Development and Progression of Scleroderma
Scleroderma is primarily the consequence of 3 major factors: blood vessel damage, an autoimmune response, and fibrosis. In many ways, these factors create a vicious cycle, thus the disease is typically progressive; this is especially so for systemic sclerosis (Gabrielli 2008; Gomer 2008).
Blood Vessel Damage
Small blood vessels are especially prone to the damage and dysfunction caused by scleroderma. Vascular dysfunction is mostly the result of inflammation and fibrosis, which cause blood vessels to become “stiff” and disrupt their ability to expand and contract (Varga 2008). A major hallmark of vascular damage that occurs in scleroderma is endothelial dysfunction. The endothelium is the delicate innermost lining of blood vessels (Varga 2008; Deanfield 2005; Patel 2001; Gabrielli 2009). In severe cases of systemic sclerosis, dramatic vascular dysfunction can be life threatening (Hummers 2008).
In addition, scleroderma is associated with increased deposition of calcium in blood vessels. In one study, systemic sclerosis patients were found to have an 11-fold increased risk of moderate-to-severe calcification in the arteries that supply the heart (Mok 2011). Moreover, autopsy investigations of systemic sclerosis patients have found extensive calcification of small blood vessels that supply the brain (Heron 1998).
Inflammation and Autoimmune Response
Inflammatory and autoimmune reactions also contribute to the tissue damage and dysfunction seen in scleroderma. Blood vessel alterations lead to an inflammatory response within the endothelium. In turn, damaged endothelial cells release inflammatory signaling molecules that recruit immune cells, in particular CD4+ helper T-cells, to the blood vessel walls. The presence of excessive inflammatory mediators serves to reinforce the continued deterioration of blood vessel integrity and subsequent generation of more inflammation and fibrosis. Autoimmunity also contributes to inflammatory damage of the blood vessels, though it is not known with certainty if an autoimmune response is the key initiating factor in scleroderma (Varga 2008; Castro 2010; Gabrielli 2009).
Fibrosis describes the hardening or stiffening of tissues that are normally soft and malleable. It occurs as a result of over activation of specialized cells called fibroblasts, which produce collagen and the "glue" (called extracellular matrix) that holds tissues together. Connective tissue is made of collagen and other proteins, so when excessive collagen is produced via overactivation of fibroblasts, connective tissue can accumulate abnormally, thus contributing to tissue fibrosis. DNA damage and pro-inflammatory oxidative stress, which is increased in patients with scleroderma, is proposed to be a major driving force behind fibroblast overactivation (Gabrielli 2012; Avouac 2010).
Fibrosis is responsible for the most obvious symptom of scleroderma – hardening of the skin. However, fibrosis of organs and blood vessels can occur as well and this contributes to some of the systemic complications associated with scleroderma.