Pathogenesis Of Systemic Scleroderma Research Articles

Mitochondrial DNA copy number in patients with systemic sclerosis.

Introduction: Systemic scleroderma (SSc) is a chronic autoimmune disease of inflammatory origin. Mitochondrial dysfunction is considered as an important mechanism in the pathogenesis of SSc. Currently mitochondrial DNA (mtDNA) copy number is used as a surrogate marker of mitochondrial dysfunction. Previous studies demonstrate that innate immune cells are important participants in inflammatory and fibrotic processes in SSc. The aim of the study was to evaluate the number of mtDNA copies in CD14+ monocytes and whole blood of patients with SSc in comparison with healthy individuals. Methods: Absolute mtDNA copy number was measured using digital PCR. It was found that the number of mtDNA copies in CD14+ monocytes was significantly higher in patients with SSc compared to control, while the number of mtDNA copies in the whole blood did not have significant differences. Results: The correlation analysis revealed an inverse association of mtDNA copy number with disease duration and the relationship between pro-inflammatory activation of CD14+ monocytes in terms of LPS-stimulated IL-6 secretion and mtDNA copy number. At the same time, basal and LPS-stimulated secretion of IL-6 by cultured CD+ monocytes were significantly higher in SSc group in comparison with control. Discussion: The study results suggest that increase of mtDNA copy number in CD14+ monocytes is a possible mechanism to maintain the reduced function of defective mitochondria in monocytes from patients with SSc associated with the development and progression of SSc.

Pathogenetic rationale for prescribing menopausal hormone therapy for systemic sclerosis

Systemic scleroderma (SS) is characterized by dysregulation of the innate and adaptive immune systems, vasculopathy, and generalized fibrosis. As with most autoimmune diseases, women predominate among patients, who get sick 3–14 times more often than men. It is assumed that gender differences and modulation of sex hormones are essential in the pathogenesis of SS. Estrogens are able to influence the immune response, have a vasodilating effect and stimulate the synthesis of collagen in the skin. The development of SS leads to a significant decrease in the quality of life, psychological disorders associated with changes in appearance, as well as the need for lifelong medication with the frequent development of side effects. Age-related estrogen deficiency associated with the onset of menopause is accompanied by a decrease in the quality of life and, in some cases, a change in the clinical manifestations of somatic diseases. This review considers the impact of menopause and menopausal hormone therapy (MHT) on the course and clinical manifestations of systemic scleroderma. It is noted that SS in some cases is accompanied by an early onset of menopause. The use of MHT is not associated with the progression of cutaneous fibrosis, and may also improve the vascular manifestations of SS.

Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models

BackgroundSystemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice.MethodsCTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson’s trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively.ResultsCompared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes.ConclusionsCTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.

Clinical and diagnostic characteristics of peripheral vasculopathy biomarkers in systemic scleroderma

Vascular lesion is a hallmark of systemic scleroderma (SS). Vasculopathy occurs in every patient with SS. It can be the earliest clinical manifestation or cause the main life‑threatening complications of the disease, and thus determine morbidity and mortality. In SS, progressive vascular damage is characterized by constant activation/damage and apoptosis of endothelial cells, intimal thickening and vasoconstriction, leading to the lumen obliteration. Vascular remodeling leads to a violation of their tone and a decrease in capillary blood flow, followed by tissue ischemia and chronic hypoxia. These phenomena are often accompanied by altered levels of vascular factors. Among the most significant biomarkers of vasculopathy in SS with the greatest evidence base we define anti‑AT1R and anti‑ETAR, soluble intercellular adhesion molecules (sICAM‑1), soluble molecules of adhesion of thrombocyte endothelial cells, placental growth factor (PlGF), pro‑angiogenic angiopoietin‑like protein‑3 (ANGPTL‑3), apelin, chemokines (CXCL5), galectin‑3, E‑selectin, tissue kallikrein, interleukins (IL)‑13 and ‑33, vascular endothelial growth factor (VEGF165b), matrix metalloproteinases‑12, endothelin‑1, nodal adhesion molecules which are associated with the development of either digital ulcers or changes on videocapillaroscopy typical for SS. This shows their active role in the pathogenesis of SS, especially during the disease manifestation. Data is presented on the most significant vascular biomarkers and the main connections between vascular biomarkers and capillaroscopic parameters and/or the presence of digital ulcers in SS. Vascular biomarkers can become prognostic factors of vascular damage at SS, which allows early treatment of vascular complications.

A case of combination of two autoimmune diseases: type 1 diabetes mellitus and systemic scleroderma in a 13-year-old girl

Systemic scleroderma is an autoimmune disease of the connective tissue of unknown etiology. It is characterized by skin induration, lesions in the musculoskeletal system and the internal organs, and the Raynaud syndrome. An important component in pathogenesis of systemic scleroderma is disturbance of microcirculation involving endothelial proliferation and destruction, wall thickening and narrowing of the microvessel lumen, vasospasm, hemocyte aggregation, stasis, deformation and reduction of the capillary network (obliterating microangiopathy). Two main forms of the disease are distinguished: the diffuse and localized ones. The systemic nature of the diffuse form of systemic scleroderma is most obvious in the skin, but the digestive tract, respiratory organs, kidneys and the cardiovascular, endocrine, musculoskeletal and genitourinary systems are also affected. The incidence rate of systemic scleroderma is 6.3—12 cases per million population. Single case reports on scleroderma combined with other autoimmune diseases, including type 1 diabetes mellitus, in children and adolescents are available in literature. A rare case of a combination of two autoimmune diseases, type 1 diabetes mellitus and systemic scleroderma, in a 13-year-old girl is reported in this paper.

СЛУЧАЙ СОЧЕТАНИЯ САХАРНОГО ДИАБЕТА 1-ГО ТИПА И СИСТЕМНОЙ СКЛЕРОДЕРМИИ У ДЕВОЧКИ 13 ЛЕТ

Systemic scleroderma is an autoimmune disease of the connective tissue of unknown etiology. It is characterized by skin induration, lesions in the musculoskeletal system and the internal organs, and the Raynaud syndrome. An important component in pathogenesis of systemic scleroderma is disturbance of microcirculation involving endothelial proliferation and destruction, wall thickening and narrowing of the microvessel lumen, vasospasm, hemocyte aggregation, stasis, deformation and reduction of the capillary network (obliterating microangiopathy). Two main forms of the disease are distinguished: the diffuse and localized ones. The systemic nature of the diffuse form of systemic scleroderma is most obvious in the skin, but the digestive tract, respiratory organs, kidneys and the cardiovascular, endocrine, musculoskeletal and genitourinary systems are also affected. The incidence rate of systemic scleroderma is 6.3—12 cases per million population. Single case reports on scleroderma combined with other autoimmune diseases, including type 1 diabetes mellitus, in children and adolescents are available in literature. A rare case of a combination of two autoimmune diseases, type 1 diabetes mellitus and systemic scleroderma, in a 13-year-old girl is reported in this paper.

Oxidative stress in the pathogenesis of systemic scleroderma: An overview.

Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional manifestations include activation of the immune system and vascular injury. SSc causes disability and death as the result of end‐stage organ failure. Two clinical subsets of the SSc are accepted: limited cutaneous SSc (lc‐SSc) and diffuse cutaneous SSc (dc‐SSc). At present, the aetiology and pathogenesis of SSc remain obscure, and consequently, disease outcome is unpredictable. Numerous studies suggest that reactive oxidizing species (ROS) play an important role in the pathogenesis of scleroderma. Over the years, several reports have supported this hypothesis for both lc‐SSc and dc‐SSc, although the specific role of oxidative stress in the pathogenesis of vascular injury and fibrosis remains to be clarified. The aim of the present review was to report and comment the recent findings regarding the involvement and role of oxidative stress in SSc pathogenesis. Biomarkers proving the link between ROS and the main pathological features of SSc have been summarized.

MicroRNA array analysis of microRNAs related to systemic scleroderma

MicroRNAs are short, 18- to 25-nt sequences of noncoding, single-stranded RNA that function as regulatory molecules and participate in a series of vital processes including early development, cell proliferation, cell differentiation, apoptosis, substance metabolism and the pathogenesis of human diseases. This study compared the microRNA profiles of patients with systemic scleroderma (SSc) and healthy control individuals to investigate the pathogenesis of SSc. Skin tissue was isolated from three patients with SSc and three healthy controls. miRNA microarray chip analysis identified 24 miRNAs that were differentially expressed in patients with SSc and 6 microRNAs that may be correlated with the pathogenesis of SSc. The results of the microarray analysis were confirmed using real-time PCR. This work suggests that miRNAs may be potential diagnosis biomarkers and are likely to be involved in the pathogenesis of SSc.

A Case of Systemic Scleroderma in Triple X Syndrome

frequently in women than men and pathogenesis of systemic scleroderma may be related to female X chromosome. but the role of X chromosome in autoimmunity has not been illustrated yet. Most recently reports, the disturbances in X chromosome and inactivation of X chromosome may be the cause of autoimmunity in abnormal sex chromosome syndrome. Also autoimmune diseases such as systemic scleroderma is increased in Turner’s syndrome. the author had experienced a woman with systemic scleroderma who had been diagnosed to triple X syndrome due to infertility in the past. which was very rare case and not reported yet. So the author report a case of systemic scleroderma with triple X syndrome with literature review.

Possible implication of the effector CD4+ T-cell subpopulation TH17 in the pathogenesis of systemic scleroderma

Systemic scleroderma is one of the most severe chronic autoimmune connective tissue diseases. In this Viewpoint, Dr Deleuran and Dr Abraham discuss the importance of understanding the development, regulation and function of the type 17 T-helper subpopulation of CD4+ T cells in order to explore treatment possibilities in systemic scleroderma.

Activation of Dermal Connective Tissue in Scleroderma

Systemic scleroderma is an acquired disorder which typically results in fibrosis of the skin and internal organs. The pathogenesis of systemic scleroderma is characterized by three distinct processes: microvascular alterations including capillary endothelial cell injury, perivascular inflammatory reaction in dermis, and excessive accumulation of collagen in the dermal layer of lesional skin. In this review, molecular mechanisms resulting in activation of collagen synthesis by dermal fibroblasts in scleroderma are discussed. Specifically, the role of inflammatory cells and the cytokines/growth factors produced by these cells in the pathogenesis of scleroderma is emphasized. The possibilities for prevention and resolution of tissue fibrosis on the basis of these observations are also discussed. Understanding the pathogenetic mechanisms of scleroderma at a molecular level is likely to provide possibilities for development of more specific therapeutic modalities for this and other fibrotic disorders.

Circulating immune complexes in systemic scleroderma and generalized morphea.

There is growing evidence that pathologic changes in the vascular system are implicated in the pathogenesis of systemic scleroderma. It has been suggested that immune complex deposition may be responsible for such changes. We measured circulating immune complexes in 10 patients with severe systemic scleroderma, 1 of whom had clinical evidence of renal disease, and in 3 patients with generalized morphea. None of the patients had significantly elevated levels. Our findings suggest that although circulating immune complexes are of diagnostic and prognostic value in other collagen vascular diseases, they do not play a major role in the pathogenesis of systemic scleroderma in patients who lack clinical evidence of renal disease.

Serum renin and renin substrate levels in scleroderma.

Scleroderma is a disease of mesenchymal tissues characterized by fibrosis and vascular changes which eventually lead to organ insufficiency. Two clinical forms have been recognized, localized and systemic scleroderma. The localized form only affects the skin and the lesions have a tendency to resolve spontaneously. Systemic scleroderma is a progressive, usually irreversible process and the organs most frequently involved are the skin, gastrointestinal tract, lungs and kidneys. The following findings strongly suggest that involvement of small blood vessels (capillaries, arterioles and small size arteries) plays an important role in the pathogenesis of systemic scleroderma: (a) the frequent presence of Raynaud's phenomenon, (b) marked reduction in the number of dermal capillaries, (c) increase in thickness of the basement membrane of muscle capillaries (16), (d) thickening and hyalinization of arterioles (e) intimal proliferation of small size arteries, and (f) eventual ischemic necrosis (2, 3, 17). Small b...