleukin-21 Interleukin-22 TGFβ
CTGF
Fibroblasts, endothelial cells, and smooth muscle cells
PDGF
Platelets, macrophages, fibroblasts, endothelial cells
Endothelin-1
Endothelial cells
916
J Mol Med (2014) 92:913–924
Table 3 Autoantibodies with diagnostic relevance in systemic sclerosis and associated overlap syndromes Antibodies
Characteristics
Frequency (%)
Anticentromere antibodies
Frequent in patients with limited SSc Associated with vasculopathy/digital ulcers, calcinosis cutis and upper GI involvement Associated with diffuse SSc Increased risk for lung fibrosis, renal crisis, severe heart involvement, and digital ulcers Associated with diffuse SSc Increased risk for renal crisis Associated with diffuse SSc Associated with skin involvement, vasculopathy, pulmonary hypertension and musculoskeletal involvement Associated with limited skin involvement, interstitial lung disease and isolated pulmonary arterial hypertension Associated with limited SSc, SSc myositis overlap and CK elevation No severe internal organ manifestations High titers are frequent in patients with MCTD Associated with less skin involvement but increased risk for pulmonary hypertension Associated with puffy fingers, RP, arthritis, and upper GI involvement Main clinical associations are overlaps with SLE and myositis Associated with SSc/myositis overlap syndromes Associated with sicca syndromes Secondary Sjoegren's syndrome
20–30
Anti-topoisomerase antibodies Anti-RNA polymerase antibodies Anti-U3RNP/fibrillarin antibodies
Anti-Th/To antibodies Anti-PmScl antibodies Anti-U1RNP antibodies
Anti-Ku antibodies Anti-Jo1 antibodies Anti-Ro/La antibodies
fibroblasts and the transition of fibroblasts to myofibroblasts (for review, see [50, 51]).
Autoantibodies, their diagnostic value, and contribution to pathophysiology A characteristic feature in systemic sclerosis is the generation of autoantibodies (for review, see [52]), which are found in the circulation. Many of these autoantibodies are directed against nuclear antigens and are very important diagnostic markers [53–55]. Determination and characterization of the autoantibodies allow not only a firm diagnosis but also the association with defined subsets. Moreover, they are important prognostic indicators (Table 3). Some, in addition, determine the risk of patients for specific organ complications, e.g., anticentromere antibodies are associated with limited cutaneous scleroderma and with the development of pulmonary hypertension, antitopoisomerase antibodies are characteristic for diffuse
30–40 5–25 4–10
5 4–11 2–14
REVIEW
Molecular and cellular basis of scleroderma Beate Eckes & Pia Moinzadeh & Gerhard Sengle & Nico Hunzelmann & Thomas Krieg
Received: 19 February 2014 / Revised: 2 June 2014 / Accepted: 5 June 2014 / Published online: 18 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Systemic sclerosis (scleroderma) is a chronic inflammatory disease that leads to fibrosis of the skin and involved internal organs. No efficient therapy is currently available. This review summarizes recent progress made in basic as well as clinical science and concludes with a concept that therapy targeting fibrosis in scleroderma needs to take into account the global microenvironment in the skin with its diverse cellular players interacting with a complex extracellular matrix environment and matrix-associated growth factors. Keywords Systemic sclerosis . Scleroderma . Extracellular microenvironment . Pathophysiology . Signaling
the mechanisms leading to the fibrotic response are similar in all these processes. Systemic sclerosis (scleroderma) is a slowly progressing chronic inflammatory disease, which leads to fibrosis of the skin and the involved internal organs [2] (Fig. 1). Clinically, systemic sclerosis is a heterogeneous disease with different subsets, which are characterized by the extent of skin fibrosis, presence of distinct circulating autoantibodies, and by the involvement of internal organs [3, 4]. It is a rare disease with a prevalence ranging from 50 to 300 cases per million. As in many other autoimmune diseases, women are at higher risk than men [4–6].
Genetic background The term “scleroderma” is descriptive and is currently used for a broad variety of diseases (Table 1). In localized scleroderma, the fibrotic reaction is exclusively found in the skin; the overlap syndromes have similar clinical features as scleroderma but show additional symptoms usually found in other inflammatory connective tissue diseases (for review, see [1]). This review will focus on systemic sclerosis (SSc) although B. Eckes : P. Moinzadeh : N. Hunzelmann : T. Krieg (*) Department of Dermatology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany e-mail: [email protected] G. Sengle Center for Biochemistry, University of Cologne, Cologne, Germany G. Sengle : T. Krieg Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany T. Krieg Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Scleroderma is not an inherited disease and does not follow Mendelian inheritance; however, several independent investigations suggest that a genetic background predisposes to the development of the disease. Family studies indicate an increased probability to develop scleroderma in families with other autoimmune diseases [7]. Moreover, inbred populations exist with a very high frequency of certain subsets of scleroderma [8–11]. More recently, genetic linkage studies and genome-wide association studies (GWAS) have identified polymorphisms associated with the predisposition of patients to develop systemic sclerosis [11–16]. Some of those have identified genes associated with the metabolism of extracellular matrix (ECM) molecules [11, 17, 18]. As for other autoimmune diseases, most investigations provide evidence for an association with genes coding for proteins involved in the control of innate immunity, macrophage activation, and T-cell functions [13, 14, 19–21]. For further improvement, several large registries have been developed worldwide [22, 23], which provide a detailed characterization of patients, defining subsets and allowing controlled follow-up clinical studies. These networks enable additional validation in large well-
914 Table 1 The clinical spectrum of sclerodermatous disease Localized scleroderma Overlap syndromes Systemic sclerosis (scleroderma) Pseudoscleroderma
characterized patient cohorts and provide the basis for mechanistic molecular studies.
Environmental risk factors and trigger mechanisms In addition to a predisposing genetic background, an early trigger is likely required to initiate the disease process. Various reports have correlated environmental factors with the incidence of scleroderma or related diseases [24–26]. These include environmental challenges such as vinyl chloride, silica, viral (e.g., cytomegalovirus and EBV) or bacterial infections, or certain drugs and chemicals. Since some aspects in the pathophysiology of scleroderma resemble the changes occurring in graft-versus-host disease, the hypothesis was raised that fetal and maternal lymphocytes can cross the placenta barrier during pregnancy, thereby initiating a chronic inflammatory reaction leading to fibrosis [27, 28]. These studies will require further validation.
J Mol Med (2014) 92:913–924
Microvascular damage as an early step in the pathophysiology Clinical symptoms and also the histological investigation of early disease stages clearly indicate that microvascular damage is an important feature in the early phases of the disease [29, 30]. Although this is more pronounced in certain subsets (limited disease), similar alterations are found in all other forms (e.g., diffuse scleroderma). For clinical routine alterations of the nail fold, capillaries can be visualized by capillaroscopy (for review, see [31]). Vascular damage includes swelling and morphological alterations in endothelial cells as well as the presence of endothelial cell toxic factors in the circulation [32–34]. More recently, circulating autoantibodies targeting vascular receptors have been detected [35]. At the ultrastructural level, gaps between adjacent endothelial cells and vacuolization as well as duplications of the basement membrane have been reported [32]. Hypoxia and reactive oxygen radicals contribute to endothelial cell damage [2]. Endothelial cells were found to induce vascular cell adhesion molecule (VCAM)-1 expression, secrete a number of cytokines and chemokines, release potent factors such as the vasoconstrictor endothelin-1, and to participate in the remodeling of vascular structures [30]. Progressive thickening of the vessel wall with duplications of the basement membrane results in a narrowing of the lumen of the capillaries and finally in the loss of the microvasculature, which is a specific feature detected by capillaroscopy. Interestingly, a recent report initially based on extensive genome-wide association studies describes elevated CXCL4 levels in the circulation of SSc patients. CXCL4 is a chemokine (also known as platelet factor 4) with anti-angiogenic activities secreted by plasmacytoid dendritic cells [23].
The inflammatory response
Fig. 1 The clinical and histological features of systemic sclerosis (scleroderma). a Edematous swelling of the fingers with fibrosis in a patient with early scleroderma. b Digital ulcerations developing in a patient with diffuse cutaneous systemic sclerosis and severe fibrosis of the digits and hand. c Histology of a skin biopsy from a patient with an early phase of SSc. Intense deposition of collagenous extracellular matrix throughout the entire dermis and the subcutaneous fat layer in diffuse SSc. Lymphohistiocytic infiltrations are seen around blood vessels. d Lymphohistiocytic infiltrations around blood vessels consisting of mononuclear cells in a patient with early diffuse SSc
Histologically, endothelial cell damage is accompanied by the presence of perivascular lymphohistiocytic infiltrates [29, 32, 36] (Fig. 1d). These consist mainly of activated CD3- and CD4-positive mononuclear cells, which release proinflammatory and fibrogenic cytokines. Mast cells and eosinophils have also been discussed to contribute to the fibrotic reaction, however, recent studies show that the early work, based mainly on electron microscopy studies, has led to an overinterpretation and indicate that mast cells are dispensable for the development of fibrosis [37, 38]. Also eosinophils, which play an important role in combating parasite infections, are probably not directly responsible for the fibrotic reaction often arising subsequently to infection and severe tissue damage. More recently, the shift from Th1 to Th2 lymphocytes and a concomitant modulation of macrophage subsets has been highlighted (for review see [39]). This is supported by
J Mol Med (2014) 92:913–924
increased serum levels of cytokines released from these inflammatory cells. More recently, activation of macrophages was identified as a major factor for the development of SScrelated progressive lung fibrosis [21]. By immunohistochemistry, B cells have further been detected in the inflammatory infiltrates, and an activated B cell signature was found by microarray analysis [40, 41]. Interestingly, depletion of B cells in a mouse model of scleroderma was reported to lead to
915
reduced fibrosis [42], yet clinical studies in patients using rituximab led to conflicting results [43–49]. From several studies based on in situ hybridization and gene expression analysis, it is believed that transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), interleukins, and connective-tissue growth factor (CTGF) are released from these early inflammatory infiltrates (Table 2); these are factors crucial for the activation of
Table 2 Cytokines and growth factors in systemic sclerosis Cellular source
Biological activity
IFNγ
Th1 cells, memory T CD8+ cells, dendritic and NK cells
TNFα
Macrophages, APC, skin mast cells and keratinocytes
Interleukin-1
Th1 cells, monocytes, macrophages, dendritic, and endothelial cells
Interleukin-2
T lymphocytes
Interleukin-4
Th2 cells, macrophages, mast cells, and NK cells
Interleukin-5 Interleukin-6
Th2 cells, as well as mast cells and eosinophils Th2 cells, macrophages, and B lymphocytes as well as epithelial cells and fibroblasts
Interleukin-8
Alveolar macrophages, lung fibroblasts and skin fibroblasts
Interleukin-10 Interleukin-13
Activated B cells and monocytes Th2 cells, NK and mast cells
Interleukin-12
Monocytes, macrophages, dendritic cells as well as B lymphocytes Th17 cells and NK cells Th17 cells and NK cells Mature Th17 cells and Th2 and NK cells Keratinocytes, macrophages, fibroblasts, T and B cells, platelets and endothelial cells
Th1 differentiation, activation of B cells Th2 cytokine inhibition Neutrophil/lymphocyte recruitment Pro-inflammatory and pro-apoptotic Pro-inflammatory, production of IL-6 and PDGFα Th1 (together with IL-1β, IL-23) and Th17 (together with IL-1β, IL-6, and IL-23) differentiation Stimulates NK and T CD8+ cells Lymphocyte proliferation and differentiation to Th1 cells in the presence of IL-12 and IFNγ as well as Th2 cells together with IL-4 Anti-inflammatory response associated with Th17 inhibition and Treg activation Th2 differentiation, Th1 cytokine inhibition as well as Treg differentiation Fibroblast proliferation, chemotaxis, and collagen production Production of TGFβ, CTGF, and TIMP-1 B cell differentiation Th2 differentiation, Th17 differentiation (together with TGFβ and IL-21) Inhibition of Treg differentiation Stimulation of collagen production and inhibition of collagenase production Stimulates fibroblast chemotaxis, chemoattractant and activator of neutrophils Induces Th2 immune response and collagen synthesis B cell proliferation and differentiation, anti-inflammatory response and fibrosis Th1 differentiation, inhibits Th17 differentiation Pro-inflammatory Pro-inflammatory and pro-fibrotic Th17 response expansion Pro-inflammatory Stimulates fibroblast proliferation and expression of TGFβ and PDGF receptors, production of CTGF and endothelin-1 Stimulates synthesis of collagen, fibronectin, proteoglycans, and TIMP (inhibition of ECM degradation) Induced by TGFβ, IL-4, and VEGF Induces fibroblast proliferation and chemotaxis of fibroblasts, stimulates ECM production Mitogen/chemoattractant for fibroblasts, synthesis of collagen, fibronectin, and proteoglycans Stimulates secretion of TGFβ, MCP-1, and IL-6 Dose-dependent vasoconstrictor and dose dependent inducer of fibroblast proliferation and collagen synthesis
Interleukin-17 Interleukin-21 Interleukin-22 TGFβ
CTGF
Fibroblasts, endothelial cells, and smooth muscle cells
PDGF
Platelets, macrophages, fibroblasts, endothelial cells
Endothelin-1
Endothelial cells
916
J Mol Med (2014) 92:913–924
Table 3 Autoantibodies with diagnostic relevance in systemic sclerosis and associated overlap syndromes Antibodies
Characteristics
Frequency (%)
Anticentromere antibodies
Frequent in patients with limited SSc Associated with vasculopathy/digital ulcers, calcinosis cutis and upper GI involvement Associated with diffuse SSc Increased risk for lung fibrosis, renal crisis, severe heart involvement, and digital ulcers Associated with diffuse SSc Increased risk for renal crisis Associated with diffuse SSc Associated with skin involvement, vasculopathy, pulmonary hypertension and musculoskeletal involvement Associated with limited skin involvement, interstitial lung disease and isolated pulmonary arterial hypertension Associated with limited SSc, SSc myositis overlap and CK elevation No severe internal organ manifestations High titers are frequent in patients with MCTD Associated with less skin involvement but increased risk for pulmonary hypertension Associated with puffy fingers, RP, arthritis, and upper GI involvement Main clinical associations are overlaps with SLE and myositis Associated with SSc/myositis overlap syndromes Associated with sicca syndromes Secondary Sjoegren's syndrome
20–30
Anti-topoisomerase antibodies Anti-RNA polymerase antibodies Anti-U3RNP/fibrillarin antibodies
Anti-Th/To antibodies Anti-PmScl antibodies Anti-U1RNP antibodies
Anti-Ku antibodies Anti-Jo1 antibodies Anti-Ro/La antibodies
fibroblasts and the transition of fibroblasts to myofibroblasts (for review, see [50, 51]).
Autoantibodies, their diagnostic value, and contribution to pathophysiology A characteristic feature in systemic sclerosis is the generation of autoantibodies (for review, see [52]), which are found in the circulation. Many of these autoantibodies are directed against nuclear antigens and are very important diagnostic markers [53–55]. Determination and characterization of the autoantibodies allow not only a firm diagnosis but also the association with defined subsets. Moreover, they are important prognostic indicators (Table 3). Some, in addition, determine the risk of patients for specific organ complications, e.g., anticentromere antibodies are associated with limited cutaneous scleroderma and with the development of pulmonary hypertension, antitopoisomerase antibodies are characteristic for diffuse
30–40 5–25 4–10
5 4–11 2–14
