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Pathophysiology of systemic sclerosis
Scl6rodermie syst6mique
371 s
Pathophysiology of systemic sclerosis C. B l a c k Royal Free Hospital, Londres, Royaume-Uni
Scleroderma (Systemic Sclerosis) is an exciting disease in 2003, both in terms of improved understanding of pathogenesis and the basic science underlying its pathology. There have also been significant advances occurring in the management of organ-based complications, especially pulmonary vascular disease. Systemic sclerosis has been a paradigm for many chronic fibrotic disorders, such as renal, hepatic and pulmonary fibrosis; it has long been recognised that advances in understanding the biology of scleroderma, both inform progress in other fields, particularly in our understanding of these commoner forms of fibrosis, and also benefit substantially from advances in related disciplines such as cardiology and respiratory medicine. The aetiopathogenesis of scleroderma is complex, but modem genetic approaches have provided the tools with which to address the most vexing aspects of the pathology, namely the overproduction of extracellular matrix by connective tissue fibroblast. The molecular basis for the fibrotic phenotype of interstitial and vascular fibrosis in scleroderma is being elucidated and this is helping to define potential therapeutic targets. There are many candidate mediators in this disease process and some of them
are derived from the endothelial cell, others from monocytes, some from lymphocytes and more recently pericyte products have excited interest. Four particularly exciting candidates are transforming growth factor beta (TGF~), connective tissue growth factor (CTGF), Endothelin-1 (ET-1) and PDGF~3 receptors. TGF~3 has long been known to be expressed in fibrotic states, although its role in chronic fibrosis not entirely clear. CTGF is a relatively recently described factor and a prototypic member of the CCN family of immediate-early response genes. It is emerging as a constitutive fibroblast product in scleroderma and potentially important as a regulator of extracellular matrix homeostasis. Endothelin-1 is one of the most potent vasoconstrictors known, and is also a mitogenic factor contributing to fibroblast activity and is also thought to have an immunomodulatory effect. PDGF~ receptors are expressed on activated pericytes and these interesting cells of mesenchymal origin are capable of differentiating into myofibroblasts. Ultimately this illustrates that therapy may be needed for several targets and combination therapy a necessity. These and other influences on the pathogenesis of the disease will be discussed in this lecture.
Utilisation des immunosuppresseurs dans le traitement de la scl rodermie D. F a r g e - B a n c e l H6pital Saint-Louis, 1, avenue Claude-Vellefaux 75475Pariscedex l~France
La scl6rodermie syst6mique est une maladie syst6mique auto-immune h6tdrog~ne caract6ris6e par un excbs de collagbne dans la peau et les diff6rents organes cibles. Bien que son m6canisme pathog6nique demeure inconnu, l'activation cellulaireT pr6dominante, la production d'auto-anticorps - notamment antitopo-isomdrases (Scl 70) caract6ristiques de la scldrodermie- et la libdration des cytokines, sont des facteurs ddterminants de l'augmentation de la synth~se collag~ne et son d6p6t, de l'activation
fibroblastique, des 16sion microvasculaires et de l'atteinte endoth61iale diffuse. L'infiltration des diffdrents tissus cibles par des cellules T survient pr6cocement au cours de la maladie scl6rodermique, particuli~rement dans les zones p6rivasculaires, et contribue par le biais de la fonction T cytotoxique ou de la production de mddiateurs solubles, g l'augmentation de la production de la matrice extracellulaire et aux alt6rations endothdliales. La numdration des lymphocytes T dans le sang pdriph6rique des
371 s
Pathophysiology of systemic sclerosis C. B l a c k Royal Free Hospital, Londres, Royaume-Uni
Scleroderma (Systemic Sclerosis) is an exciting disease in 2003, both in terms of improved understanding of pathogenesis and the basic science underlying its pathology. There have also been significant advances occurring in the management of organ-based complications, especially pulmonary vascular disease. Systemic sclerosis has been a paradigm for many chronic fibrotic disorders, such as renal, hepatic and pulmonary fibrosis; it has long been recognised that advances in understanding the biology of scleroderma, both inform progress in other fields, particularly in our understanding of these commoner forms of fibrosis, and also benefit substantially from advances in related disciplines such as cardiology and respiratory medicine. The aetiopathogenesis of scleroderma is complex, but modem genetic approaches have provided the tools with which to address the most vexing aspects of the pathology, namely the overproduction of extracellular matrix by connective tissue fibroblast. The molecular basis for the fibrotic phenotype of interstitial and vascular fibrosis in scleroderma is being elucidated and this is helping to define potential therapeutic targets. There are many candidate mediators in this disease process and some of them
are derived from the endothelial cell, others from monocytes, some from lymphocytes and more recently pericyte products have excited interest. Four particularly exciting candidates are transforming growth factor beta (TGF~), connective tissue growth factor (CTGF), Endothelin-1 (ET-1) and PDGF~3 receptors. TGF~3 has long been known to be expressed in fibrotic states, although its role in chronic fibrosis not entirely clear. CTGF is a relatively recently described factor and a prototypic member of the CCN family of immediate-early response genes. It is emerging as a constitutive fibroblast product in scleroderma and potentially important as a regulator of extracellular matrix homeostasis. Endothelin-1 is one of the most potent vasoconstrictors known, and is also a mitogenic factor contributing to fibroblast activity and is also thought to have an immunomodulatory effect. PDGF~ receptors are expressed on activated pericytes and these interesting cells of mesenchymal origin are capable of differentiating into myofibroblasts. Ultimately this illustrates that therapy may be needed for several targets and combination therapy a necessity. These and other influences on the pathogenesis of the disease will be discussed in this lecture.
Utilisation des immunosuppresseurs dans le traitement de la scl rodermie D. F a r g e - B a n c e l H6pital Saint-Louis, 1, avenue Claude-Vellefaux 75475Pariscedex l~France
La scl6rodermie syst6mique est une maladie syst6mique auto-immune h6tdrog~ne caract6ris6e par un excbs de collagbne dans la peau et les diff6rents organes cibles. Bien que son m6canisme pathog6nique demeure inconnu, l'activation cellulaireT pr6dominante, la production d'auto-anticorps - notamment antitopo-isomdrases (Scl 70) caract6ristiques de la scldrodermie- et la libdration des cytokines, sont des facteurs ddterminants de l'augmentation de la synth~se collag~ne et son d6p6t, de l'activation
fibroblastique, des 16sion microvasculaires et de l'atteinte endoth61iale diffuse. L'infiltration des diffdrents tissus cibles par des cellules T survient pr6cocement au cours de la maladie scl6rodermique, particuli~rement dans les zones p6rivasculaires, et contribue par le biais de la fonction T cytotoxique ou de la production de mddiateurs solubles, g l'augmentation de la production de la matrice extracellulaire et aux alt6rations endothdliales. La numdration des lymphocytes T dans le sang pdriph6rique des