Scleroderma

St´ephane Chabaud and V´eronique J. Moulin
Received 1 June 2011; Revised 6 July 2011; Accepted 6 July 2011

Systemic sclerosis (scleroderma, SSc) is a heterogeneous disease which develops into three forms: limited, intermediate, and diffuse. The limited form only affects skin of the limbs. In addition to cutaneous disorders, the diffuse one also affects internal organs such as lungs, heart, and kidneys. After a debilitating phase, the most severe form leads to death. This disease is characterized by a strong autoimmune reaction, although it is not clear whether this is a consequence of the disease or a causal factor. Nevertheless, autoantibodies, principally raised against nuclear epitopes, are used like prognostic markers.

In the United States, the disease strikes more African American people and females than Caucasians and males. Besides, the disease appears more prematurely in the African American group and hits them more severely than the Caucasians. The mortality rate for SSc in the group of women has increased by seventy percent over the last twenty years without convincing explanations. The cost of the medical care associated with this disease was estimated at more than $20,000 per patient per year in Canada. The disease is particularly devastating because it strikes people during the most productive period of their professional life.

The causes of SSc are not clearly identified. Genetic factors could not be excluded, but environmental influence seems to be more important. Notably, chronic exposition to chemicals, such as organic solvents and silicone, viral infection by cytomegalovirus (CMV), a member of herpesviruses family, and microchimerism, could all play a role in the disease.

It is thought that SSc begins with vasculopathies through massive endothelial cells death that would lead to obliteration of small arteries and arterioles. It is however unclear if autoantibodies are produced before vascular damages and/or in response to it. Subsequently, cell-to-cell communications are substantially altered, notably by cytokine and growth factor secretion dysregulation. The consequence of these biological changes is an excessive extracellular matrix (ECM) deposition, fibrosis, in tissues followed by their loss of function. SSc varies during the progression of the disease, showing noteworthy changes in fibroblasts phenotype. At the early stage of the disease, cells respond to TGFβ, but become totally insensitive at the late stage for the most affected patients, explaining why treatments targeting this cytokine remain mostly ineffective.

Over the last decades, various models had been used to study SSc. Some animals develop a disease similar to this pathology such as UCD-200 chicken, Tsk-1 and -2 mice. Normal mice could also show some symptoms of the disease after a treatment with Scl-GvHD, Bleomycin, or growth factor injection. Nevertheless, several observations made on these animal models are quite different than those ascertained in humans. Primary cultures of cells isolated from patients are also widely used, and, more recently, a new tissue-engineered reconstructed skin model was shown as a powerful tool to assess the mechanisms involved in the progression of human SSc.

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