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.
The Role of Oxidative Stress and Inflammation in Scleroderma
Accumulation of free radicals is thought to play a significant role in the development and progression of scleroderma, especially in tissue fibrosis. It has been suggested that perturbed balance between endogenous free radical formation and antioxidant defense mechanisms may be present in scleroderma, leading to excessive generation of reactive oxygen species (Gabrielli 2012). Indeed, increased oxidative DNA damage has been observed in scleroderma patients compared to healthy controls (Avouac 2010).
There are a few theories about how free radicals contribute to tissue fibrosis in scleroderma. First, free radicals may directly activate specialized cells called fibroblasts, which produce collagen and the extracellular matrix. Another theory suggests that, rather than directly activating fibroblasts, free radicals may make it much more difficult for excess connective tissue to be broken down and cleared by the body, leading to accumulation of fibrous tissue indirectly. Most likely, both of these mechanisms, and probably others yet to be discovered, are involved in the relationship between oxidative stress and tissue fibrosis in scleroderma (Gabrielli 2012).
Despite uncertainties surrounding the exact contribution of reactive oxygen species to scleroderma, scientists propose that therapy with antioxidants may effectively mitigate some of the fibrotic changes induced by oxidative stress. For example, evidence from animal and human studies suggests the antioxidant phytochemical epigallocatechin gallate (EGCG) found in green tea may guard against fibrotic changes (Dooley 2010, 2012).
Inflammation also plays a role in mediating the development of scleroderma. Particularly, the blood vessel damage characteristic of scleroderma is largely driven by inflammatory reactions. Inflammation may also contribute to tissue fibrosis (Barnes 2011).
The inflammatory mediator interleukin-6 (IL-6) has attracted significant interest from the research community as a potential therapeutic target in scleroderma treatment. Interestingly, fibroblasts isolated from skin lesions of individuals with systemic sclerosis express higher levels of IL-6 than fibroblasts from healthy individuals (Feghali 1992). Clinical trials are underway investigating the efficacy of IL-6 modulation in scleroderma treatment (Barnes 2011).
Additional evidence in support of an important role for inflammation in scleroderma comes from findings that components of the immune system called T-cells have been found at sites of fibrosis in an “activated” state. This means that these immune cells are recruited to the site of fibrosis and are actively promoting inflammatory reactions, including the generation of IL-6 (O'Reilly 2012). Moreover, the degree of skin thickening at sites of cutaneous fibrosis in scleroderma correlates with the number of T-cells that have infiltrated the tissue, suggesting an intimate relationship between fibrotic changes and the presence of inflammatory immune cells (Fleischmajer 1977). Treatment modalities targeting T-cells have shown some promise and are continually being evaluated (O'Reilly 2012).