may influence severity and development of the disease. Evidence implicating cytomegalovirus (CMV) as the original epitope of the immune reaction is limited, as is parvovirus B19. Organic solvents and other chemical agents have been linked with scleroderma. One of the suspected mechanisms behind the autoimmune phenomenon is the existence of microchimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material. A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic kidney failure. This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, has been linked to exposure to gadolinium-containing radiocontrast. Bleomycin (a chemotherapeutic agent) and possibly taxane chemotherapy may cause scleroderma, and occupational exposure to solvents has been linked to an increased risk of systemic sclerosis. 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 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 (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 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. Indeed, a common CTGF gene polymorphism is present at an increased level in systemic sclerosis. 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