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| ==Pathophysiology== | | ==Pathophysiology== |
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| The overproduction of collagen is thought to result from an [[autoimmune disorder|autoimmune dysfunction]], in which the immune system would start to attack the [[kinetochore]] of the chromosomes. This would lead to genetic malfunction of nearby genes. [[T cell]]s accumulate in the skin; these are thought to secrete [[cytokine]]s 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.<ref name="pmid14706971">{{cite journal |author=Jimenez SA, Derk CT |title=Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis |journal=[[Annals of Internal Medicine]] |volume=140 |issue=1 |pages=37–50 |year=2004 |month=January |pmid=14706971 |doi= |url=http://www.annals.org/article.aspx?volume=140&page=37 |accessdate=2012-08-30}}</ref>
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| A significant player in the process is [[transforming growth factor]] (TGFβ). 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 (genetics)|transcription]] of the proteins and enzymes responsible for collagen deposition. ''Sp1'' is a [[transcription factor]] most closely studied in this context. Apart from TGFβ, connective tissue growth factor (CTGF) has a possible role.<ref name="pmid14706971">{{cite journal |author=Jimenez SA, Derk CT |title=Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis |journal=[[Annals of Internal Medicine]] |volume=140 |issue=1 |pages=37–50 |year=2004 |month=January |pmid=14706971 |doi= |url=http://www.annals.org/article.aspx?volume=140&page=37 |accessdate=2012-08-30}}</ref>
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| 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 have similarly been implicated. Increased [[endothelin]] and decreased [[vasodilation]] has been documented.<ref name="pmid14706971">{{cite journal |author=Jimenez SA, Derk CT |title=Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis |journal=[[Annals of Internal Medicine]] |volume=140 |issue=1 |pages=37–50 |year=2004 |month=January |pmid=14706971 |doi= |url=http://www.annals.org/article.aspx?volume=140&page=37 |accessdate=2012-08-30}}</ref>
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| Jimenez & Derk<ref name="pmid14706971">{{cite journal |author=Jimenez SA, Derk CT |title=Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis |journal=[[Annals of Internal Medicine]] |volume=140 |issue=1 |pages=37–50 |year=2004 |month=January |pmid=14706971 |doi= |url=http://www.annals.org/article.aspx?volume=140&page=37 |accessdate=2012-08-30}}</ref> describe three theories about the development of scleroderma:
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| * The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
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| * 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.
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| * Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes which alter the cell's behavior.
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| ===Gross Pathology===
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| ====Cardiovascular==== | | ====Cardiovascular==== |
