The Pathogenesis of Systemic Sclerosis

Department of Medicine, University of California, San Francisco, 94143, USA.
Annual Review of Pathology Mechanisms of Disease (Impact Factor: 18.75). 02/2011; 6(1):509-37. DOI: 10.1146/annurev-pathol-011110-130312
Source: PubMed


Systemic sclerosis (SSc), also known as scleroderma, is a rare connective tissue disease characterized by vascular and immune dysfunction, leading to fibrosis that can damage multiple organs. Its pathogenesis is complex and poorly understood. Two major clinical subtypes are the limited and diffuse forms. Research into SSc has been hampered by its rarity, its clinical heterogeneity, and the lack of mouse models that accurately recapitulate the disease. Clinical and basic studies have yielded some mechanistic clues regarding pathogenesis. Recent insights gained through the use of microarrays have revealed distinctive subsets of SSc within and beyond the limited and diffuse subsets. In this review, we discuss potential mechanisms underlying the vascular, autoimmune, and fibrotic points of dysregulation. Proper categorization of SSc patients for research studies by use of microarrays or other biomarkers is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies.

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    • "It is relatively rare, affecting between 50,000 and 100,000 North Americans, and up to 250,000 Europeans [1] [2]. Although less common than other rheumatic diseases, it has one of the highest mortality rates [3]. "
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    ABSTRACT: Background: The chitinase-like protein, Chi3L1, is associated with increased fibrotic activity as well as inflammatory processes. The capacity of skin cells from systemic sclerosis (SSc) patients to produce Chi3L1, and the stimulation of its synthesis by cytokines or growth factors known to be associated with SSc, was investigated. Methods: Cells were isolated from forearm and/or abdomen skin biopsies taken from SSc patients and normal individuals and stimulated with cytokines and growth factors to assess Chi3L1 expression. Chi3L1-expressing cells were characterized by immunohistochemical staining. Results: Chi3L1 was not secreted by skin cells from normal individuals nor was its synthesis induced by any of the cytokines or growth factors investigated. In contrast, Chi3L1 secretion was induced by OSM or IL-1 in cells from all forearm biopsies of SSc patients, and endogenous secretion in the absence of cytokines was detected in several specimens. Patients with Chi3L1-producing cells at both the arm and abdomen had a disease duration of less than 3. years. Endogenous Chi3L1 production was not a property of the major fibroblast population nor of myofibroblasts, but rather was related to the presence of stem-like cells not present in normal skin. Other cells, however, contributed to the upregulation of Chi3L1 by OSM. Conclusions: The emergence of cells primed to respond to OSM with increased Chi3L1 production appears to be associated with pathological processes active in SSc. General significance: The presence of progenitor cells expressing the chilectin Chi3L1 in SSc skin appears to play a role in the initiation of the disease process.
    Biochimica et Biophysica Acta - Clinical 06/2014; 1:2–11. DOI:10.1016/j.bbacli.2013.12.001
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    • "Systemic sclerosis (SSc) is an autoimmune multisystem disease of unknown etiology, characterized by structural abnormalities in small blood vessels and excessive deposition of extracellular matrix components [1,2]. Patients with diffuse SSc have a greater likelihood of organ damage, reduced quality of life, and long-term morbidity and mortality, leading to a high economic and patient burden [3,4]. "
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    ABSTRACT: Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Subjects (>=18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.Trial Registration: NCT00930683.
    Arthritis research & therapy 02/2014; 16(1):R57. DOI:10.1186/ar4492 · 3.75 Impact Factor
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    • "Besides the importance of fibrosis in SSc, many studies propose that microvascular damage and inflammation can precede fibrosis [4,30]. Additionally, autoimmune-mediated damage to endothelial cells has been demonstrated to cause endothelial dysfunction [31], which can lead to vessel leaks and lymphocyte infiltration [4,32]. In this regard, anti-AT1R and anti-ETAR Abs induced microvascular endothelial cell (HMEC-1) dysfunction after exposure to positive SSc-IgG, resulting in reduced endothelial repair in an Ab-level-dependent manner. "
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    ABSTRACT: Vasculopathy, inflammatory fibrosis and functional autoantibodies (Abs) are major manifestations of systemic sclerosis (SSc). Abs directed against the angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) are associated with characteristic disease features including vascular, inflammatory and fibrotic complications indicating their role in SSc pathogenesis. Therefore, the impact of anti-AT1R and anti-ETAR Abs on initiation of inflammation and fibrosis was analyzed. Anti-AT1R and anti-ETAR Ab positive immunoglobulin G (IgG) from SSc patients (SSc-IgG) was used for experiments. Healthy donor IgG served as a normal control and AT1R and ETAR activation was inhibited by antagonists. Protein expression was measured by ELISA, mRNA expression by Real Time-PCR, endothelial repair by a scratch assay and collagen expression by immunocytochemistry. Transendothelial neutrophil migration was measured by a culture insert system and neutrophil ROS activation by immunofluorescence. Neutrophils in bronchoalveolar lavage fluids (BALF) were analyzed microscopically after passive transfer of SSc-IgG or NC-IgG into naive C57BL/6J mice. KC plasma levels were quantified by a suspension array system. Histological analyses were performed using light microscopy. Anti-AT1R and anti-ETAR Ab positive SSc-IgG induced activation of human microvascular endothelial cells (HMEC-1). Elevated protein and mRNA levels of the proinflammatory chemokine interleukin-8 (IL-8, CXCL8) and elevated mRNA levels of the vascular cell adhesion molecule-1 (VCAM-1) were induced in HMEC-1. Furthermore, activation of HMEC-1 with SSc-IgG increased neutrophil migration through an endothelial cell layer and activation of reactive oxygen species (ROS). SSc-IgG decreased HMEC-1 wound repair and induced type I collagen production in healthy donor skin fibroblasts. Effects of migration, wound repair and collagen expression were dependent on the Ab-levels. Passive transfer of anti-AT1R and anti-ETAR Ab positive SSc-IgG into naive C57BL/6J mice increased neutrophil BALF counts. In parallel, increased levels of the murine functional IL-8 homologue, chemokine KC, were found in the plasma of SSc-IgG treated mice as well as structural alterations of the lungs. We conclude that angiotensin and endothelin receptor activation via anti-AT1R and anti-ETAR Abs mediate pathogenic effects, indicating their contribution to pathogenesis of SSc. Therefore, anti-AT1R and anti-ETAR Abs could provide novel targets for therapeutic intervention in the treatment of SSc.
    Arthritis research & therapy 01/2014; 16(1):R29. DOI:10.1186/ar4457 · 3.75 Impact Factor
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