Materiały źródłowe

• #1 Pathogenesis of Systemic Sclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4459100/

  Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. […] The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

• #2 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  Systemic sclerosis is a systemic disease that affects numerous organ systems in addition to the skin. The pathogenesis of systemic sclerosis is complex. […] Increasing evidence suggests interaction between environmental and genetic factors, with a regulatory epigenetic mechanism involving changes in the expression of DNA and microRNA. […] The clinical and pathologic manifestations result from three distinct processes: 1) severe fibroproliferative vascular lesions of small arteries and arterioles, 2) excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and various internal organs, and 3) alterations of humoral and cellular immunity. It is not clear which of those processes is of primary importance or how they are temporally related during the development and progression of the disease.

• #3 Pathogenesis of systemic sclerosis (scleroderma) – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-systemic-sclerosis-scleroderma/print

  Pathogenesis of systemic sclerosis (SSc; scleroderma) is complex and remains incompletely understood. Immune activation, vascular damage, and excessive synthesis of extracellular matrix with deposition of increased amounts of structurally normal collagen are all known to be important in the development of this illness. […] Most hypotheses of the pathogenesis of SSc focus on the interplay between early immunological events and vascular changes, which result in the generation of a population of activated fibrogenic fibroblasts generally considered to be the effector cell in the disease. […] There is no doubt that vascular and immunologic processes are central to the pathogenesis of scleroderma, although it is unclear what the initial events are and how different processes respectively trigger, amplify, and facilitate the development of the skin- and organ-based fibrosis with vasculopathy that is the hallmark of the disease.

• #4 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  Systemic sclerosis is a systemic disease that affects numerous organ systems in addition to the skin. The pathogenesis of systemic sclerosis is complex. […] Increasing evidence suggests interaction between environmental and genetic factors, with a regulatory epigenetic mechanism involving changes in the expression of DNA and microRNA. […] The clinical and pathologic manifestations result from three distinct processes: 1) severe fibroproliferative vascular lesions of small arteries and arterioles, 2) excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and various internal organs, and 3) alterations of humoral and cellular immunity. It is not clear which of those processes is of primary importance or how they are temporally related during the development and progression of the disease.

• #5 Scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Scleroderma

  Scleroderma is caused by genetic and environmental factors. Mutations in HLA genes seem to play a crucial role in the pathogenesis of some cases; likewise silica, aromatic and chlorinated solvents, ketones, trichloroethylene, welding fumes, and white spirits exposure seems to contribute to the condition in a small proportion of affected persons. […] Scleroderma is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes, and production of altered connective tissue. Its proposed pathogenesis is the following: […] It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress, or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage, it is predominantly a Th1- and Th17-mediated disease.

• #6

  https://reu.termedia.pl/Systemic-sclerosis-multidisciplinary-disease-clinical-features-and-treatment,111844,0,2.html

  Systemic sclerosis is a chronic autoimmune disease of still not fully understood pathogenesis. Fibrosis, vascular wall damage, and disturbances of innate and acquired immune responses with autoantibody production are prominent features. […] As the knowledge about SSc pathogenesis broadens, factors that cause or influence the development of fibrosis, such as infections, chemical (silica, vinyl chloride) and physical factors are still being analyzed. Their activation is associated with genetic susceptibility correlated with the presence of certain susceptibility genes: HLA (e.g. A23, B18 or DR11) and non-HLA (e.g. CD247, signal transducer and activator of transcription protein 4 (STAT4) and interferon regulatory factor 5 (IRF5), B cell scaffold protein with ankyrin repeats gene (BANK1). […] Epigenetic modifications that play a role in SSc pathogenesis include DNA demethylation of eNOS, CD40L and CD70 (regulatory genes).

• #7 Scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Scleroderma

  Scleroderma is caused by genetic and environmental factors. Mutations in HLA genes seem to play a crucial role in the pathogenesis of some cases; likewise silica, aromatic and chlorinated solvents, ketones, trichloroethylene, welding fumes, and white spirits exposure seems to contribute to the condition in a small proportion of affected persons. […] Scleroderma is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes, and production of altered connective tissue. Its proposed pathogenesis is the following: […] It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress, or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage, it is predominantly a Th1- and Th17-mediated disease.

• #8 Scleroderma: A Fascinating, Troubling Disease – Page 3

  https://www.medscape.com/viewarticle/473349_3

  Scleroderma is an autoimmune connective-tissue disease whose hallmark is excessive collagen deposited around capillaries and in affected tissues, such as the skin, lungs, kidneys, and esophagus. The etiology is unknown, but its pathogenesis involves an activated immune system, abnormal vascular endothelium, and an exaggerated production of fibroblasts that results in abnormal collagen buildup. […] There is an interrelationship among immune, vascular, endothelial, fibroblast, and genetic processes that results in the manifestations of scleroderma. […] If there is a genetic background and an external stimulus, the immune system is activated, resulting in vascular injury, fibroblast proliferation, and collagen deposition in the skin and, often, internal organs. […] Some examples of external stimuli are cold (in the case of Raynaud’s phenomenon), toxic substances, such as organic solvents and silica dust, and organ transplantation.

• #9 Pathogenesis of Systemic Sclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4459100/

  The realization that an interferon (IFN) signature exists in most patients with SSc implies activation of the innate immune system and lends validity to the long-held suspicion that infections (such as with cytomegalovirus, Epstein-Barr virus, and more recently Toxoplasma gondii) could be SSc triggers in receiving more attention and a re-examination. […] There are many unresolved questions related to the etiopathogenesis of SSc. For example, it is unclear whether the innate/adaptive immune system abnormalities, vasculopathy, and fibroblast dysfunctions are separate, unrelated processes or are mechanistically linked, which of the three processes is of utmost importance and how interaction among the three processes leads to the development of the disease. […] The endocannabinoid system (ECS) (which influences functions of the immune system, vasculature, and fibroblasts) may be dysregulated in SSc as suggested by recent studies of SSc dermal fibroblasts.

• #10 Pathogenesis of systemic sclerosis (scleroderma) – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-systemic-sclerosis-scleroderma/print

  In addition, persistent tissue damage is implicated as a potential mechanism driving fibrosis and vasculopathy in SSc. […] Together, it is hypothesized that aberrant tissue damage response may represent the fourth pillar of pathogenesis in SSc alongside inflammation, vasculopathy and fibrosis. […] Many of the genetic loci associated with scleroderma susceptibility in large-scale genetic analyses are also associated with systemic lupus and other autoimmune conditions. […] Moreover, even when non-immune genes are associated in subphenotype analyses of genetic loci, these associations are often defined by hallmark scleroderma autoantibodies, again supporting the key role of the immune system in the development and clinical features of the disease. […] The multiple factors felt to be involved in the pathogenesis of SSc are reviewed here. […] Vascular and endothelial cell changes, primarily mediating vascular tone, appear to precede other features of systemic sclerosis (SSc).

• #11 The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity

  https://www.mdpi.com/1422-0067/24/18/14287

  Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. […] Microvascular injury and vasculopathy are the initial pathological features of the disease. […] Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. […] Endothelial injury is an important initial step in the pathogenesis of SSc. […] The progressive microvascular damage in the nailfold of patients with Raynaud’s phenomenon predicts the development of definite SSc, suggesting the significant association between early vasculopathy and SSc. […] Vasculopathy has been hypothesized to trigger inflammation and fibrosis in SSc. […] The activation and apoptosis of ECs were found to be mediated by IL-6, suggesting its major role in the early stage of SSc.

• #12 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The common SSc-specific pathologic cascade across multiple organs is summarized in Figure 1. Vasculopathy is a critical pathological step bridging between autoimmunity and fibrosis. […] The initial target of autoimmune attacks is believed to be endothelial cells of small blood vessels, including capillaries and arterioles. […] Evidence suggests that dysregulated angiogenesis (imbalance of pro-angiogenic and anti-angiogenic factors) and defective vasculogenesis (decreased number, dysfunction and/or impaired recruitment of circulating bone marrow-derived progenitor cells) underpin the complex vascular pathology of SSc, resulting in the development of vascular structural alterations, such as capillary dilation, capillary loss and arteriolar stenosis. […] The interaction of endothelial cells with circulating immune cells through cell adhesion molecules and chemokine promotes the activation of inflammatory cells and their infiltration into the affected organs of SSc.

• #13 Scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Scleroderma

  Scleroderma is caused by genetic and environmental factors. Mutations in HLA genes seem to play a crucial role in the pathogenesis of some cases; likewise silica, aromatic and chlorinated solvents, ketones, trichloroethylene, welding fumes, and white spirits exposure seems to contribute to the condition in a small proportion of affected persons. […] Scleroderma is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes, and production of altered connective tissue. Its proposed pathogenesis is the following: […] It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress, or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage, it is predominantly a Th1- and Th17-mediated disease.

• #14 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  Numerous studies have suggested a sequence of pathogenetic events initiated by unknown etiologic factors in a genetically receptive host, which trigger microvascular injury characterized by structural and functional endothelial cell abnormalities. The endothelial cell abnormalities result in either increased production and release of numerous potent mediatorsincluding cytokines, chemokines, polypeptide growth factors, and various other substances such as prostaglandins, and reactive oxygen species (ROS)or in the reduction of important compounds such as prostacyclin and nitric oxide. […] The endothelial cell dysfunction allows the chemokine- and cytokine-mediated attraction of inflammatory cells and fibroblast precursors (fibrocytes) from the bloodstream and bone marrow and their transmigration into the surrounding tissues, resulting in the establishment of a chronic inflammatory process with participation of macrophages and T and B lymphocytes, with further production and secretion of cytokines and growth factors from these cells.

• #15 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7565034/

  Evidence suggests that dysregulated angiogenesis (imbalance of pro-angiogenic and anti-angiogenic factors) and defective vasculogenesis (decreased number, dysfunction and/or impaired recruitment of circulating bone marrow-derived progenitor cells) underpin the complex vascular pathology of SSc, resulting in the development of vascular structural alterations, such as capillary dilation, capillary loss and arteriolar stenosis. […] Overall, SSc fibroblasts maintain their activated status through the self-activation system and the feed-forward loop by interacting with other cell types, eventually leading to the irreversible fibrotic remodeling of multiple organs. […] In addition to anti-endothelial cell antibodies and antinuclear antibodies, there is another set of autoantibodies that function as agonists of cell surface receptors.

• #16 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The common SSc-specific pathologic cascade across multiple organs is summarized in Figure 1. Vasculopathy is a critical pathological step bridging between autoimmunity and fibrosis. […] The initial target of autoimmune attacks is believed to be endothelial cells of small blood vessels, including capillaries and arterioles. […] Evidence suggests that dysregulated angiogenesis (imbalance of pro-angiogenic and anti-angiogenic factors) and defective vasculogenesis (decreased number, dysfunction and/or impaired recruitment of circulating bone marrow-derived progenitor cells) underpin the complex vascular pathology of SSc, resulting in the development of vascular structural alterations, such as capillary dilation, capillary loss and arteriolar stenosis. […] The interaction of endothelial cells with circulating immune cells through cell adhesion molecules and chemokine promotes the activation of inflammatory cells and their infiltration into the affected organs of SSc.

• #17 Mechanisms of Disease: the role of immune cells in the pathogenesis of systemic sclerosis | Nature Reviews Rheumatology

  https://www.nature.com/articles/ncprheum0346

  Systemic sclerosis is characterized by extensive fibrosis, microvascular stenosis and autoantibody production. All three characteristics can be accounted for by activation of cells of the immune system. Activation of T cells is antigen-driven and occurs early in the course of the disease, before microscopic evidence of fibrosis. Activated T cells are predominantly of the type 2 T-helper lineage, and produce interleukin-4 and interleukin-13, which induce fibrosis. […] Immune cells are activated early in the course of systemic sclerosis pathogenesis, even before fibrosis has developed. […] The activation of T cells is antigen-driven, but the antigen (or antigens) is yet unknown. […] Activated T cells are mainly of the type 2 T-helper profile and produce IL-4, which promotes fibrosis and antagonizes the antifibrotic effects of interferon-. […] B cells promote fibrosis through the production of autoantibodies. […] Treatments that target immune cells or their harmful soluble mediators have shown promise, and clinical trials are underway.

• #18 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  Numerous studies have suggested a sequence of pathogenetic events initiated by unknown etiologic factors in a genetically receptive host, which trigger microvascular injury characterized by structural and functional endothelial cell abnormalities. The endothelial cell abnormalities result in either increased production and release of numerous potent mediatorsincluding cytokines, chemokines, polypeptide growth factors, and various other substances such as prostaglandins, and reactive oxygen species (ROS)or in the reduction of important compounds such as prostacyclin and nitric oxide. […] The endothelial cell dysfunction allows the chemokine- and cytokine-mediated attraction of inflammatory cells and fibroblast precursors (fibrocytes) from the bloodstream and bone marrow and their transmigration into the surrounding tissues, resulting in the establishment of a chronic inflammatory process with participation of macrophages and T and B lymphocytes, with further production and secretion of cytokines and growth factors from these cells.

• #19 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The immunologic alterations include innate immunity abnormalities, tissue infiltration with macrophages and T and B lymphocytes; production of numerous disease-specific autoantibodies; and dysregulation of cytokine, chemokine, and growth factor production. The released cytokines and growth factors induce the activation and phenotypic conversion of various cellular types, including resident fibroblasts, epithelial cells, endothelial cells, and pericytes into activated myofibroblasts, the cells ultimately responsible for initiation and establishment of the fibrotic process. […] This sequence of events results in the development of a severe and often progressive fibroproliferative vasculopathy, and exaggerated and widespread accumulation of fibrotic tissue, the hallmark of the fibrotic process characteristic of the disease.

• #20 Mechanisms of Disease: the role of immune cells in the pathogenesis of systemic sclerosis | Nature Reviews Rheumatology

  https://www.nature.com/articles/ncprheum0346

  Systemic sclerosis is characterized by extensive fibrosis, microvascular stenosis and autoantibody production. All three characteristics can be accounted for by activation of cells of the immune system. Activation of T cells is antigen-driven and occurs early in the course of the disease, before microscopic evidence of fibrosis. Activated T cells are predominantly of the type 2 T-helper lineage, and produce interleukin-4 and interleukin-13, which induce fibrosis. […] Immune cells are activated early in the course of systemic sclerosis pathogenesis, even before fibrosis has developed. […] The activation of T cells is antigen-driven, but the antigen (or antigens) is yet unknown. […] Activated T cells are mainly of the type 2 T-helper profile and produce IL-4, which promotes fibrosis and antagonizes the antifibrotic effects of interferon-. […] B cells promote fibrosis through the production of autoantibodies. […] Treatments that target immune cells or their harmful soluble mediators have shown promise, and clinical trials are underway.

• #21 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The common SSc-specific pathologic cascade across multiple organs is summarized in Figure 1. Vasculopathy is a critical pathological step bridging between autoimmunity and fibrosis. […] The initial target of autoimmune attacks is believed to be endothelial cells of small blood vessels, including capillaries and arterioles. […] Evidence suggests that dysregulated angiogenesis (imbalance of pro-angiogenic and anti-angiogenic factors) and defective vasculogenesis (decreased number, dysfunction and/or impaired recruitment of circulating bone marrow-derived progenitor cells) underpin the complex vascular pathology of SSc, resulting in the development of vascular structural alterations, such as capillary dilation, capillary loss and arteriolar stenosis. […] The interaction of endothelial cells with circulating immune cells through cell adhesion molecules and chemokine promotes the activation of inflammatory cells and their infiltration into the affected organs of SSc.

• #22 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The vascular alterations preferentially affect small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis. Severe alterations in small blood vessels of skin and internal organs, including endothelial dysfunction, subendothelial fibrosis, and perivascular cellular infiltration with activated T cells and macrophages, are almost universally present in systemic sclerosisaffected tissues. […] Endothelial dysfunction and fibrosis appear to be closely related phenomena. The vascular alterations, including the phenotypic conversion of endothelial cells into activated mesenchymal myofibroblasts, may be the initiating event and the common pathogenetic alteration leading to the fibrotic and chronic inflammatory involvement of multiple organs. […] The activation of endothelial cells induces the expression of chemokines and cell adhesion molecules, and causes the attraction, transendothelial migration, and perivascular accumulation of immunologic-inflammatory cells, including T- and B-lymphocytes and macrophages. The inflammatory cells produce and secrete a variety of cytokines and/or growth factors, including transforming growth factor beta (TGF-) and other profibrotic mediators such as endothelin-1. Those induce increased proliferation of smooth muscle cells, marked accumulation of subendothelial fibrotic tissue, and initiation of platelet aggregation and intravascular thrombosis, eventually causing microvascular occlusion.

• #23 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The fibrotic process is characterized by the excessive production and deposition of types I, III, and VI collagens and other ECM and connective tissue macromolecules, including cartilage oligomeric matrix protein (COMP), glycosaminoglycans, tenascin, and fibronectin. […] This crucial component results from the accumulation in skin and other affected tissues of myofibroblasts, which are cells possessing unique biological functions that include increased production of fibrillar type I and type III collagens, expression of -smooth muscle actin, and reduction in the expression of genes encoding ECMdegradative enzymes. Thus, the accumulation of myofibroblasts in affected tissues and the uncontrolled persistence of their elevated biosynthetic functions are crucial determinants of the extent and rate of progression of the fibrotic process in systemic sclerosis.

• #24 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The fibrotic process is characterized by the excessive production and deposition of types I, III, and VI collagens and other ECM and connective tissue macromolecules, including cartilage oligomeric matrix protein (COMP), glycosaminoglycans, tenascin, and fibronectin. […] This crucial component results from the accumulation in skin and other affected tissues of myofibroblasts, which are cells possessing unique biological functions that include increased production of fibrillar type I and type III collagens, expression of -smooth muscle actin, and reduction in the expression of genes encoding ECMdegradative enzymes. Thus, the accumulation of myofibroblasts in affected tissues and the uncontrolled persistence of their elevated biosynthetic functions are crucial determinants of the extent and rate of progression of the fibrotic process in systemic sclerosis.

• #25 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The activation of fibroblasts is the final consequence of the SSc-specific disease cascade. In the involved organs, there are lots of α-SMA-positive myofibroblasts, which produce excessive amounts of extracellular matrix (ECM). […] A key growth factor involved in the activation of SSc dermal fibroblasts is TGF-β, a potent inducer of ECM including fibrillar collagens constituting the dermis. […] Overall, SSc fibroblasts maintain their activated status through the self-activation system and the feed-forward loop by interacting with other cell types, eventually leading to the irreversible fibrotic remodeling of multiple organs.

• #26 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The activation of fibroblasts is the final consequence of the SSc-specific disease cascade. In the involved organs, there are lots of α-SMA-positive myofibroblasts, which produce excessive amounts of extracellular matrix (ECM). […] A key growth factor involved in the activation of SSc dermal fibroblasts is TGF-β, a potent inducer of ECM including fibrillar collagens constituting the dermis. […] Overall, SSc fibroblasts maintain their activated status through the self-activation system and the feed-forward loop by interacting with other cell types, eventually leading to the irreversible fibrotic remodeling of multiple organs.

• #27 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The immunologic alterations include the production of numerous autoantibodies, some with very high specificity for the disease, as well as abnormalities in the innate and acquired cellular immune responses. […] One of the growth factors that plays a crucial role in the fibrosis that accompanies systemic sclerosis is TGF-. One of the most important effects of TGF- is the stimulation of ECM synthesis by stimulating the production of various collagens and other ECM proteins. […] Besides its potent ECM stimulatory effects, TGF- also induces the generation of myofibroblasts and decreases the production of collagen-degrading metalloproteinases. TGF- also stimulates the production of protease inhibitors, which prevent ECM breakdown.

• #28 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7565034/

  Evidence suggests that dysregulated angiogenesis (imbalance of pro-angiogenic and anti-angiogenic factors) and defective vasculogenesis (decreased number, dysfunction and/or impaired recruitment of circulating bone marrow-derived progenitor cells) underpin the complex vascular pathology of SSc, resulting in the development of vascular structural alterations, such as capillary dilation, capillary loss and arteriolar stenosis. […] Overall, SSc fibroblasts maintain their activated status through the self-activation system and the feed-forward loop by interacting with other cell types, eventually leading to the irreversible fibrotic remodeling of multiple organs. […] In addition to anti-endothelial cell antibodies and antinuclear antibodies, there is another set of autoantibodies that function as agonists of cell surface receptors.

• #29 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  The activation of fibroblasts is the final consequence of the SSc-specific disease cascade. In the involved organs, there are lots of α-SMA-positive myofibroblasts, which produce excessive amounts of extracellular matrix (ECM). […] A key growth factor involved in the activation of SSc dermal fibroblasts is TGF-β, a potent inducer of ECM including fibrillar collagens constituting the dermis. […] Overall, SSc fibroblasts maintain their activated status through the self-activation system and the feed-forward loop by interacting with other cell types, eventually leading to the irreversible fibrotic remodeling of multiple organs.

• #30 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  Historically, the pathogenesis of scleroderma has been poorly understood, but advances in recent years have shed light on some of the molecular and cellular pathways involved in the disease. […] Although not fully understood, the initial insult is thought to be vascular in nature, with injury to the vascular endothelial cells. […] Damage to the endothelium and platelet aggregation result in the release of reactive oxygen species (ROS) and vasoactive mediators, such as thrombin, thromboxane and endothelin-1. […] The central mediator of SSc fibrosis is the pleotropic cytokine, transforming growth factor- (TGF-). […] Active TGF- then stimulates fibroblasts to proliferate and convert to myofibroblasts, which are responsible for laying down the extracellular matrix (ECM). […] Interleukin 6 (IL-6) is also secreted by activated immune cells and plays a role in fibroblast accumulation.

• #31 Current perspectives on the immunopathogenesis of systemic sclerosis | ITT

  https://www.dovepress.com/current-perspectives-on-the-immunopathogenesis-of-systemic-sclerosis-peer-reviewed-fulltext-article-ITT

  Immunological abnormalities of innate and adaptive immune system have long been recognized in SSc, including chronic mononuclear cell infiltration of affected tissues, dysregulation of cytokine and growth factor production, and production of autoantibodies. […] However, the mechanisms responsible for the initiation of autoimmunity leading to fibrosis and the role of immune effector pathways in the pathogenesis of SSc remain incompletely understood. […] Several recent studies implicate TLR signaling as one of the early steps during inflammatory and fibrotic processes of SSc. […] Recent studies have focused on TGF and to a lesser extent on IL-13 as major profibrotic factors in the pathogenesis of SSc. […] TGF has long been implicated in the pathogenesis of SSc. […] Multiple studies indicate that the immunopathological response in SSc is dominated by type 2 cytokines, such as IL-4 and IL-13. […] Chemokines play a crucial role in the inflammatory, vascular, and fibrotic processes of SSc. […] Autoantibodies directed against a variety of intracellular antigens are present in nearly all patients and are considered a hallmark of SSc.

• #32 Scleroderma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/331864-overview

  The immunologic alterations include the production of numerous autoantibodies, some with very high specificity for the disease, as well as abnormalities in the innate and acquired cellular immune responses. […] One of the growth factors that plays a crucial role in the fibrosis that accompanies systemic sclerosis is TGF-. One of the most important effects of TGF- is the stimulation of ECM synthesis by stimulating the production of various collagens and other ECM proteins. […] Besides its potent ECM stimulatory effects, TGF- also induces the generation of myofibroblasts and decreases the production of collagen-degrading metalloproteinases. TGF- also stimulates the production of protease inhibitors, which prevent ECM breakdown.

• #33

  https://link.springer.com/article/10.1007/s12016-021-08889-8

  Fibroproliferative modifications of vessel walls and rarefaction of capillaries underpin vasculopathy in SSc which affects mainly the micro-circulation, but also the macro-circulation. Endothelial cell (EC) dysfunction and damage are considered cornerstones of SSc vasculopathy. […] Transition to inflammatory events then occurs with opening of tight EC junctions, fluid leakage in the extravascular space, and enhanced expression of adhesion molecules, all favoring the recruitment of mononuclear cells. […] Infectious agents, autoantibodies, toxic compounds, and cytolytic T and NK cells may be causes of EC apoptosis. […] Significant intimal proliferation and accumulation of proteoglycans in the arterioles and small sized arteries are common in SSc. […] The activity of TGF- is tightly regulated at several levels including the availability of the biological active form, receptor binding, and most importantly the intracellular signaling pathway level which offers potential targets of treatment.

• #34 Systemic scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Systemic_scleroderma

  Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. […] Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack the kinetochore of the chromosomes. This would lead to genetic malfunction of nearby genes. T cells accumulate in the skin; these are thought to secrete cytokines and other proteins that stimulate collagen deposition. Stimulation of the fibroblast, in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect. […] A significant player in the process is transforming growth factor (TGF). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting of SMAD2/SMAD3, SMAD4, and the inhibitor SMAD7) is responsible for the secondary messenger system that induces transcription of the proteins and enzymes responsible for collagen deposition.

• #35 The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity

  https://www.mdpi.com/1422-0067/24/18/14287

  Disruption to T-cell homeostasis has been suggested in SSc. […] The expression of cell adhesion molecules on inflammatory cells and ECs plays a pivotal role in immune polarization. […] Many studies have found evidence of monocyte/macrophage activation in the fibrotic process, with profibrotic M2 macrophage being the prominent player. […] Vasculopathy is important in SSc. […] The activation of immune cells promotes the production of proinflammatory cytokines, which subsequently activate the potential precursors of extracellular matrix (ECM)-producing myofibroblasts, such as pericytes, resident fibroblasts, endothelial cells, or adipocytes. […] The pivotal inducer of EndoMT is postulated to be the TGF-β family. […] The activated platelets and endothelial cells secrete profibrotic mediators, inducing TGF-β1, serotonin, endothelin-1 (ET-1), and platelet-derived microparticles (PMPs), which further amplify the fibrosis in SSc.

• #36 Systemic Sclerosis Pathogenesis Appears Linked to Changes in Endothelial Cells, Researcher Tells SSc World Congress 2016 | Scleroderma NewsEnvelope icon

  https://sclerodermanews.com/news/4943/

  Scientists from the University of Florence, Italy, presented a study investigating the participation of the Endothelial-to-Mesenchymal transition (EndoMT) process in the pathogenesis of systemic sclerosis (SSc) at the 4th Systemic Sclerosis World Congress in Lisbon, Portugal, that concluded Feb. 20, 2016. […] The proposed pathogenesis pathway involves the generation of myofibroblasts, whose dysregulated activity leads to excessive deposits of collagen and other proteins, and, consequently, fibrosis. […] It has also been suggested that endothelial cells (ECs) may transform into more myofibroblastic-like cells through a process called EndoMT. […] EndoMT has been implicated in the pathogenesis of SSc-associated pulmonary fibrosis and pulmonary arterial hypertension. […] Our findings provide the first direct evidence that EndoMT may contribute to the development of dermal fibrosis in SSc.

• #37 Current perspectives on the immunopathogenesis of systemic sclerosis | ITT

  https://www.dovepress.com/current-perspectives-on-the-immunopathogenesis-of-systemic-sclerosis-peer-reviewed-fulltext-article-ITT

  Immunological abnormalities of innate and adaptive immune system have long been recognized in SSc, including chronic mononuclear cell infiltration of affected tissues, dysregulation of cytokine and growth factor production, and production of autoantibodies. […] However, the mechanisms responsible for the initiation of autoimmunity leading to fibrosis and the role of immune effector pathways in the pathogenesis of SSc remain incompletely understood. […] Several recent studies implicate TLR signaling as one of the early steps during inflammatory and fibrotic processes of SSc. […] Recent studies have focused on TGF and to a lesser extent on IL-13 as major profibrotic factors in the pathogenesis of SSc. […] TGF has long been implicated in the pathogenesis of SSc. […] Multiple studies indicate that the immunopathological response in SSc is dominated by type 2 cytokines, such as IL-4 and IL-13. […] Chemokines play a crucial role in the inflammatory, vascular, and fibrotic processes of SSc. […] Autoantibodies directed against a variety of intracellular antigens are present in nearly all patients and are considered a hallmark of SSc.

• #38

  https://link.springer.com/article/10.1007/s11926-012-0297-8

  The fundamental mechanisms that drive the pathogenesis of systemic sclerosis (SSc) remain elusive, despite over 50 years of investigation. […] Here, we review recent progress in the understanding of the immunopathogenesis of SSc. In particular, we consider interleukin-13 (IL13), and its upstream and downstream pathways, as an example of an immune system-derived mediator involved in fibrotic and vascular pathology. […] Emerging results linking pattern-recognition receptors and interferon pathways to SSc are also stressed. […] We discuss genetic data linking the immune system to SSc risk and efforts to apply animal models to subsets of patients recently resolved by gene expression profiling. […] These developments will help build a context for better understanding of previous observations and design of the next generation of studies that may eventually lead to effective treatment.

• #39

  https://link.springer.com/article/10.1007/s11926-012-0297-8

  Here we describe the contribution of IL-13 to the SclGVHD model, including the cellular sources and effects of IL-13. […] This paper identifies expression of type I interferon and TGF target genes in the skin of SSc patients and demonstrates that chronic subcutaneous infusion of type I interferon eliciting poly I:C stimulates inflammation and fibrosis. […] The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. […] Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. […] Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement. […] IL-33 induces IL-13-dependent cutaneous fibrosis. […] The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?

• #40 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  Historically, the pathogenesis of scleroderma has been poorly understood, but advances in recent years have shed light on some of the molecular and cellular pathways involved in the disease. […] Although not fully understood, the initial insult is thought to be vascular in nature, with injury to the vascular endothelial cells. […] Damage to the endothelium and platelet aggregation result in the release of reactive oxygen species (ROS) and vasoactive mediators, such as thrombin, thromboxane and endothelin-1. […] The central mediator of SSc fibrosis is the pleotropic cytokine, transforming growth factor- (TGF-). […] Active TGF- then stimulates fibroblasts to proliferate and convert to myofibroblasts, which are responsible for laying down the extracellular matrix (ECM). […] Interleukin 6 (IL-6) is also secreted by activated immune cells and plays a role in fibroblast accumulation.

• #41 The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity

  https://www.mdpi.com/1422-0067/24/18/14287

  Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. […] Microvascular injury and vasculopathy are the initial pathological features of the disease. […] Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. […] Endothelial injury is an important initial step in the pathogenesis of SSc. […] The progressive microvascular damage in the nailfold of patients with Raynaud’s phenomenon predicts the development of definite SSc, suggesting the significant association between early vasculopathy and SSc. […] Vasculopathy has been hypothesized to trigger inflammation and fibrosis in SSc. […] The activation and apoptosis of ECs were found to be mediated by IL-6, suggesting its major role in the early stage of SSc.

• #42

  https://link.springer.com/article/10.1007/s11926-012-0297-8

  Here we describe the contribution of IL-13 to the SclGVHD model, including the cellular sources and effects of IL-13. […] This paper identifies expression of type I interferon and TGF target genes in the skin of SSc patients and demonstrates that chronic subcutaneous infusion of type I interferon eliciting poly I:C stimulates inflammation and fibrosis. […] The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. […] Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. […] Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement. […] IL-33 induces IL-13-dependent cutaneous fibrosis. […] The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis?

• #43 Current perspectives on the immunopathogenesis of systemic sclerosis | ITT

  https://www.dovepress.com/current-perspectives-on-the-immunopathogenesis-of-systemic-sclerosis-peer-reviewed-fulltext-article-ITT

  Immunological abnormalities of innate and adaptive immune system have long been recognized in SSc, including chronic mononuclear cell infiltration of affected tissues, dysregulation of cytokine and growth factor production, and production of autoantibodies. […] However, the mechanisms responsible for the initiation of autoimmunity leading to fibrosis and the role of immune effector pathways in the pathogenesis of SSc remain incompletely understood. […] Several recent studies implicate TLR signaling as one of the early steps during inflammatory and fibrotic processes of SSc. […] Recent studies have focused on TGF and to a lesser extent on IL-13 as major profibrotic factors in the pathogenesis of SSc. […] TGF has long been implicated in the pathogenesis of SSc. […] Multiple studies indicate that the immunopathological response in SSc is dominated by type 2 cytokines, such as IL-4 and IL-13. […] Chemokines play a crucial role in the inflammatory, vascular, and fibrotic processes of SSc. […] Autoantibodies directed against a variety of intracellular antigens are present in nearly all patients and are considered a hallmark of SSc.

• #44 Current perspectives on the immunopathogenesis of systemic sclerosis | ITT

  https://www.dovepress.com/current-perspectives-on-the-immunopathogenesis-of-systemic-sclerosis-peer-reviewed-fulltext-article-ITT

  Immunological abnormalities of innate and adaptive immune system have long been recognized in SSc, including chronic mononuclear cell infiltration of affected tissues, dysregulation of cytokine and growth factor production, and production of autoantibodies. […] However, the mechanisms responsible for the initiation of autoimmunity leading to fibrosis and the role of immune effector pathways in the pathogenesis of SSc remain incompletely understood. […] Several recent studies implicate TLR signaling as one of the early steps during inflammatory and fibrotic processes of SSc. […] Recent studies have focused on TGF and to a lesser extent on IL-13 as major profibrotic factors in the pathogenesis of SSc. […] TGF has long been implicated in the pathogenesis of SSc. […] Multiple studies indicate that the immunopathological response in SSc is dominated by type 2 cytokines, such as IL-4 and IL-13. […] Chemokines play a crucial role in the inflammatory, vascular, and fibrotic processes of SSc. […] Autoantibodies directed against a variety of intracellular antigens are present in nearly all patients and are considered a hallmark of SSc.

• #45 Pathogenesis of Systemic Sclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4459100/

  Lysophospholipids [lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)] and their different receptors (which regulate immunity, vascular physiology, and fibrosis) are dysregulated in SSc and likely contribute to the pathogenesis of the disease. […] Vitamin D (VitD) status also impacts function of most cell types and likely influences pathogenesis and clinical features of SSc.

• #46 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  The bioactive lipid mediators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are also implicated in SSc pathogenesis. […] The interplay of these mediators leads to progressive ECM accumulation and structural remodeling, which causes further activation of fibroblasts and results in the progression of fibrosis. […] Effective therapies to prevent or halt this progression will need to disrupt the cellular events illustrated in Figure 1. […] The incomplete understanding of the pathogenesis of scleroderma has historically been one barrier to the development of effective treatments for the disease. […] Given the central role of TGF- in the development of scleroderma fibrosis, it is a natural target for therapy in SSc. […] A recent open-label trial of fresolimumab, a monoclonal antibody against TGF- that neutralizes all isoforms of the molecule, compared two doses of the drug in patients with early (less than two years) dcSSc.

• #47

• #48 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7565034/

  The anti-PDGFR antibody induces the collagen production of fibroblasts, and the proliferation and migration of pulmonary vascular smooth muscle cells, possibly contributing to the development of organ fibrosis and PAH. […] Overall, the pathogenesis of SRC should be understood based on two distinct vascular changes, namely, structural changes (capillary loss and arteriolar stenosis) and functional abnormality (renal vasospasm), as is the case with heart involvement.

• #49 Pathogenesis of Systemic Sclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4459100/

  Lysophospholipids [lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)] and their different receptors (which regulate immunity, vascular physiology, and fibrosis) are dysregulated in SSc and likely contribute to the pathogenesis of the disease. […] Vitamin D (VitD) status also impacts function of most cell types and likely influences pathogenesis and clinical features of SSc.

• #50 Scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Scleroderma

  Fibroblasts are recruited and activated by multiple cytokines and growth factors to generate myofibroblasts. Dysregulated transforming growth factor (TGF-) signalling in fibroblasts and myofibroblasts has been observed in multiple studies of scleroderma-affected individuals. Activation of fibroblasts and myofibroblasts leads to excessive deposition of collagen and other related proteins, leading to fibrosis. B cells are implicated in this stage, IL-6 and TGF- produced by the B cells decrease collagen degradation and increase extracellular matrix production. Endothelin signalling is implicated in the pathophysiology of fibrosis. […] Vitamin D is implicated in the pathophysiology of the disease. An inverse correlation between plasma levels of vitamin D and scleroderma severity has been noted, and vitamin D is known to play a crucial role in regulating (usually suppressing) the actions of the immune system.

• #51

  https://link.springer.com/article/10.1007/s12016-021-08889-8

  Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. […] The most commonly postulated model of disease progression in SSc is sequential, with immune activation and subsequent vasculopathy leading to activation of fibroblasts and fibrosis as the end effect of these processes. […] Thus, SSc can be viewed as a three-leg pathology in which major dysfunctional cell types are immune cells, endothelial cells, and fibroblasts which intensely interact mostly via soluble mediators directly or indirectly leading to myo-fibroblast hyperactivation. […] The term of intermediate pathophenotypes has been proposed by C. Feghali-Bostwick and J. Varga to accommodate the dynamic processes underlying heterogeneity in SSc and our understanding of the mechanisms involved in SSc pathogenesis at cellular and tissue levels.

• #52 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung.

• #53 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung.

• #54 The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

  https://www.mdpi.com/2077-0383/9/9/2687

  Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung.

• #55

  https://link.springer.com/article/10.1007/s12016-021-08889-8

  Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. […] The most commonly postulated model of disease progression in SSc is sequential, with immune activation and subsequent vasculopathy leading to activation of fibroblasts and fibrosis as the end effect of these processes. […] Thus, SSc can be viewed as a three-leg pathology in which major dysfunctional cell types are immune cells, endothelial cells, and fibroblasts which intensely interact mostly via soluble mediators directly or indirectly leading to myo-fibroblast hyperactivation. […] The term of intermediate pathophenotypes has been proposed by C. Feghali-Bostwick and J. Varga to accommodate the dynamic processes underlying heterogeneity in SSc and our understanding of the mechanisms involved in SSc pathogenesis at cellular and tissue levels.

• #56

  https://link.springer.com/article/10.1007/s12016-021-08889-8

  Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. […] The most commonly postulated model of disease progression in SSc is sequential, with immune activation and subsequent vasculopathy leading to activation of fibroblasts and fibrosis as the end effect of these processes. […] Thus, SSc can be viewed as a three-leg pathology in which major dysfunctional cell types are immune cells, endothelial cells, and fibroblasts which intensely interact mostly via soluble mediators directly or indirectly leading to myo-fibroblast hyperactivation. […] The term of intermediate pathophenotypes has been proposed by C. Feghali-Bostwick and J. Varga to accommodate the dynamic processes underlying heterogeneity in SSc and our understanding of the mechanisms involved in SSc pathogenesis at cellular and tissue levels.

• #57 Pathogenesis of systemic sclerosis (scleroderma) – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-systemic-sclerosis-scleroderma/print

  In addition, persistent tissue damage is implicated as a potential mechanism driving fibrosis and vasculopathy in SSc. […] Together, it is hypothesized that aberrant tissue damage response may represent the fourth pillar of pathogenesis in SSc alongside inflammation, vasculopathy and fibrosis. […] Many of the genetic loci associated with scleroderma susceptibility in large-scale genetic analyses are also associated with systemic lupus and other autoimmune conditions. […] Moreover, even when non-immune genes are associated in subphenotype analyses of genetic loci, these associations are often defined by hallmark scleroderma autoantibodies, again supporting the key role of the immune system in the development and clinical features of the disease. […] The multiple factors felt to be involved in the pathogenesis of SSc are reviewed here. […] Vascular and endothelial cell changes, primarily mediating vascular tone, appear to precede other features of systemic sclerosis (SSc).

• #58 Systemic scleroderma – Wikipedia

  https://en.wikipedia.org/wiki/Systemic_scleroderma

  Damage to endothelium is an early abnormality in the development of scleroderma, and this, too, seems to be due to collagen accumulation by fibroblasts, although direct alterations by cytokines, platelet adhesion, and a type II hypersensitivity reaction similarly have been implicated. Increased endothelin and decreased vasodilation have been documented. […] Jimenez and Derk describe three theories about the development of scleroderma: The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult. The initial event is fetomaternal cell transfer causing microchimerism, with a second summative cause (e.g. environmental) leading to the actual development of the disease. Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes that alter the cells’ behavior.

• #59 Scleroderma: A Fascinating, Troubling Disease – Page 3

  https://www.medscape.com/viewarticle/473349_3

  The vasospasm that is manifested as Raynaud’s phenomenon can stimulate the immune system, thus resulting in a „mini-feedback loop” in which immune activation results in vascular damage (or vice versa). […] One other external stimulus being studied is that of microchimerism. […] Given a susceptible genetic background, this situation could explain the autoimmune response in those patients because the fetal cells are seen as „not me” but are also enough like the mother’s cells that they are not rejected outright, and vice versa. […] There is generally no specific, highly penetrant genetic predisposition to scleroderma, although there is an HLA-associated increase in prevalence.

• #60 Systemic Sclerosis Pathogenesis – Is Blood Rheology the Key? – Scleroderma Education Project

  https://sclerodermainfo.org/research/systemic-sclerosis-pathogenesis-blood-rheology/

  Abnormally clumped red blood cells may be a significant component of the etiopathogenic processes in SSc, potentially contributing to the vascular damage cited above. […] The exact mechanisms of endothelial damage from clumped RBCs are currently unknown, but likely include direct mechanical effects tending to remodel vessel walls and changes due to local ischemia caused by abnormal distribution of red cells in the microcirculation. […] The hypothesis advanced in this paper is that abnormally clumped RBCs may be a significant component of the etiopathogenic processes in SSc, potentially causing or contributing to the vascular damage to the endothelial layers of the microcapillaries that appear to trigger the downstream fibrotic processes and systemic fibrosis that are the hallmark of SSc.

• #61 Unveiling the Primary Cilia Signature Driving Systemic Sclerosis Pathogenesis – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/unveiling-the-primary-cilia-signature-driving-systemic-sclerosis-pathogenesis/

  Unveiling the Primary Cilia Signature Driving Systemic Sclerosis Pathogenesis […] Fibrosis in multiple organs is the defining hallmark that accounts for the high mortality associated with systemic sclerosis (SSc). Understanding how SSc patients develop fibrosis is crucial for developing new treatments. Our goal is to discover fibrosis-driving cellular mechanisms that can lead to novel therapeutics for SSc. Here we focus on non-motile primary cilia (PC), dynamic solitary cellular organelles, that serve as antennae for both chemical and mechanical cues. […] A robust skin transcriptomic meta-analysis of multiple independent datasets with both microarrays (n=8) and scRNA-seq (n=3), revealed a distinct cilia gene signature associated with SSc. Gene ontology analysis showed a predominant downregulation of ciliary assembly genes and concomitant upregulation of ciliary disassembly genes in SSc biopsies.

• #62 Unveiling the Primary Cilia Signature Driving Systemic Sclerosis Pathogenesis – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/unveiling-the-primary-cilia-signature-driving-systemic-sclerosis-pathogenesis/

  Differential expression of PC genes (the primary cilia signature) in the skin is associated with SSc, and PC shortening is an early hallmark event in SSc pathogenesis that drives fibrotic reprogramming of dermal fibroblasts. Accordingly, PC may represent a therapeutic target for SSc, suggesting the possibility of ciliotherapy as a treatment.

• #63 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  The bioactive lipid mediators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are also implicated in SSc pathogenesis. […] The interplay of these mediators leads to progressive ECM accumulation and structural remodeling, which causes further activation of fibroblasts and results in the progression of fibrosis. […] Effective therapies to prevent or halt this progression will need to disrupt the cellular events illustrated in Figure 1. […] The incomplete understanding of the pathogenesis of scleroderma has historically been one barrier to the development of effective treatments for the disease. […] Given the central role of TGF- in the development of scleroderma fibrosis, it is a natural target for therapy in SSc. […] A recent open-label trial of fresolimumab, a monoclonal antibody against TGF- that neutralizes all isoforms of the molecule, compared two doses of the drug in patients with early (less than two years) dcSSc.

• #64 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  The bioactive lipid mediators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are also implicated in SSc pathogenesis. […] The interplay of these mediators leads to progressive ECM accumulation and structural remodeling, which causes further activation of fibroblasts and results in the progression of fibrosis. […] Effective therapies to prevent or halt this progression will need to disrupt the cellular events illustrated in Figure 1. […] The incomplete understanding of the pathogenesis of scleroderma has historically been one barrier to the development of effective treatments for the disease. […] Given the central role of TGF- in the development of scleroderma fibrosis, it is a natural target for therapy in SSc. […] A recent open-label trial of fresolimumab, a monoclonal antibody against TGF- that neutralizes all isoforms of the molecule, compared two doses of the drug in patients with early (less than two years) dcSSc.

• #65 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  Another drug targeting the TGF- pathway, abituzumab, a monoclonal antibody against v integrin, will be evaluated in an upcoming Phase 2 trial for SSc-ILD. […] Based on the preclinical work of LPA and its receptor, LPA1, in dermal fibrosis, a Phase 2 trial of an LPA1 antagonist, SAR100842, was recently completed and showed an excellent safety profile and promising clinical efficacy. […] Given the role of endothelin-1 in fibrosis and the use of endothelin-1 receptor antagonists (ERAs) in the treatment of SSc-associated PH, there has been promise that these medications might additionally provide benefit in skin fibrosis. […] A number of other new therapeutics are currently under evaluation for SSc fibrosis. […] There has been significant progress in understanding the pathogenesis of scleroderma and consequently in the development of novel targeted therapies for patients with this devastating disease.

• #66 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  Another drug targeting the TGF- pathway, abituzumab, a monoclonal antibody against v integrin, will be evaluated in an upcoming Phase 2 trial for SSc-ILD. […] Based on the preclinical work of LPA and its receptor, LPA1, in dermal fibrosis, a Phase 2 trial of an LPA1 antagonist, SAR100842, was recently completed and showed an excellent safety profile and promising clinical efficacy. […] Given the role of endothelin-1 in fibrosis and the use of endothelin-1 receptor antagonists (ERAs) in the treatment of SSc-associated PH, there has been promise that these medications might additionally provide benefit in skin fibrosis. […] A number of other new therapeutics are currently under evaluation for SSc fibrosis. […] There has been significant progress in understanding the pathogenesis of scleroderma and consequently in the development of novel targeted therapies for patients with this devastating disease.

• #67 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  Another drug targeting the TGF- pathway, abituzumab, a monoclonal antibody against v integrin, will be evaluated in an upcoming Phase 2 trial for SSc-ILD. […] Based on the preclinical work of LPA and its receptor, LPA1, in dermal fibrosis, a Phase 2 trial of an LPA1 antagonist, SAR100842, was recently completed and showed an excellent safety profile and promising clinical efficacy. […] Given the role of endothelin-1 in fibrosis and the use of endothelin-1 receptor antagonists (ERAs) in the treatment of SSc-associated PH, there has been promise that these medications might additionally provide benefit in skin fibrosis. […] A number of other new therapeutics are currently under evaluation for SSc fibrosis. […] There has been significant progress in understanding the pathogenesis of scleroderma and consequently in the development of novel targeted therapies for patients with this devastating disease.

• #68 Targeted Therapy for Scleroderma Fibrosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/targeted-therapy-scleroderma-fibrosis/?singlepage=1

  The bioactive lipid mediators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are also implicated in SSc pathogenesis. […] The interplay of these mediators leads to progressive ECM accumulation and structural remodeling, which causes further activation of fibroblasts and results in the progression of fibrosis. […] Effective therapies to prevent or halt this progression will need to disrupt the cellular events illustrated in Figure 1. […] The incomplete understanding of the pathogenesis of scleroderma has historically been one barrier to the development of effective treatments for the disease. […] Given the central role of TGF- in the development of scleroderma fibrosis, it is a natural target for therapy in SSc. […] A recent open-label trial of fresolimumab, a monoclonal antibody against TGF- that neutralizes all isoforms of the molecule, compared two doses of the drug in patients with early (less than two years) dcSSc.

• #69 Epigenetic mechanism of systemic sclerosis

  https://www.nature.com/articles/d41573-019-00112-w

  The pathogenic mechanism of systemic sclerosis (SSc), an autoimmune disease that results in progressive fibrosis of connective tissue, remains unknown. Here, Shin et al. report that constitutive epigenetic activation of a novel enhancer of transforming growth factor-2, which regulates collagen synthesis and deposition in the extracellular matrix, locks lesional fibroblasts from patients with SSc in a profibrotic state, through a BRD4 and NF-B-dependent mechanism. […] Treatment of SSc patient-derived skin explants with the bromodomain inhibitor JQ1 repressed collagen synthesis and reversed fibrosis.

• #70 Systemic sclerosis : pathogenesis and target therapies | Institut Cochin

  https://institutcochin.fr/en/research-project/systemic-sclerosis-pathogenesis-and-target-therapies

  We believe that innate immunity and macrophage training play a key role in the pathogenesis of SSc. The worsening of the disease could be caused by inappropriate entrained immunity of macrophages, induced by a form of dysbiosis. Our main objective is to decipher the links between diet, microbiota and trained immunity in the context of SSc. This new study should provide fundamental information on the immune impact of diet and environment on the gut and lung microbiota in SSc. Our results could allow the development of alternative therapeutic tools targeting the diet and the microbiota, thus constituting a less invasive therapy than the immunosuppressive drugs used today.

• #71

  https://grantome.com/grant/NIH/R61-AR076821-01

  Systemic sclerosis (SSc) is a prototypic fibrotic illness affecting virtually every organ. […] In addition to fibrosis, vascular injury and gut dysbiosis are prominent; however, how these distinct processes are governed by gene-environment interactions, and how they are linked together in pathogenesis is largely unknown, precluding development of disease-modifying therapy. […] Our hypothesis is that choline-rich diets via a metaorganismal axis generate elevated TMAO, which promotes vascular injury and organ fibrosis via endothelial-mesenchymal transition (endoMT) and other pathways implicated in SSc pathogenesis. […] This project seeks to validate an entirely novel SSc paradigm that links the environment/diet and genetic risk (FMO3 variants) in a metaorganismal pathway that underlies SSc pathogenesis and can be selectively targeted for therapy.

• #72 Systemic Sclerosis (SSc) Review | Rheumatology | EMJ Reviews

  https://www.emjreviews.com/rheumatology/article/systemic-sclerosis/

  Increasing understanding of the pathogenesis of SSc has driven the recent flurry of clinical trials for drug therapies for SSc. However, demonstration of treatment efficacy of drug therapies is a significant challenge. Future studies need to consider the heterogeneity of the disease and important aspects of study design, such as patient selection and the incorporation of novel endpoints of treatment efficacy.

• #73 Progress Continues in Systemic Sclerosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/progress-continues-in-systemic-sclerosis/?singlepage=1

  Systemic sclerosis is a rare disease, and familial SSc is observed for only a small number of cases. Therefore, it is unlikely for most rheumatologists to see a multicase family. […] Both studies found a strong association with the HLA Class II region on chromosome 6, firmly establishing that SSc is an autoimmune disease. […] Several pathophysiologic mechanisms exist leading to elevated pulmonary arterial pressures in individuals with SSc. Because SSc is considered a subgroup belonging to the disease entity of PAH, the pathologic anatomy of pulmonary vessels has been regarded as similar to the vascular changes found in other forms of PAH. […] As shown in Figure 1 (above), a number of cytokines and proteins have potential roles in the pathogenesis of this disease. […] While SSc is often said to be the most fearsome of the autoimmune diseases, molecular targets for therapy have been defined and pilot trials of targeted therapies are underway. […] Important advances have been gained in our understanding of the genetics, pathobiology and treatment of severe SSc.

• #74 Progress Continues in Systemic Sclerosis – The Rheumatologist

  https://www.the-rheumatologist.org/article/progress-continues-in-systemic-sclerosis/?singlepage=1

  Systemic sclerosis is a rare disease, and familial SSc is observed for only a small number of cases. Therefore, it is unlikely for most rheumatologists to see a multicase family. […] Both studies found a strong association with the HLA Class II region on chromosome 6, firmly establishing that SSc is an autoimmune disease. […] Several pathophysiologic mechanisms exist leading to elevated pulmonary arterial pressures in individuals with SSc. Because SSc is considered a subgroup belonging to the disease entity of PAH, the pathologic anatomy of pulmonary vessels has been regarded as similar to the vascular changes found in other forms of PAH. […] As shown in Figure 1 (above), a number of cytokines and proteins have potential roles in the pathogenesis of this disease. […] While SSc is often said to be the most fearsome of the autoimmune diseases, molecular targets for therapy have been defined and pilot trials of targeted therapies are underway. […] Important advances have been gained in our understanding of the genetics, pathobiology and treatment of severe SSc.

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