Centre for Rheumatology & Connective Tissue Disease
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 good
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 and life threatening and is characterised
by the excessive extracellular matrix deposition within connective tissue of the
body (i.e. skin and visceral organs). In addition to fibrosis, scleroderma is
also characterised by prominent vascular and immunological abnormalities, that
are associated with and often precede the fibrotic 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
disease process: (1) Vascular dysfunction in terms of alteration in vascular
tone, endothelial cell activation/damage and oxidative stress; (2) an autoimmune
process resulting in immune activation; (3) extravascular inflammation mediated
by leukocytes; and (4) 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
controls in 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.
Although we are primarily studying 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.
