Connective tissue diseases are a spectrum of disorders with subsets that can be distinguished both clinically and serologically. The disease generally evolves over a number of years, leading in the most severe forms to organ failure and death.
These disorders, of which scleroderma is an example, have an underlying autoimmune pathology and may be viewed as paradigms of immunologically triggered fibrosis. They have complex aetiologies that presumably reflect interactions between several distinct genetic loci.
Scleroderma is heterogeneous disease that can be life-threatening and is generally characterised by the excessive extracellular matrix deposition within connective tissue of the body (ie skin and visceral organs). This process is termed fibrosis or scarring. In addition to fibrosis, scleroderma is also characterised by prominent vascular and immunological abnormalities, that are associated with and often precede the fibrogenic process. It is therefore likely that immune cell and vascular dysfunction in this disease have a significant impact on the activation of the genetic programme that is responsible for the connective tissue fibrosis. Accumulated evidence over a number of years by many workers suggests that at least four distinct yet interactive components are involved in the initiation and progression of the scleroderma disease process:
- Vascular dysfunction in terms of alteration in vascular tone, endothelial cell activation/damage and oxidative stress.
- An autoimmune process resulting in immune activation.
- Extravascular inflammation mediated by leukocytes.
- An uncontrolled connective tissue fibrosis.
Many studies have conducted investigations looking at single 'snapshots' in the evolution of the disease and measurable differences can be detected between patients and non-patients within a variety of parameters, some of which include factors indicating a disturbance of leukocyte activity, and of endothelial cell function and fibroblast function. However the inter-relationship between these parameters over disease evolution or organ based pathology is not well understood. Our current research efforts are therefore aimed at using complementary cell culture and molecular approaches to increase our knowledge of the pathogenesis of scleroderma.
The most important aspect of therapy is, at present, based on not only the accurate, early assessment of patients and the ability to predict the patients that may progress to develop particular disease manifestations, but our increased understanding of disease pathogenesis, particularly the early events, which are likely to have an underlying immunological drive.
Although the disease model we are primarily studying is scleroderma, many human diseases are characterised by fibrosis, and many of them may be immunologically driven. Thus fibrosis within the context of human disease is widely prevalent and often debilitating and life-threatening and represent a major problem in current medical practice. These diseases and disorders with a common fibrotic component remain largely unaddressed. The fibrotic disorders include, post-surgical scarring following transplantation, acute fibrosis initiated by severe trauma and often complicated by infection, liver cirrhosis, atherosclerosis and kidney fibrosis linked to diabetes, and autoimmune diseases such as dermatomyositis, scleroderma and rheumatoid arthritis. All forms of fibrosis progress through the same common stages resulting in excessive scarring, tissue damage and in extreme cases organ failure. An estimate of the prevalence of these diseases within Europe, the United States and Japan arrives at the number of existing patients with diseases showing common fibrotic pathologies at around 80 million. If one includes fibrotic diseases associated with or initiated by surgical procedures (per year) this figure increases to over 100 million. Thus these diseases represent a major concern and a significant human health issue.