Editing Systemic scleroderma (section)

==Pathophysiology==
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 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=JimenezDerk/>
[[File:NIH 3T3.jpg|thumb|Fibroblasts]]
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=JimenezDerk/> Indeed, a common ''CTGF'' gene polymorphism is present at an increased level in systemic sclerosis.<ref>{{cite journal  |vauthors=Fonseca C, Lindahl GE, Ponticos M, etal |title=A polymorphism in the CTGF promoter region associated with systemic sclerosis |journal=N. Engl. J. Med. |volume=357 |issue=12 |pages=1210–20 |date=September 2007 |pmid=17881752 |doi=10.1056/NEJMoa067655 |s2cid=7042371 |doi-access=free }}</ref>

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.<ref name=JimenezDerk/>

Jimenez and Derk<ref name=JimenezDerk/> 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.