Molecular analysis of the cause and expression of autoimmune diseases

Dr M.J. Rowley

Autoimmune diseases are disorders in which various tissues of the body are attacked and destroyed by the very system that is there for their protection, the immune system. The autoimmune response is the underlying cause of many chronic, progressive and previously unexplained diseases. The autoimmunity group is studying three autoimmune diseases, each of which has a specific target tissue. Autoantigenic molecules for each disease are given in brackets.

• rheumatoid arthritis, the synovial cartilaginous tissue of joints (type II collagen)
• type I diabetes, the insulin-secreting islet cells of the pancreas (glutamic acid decarboxylase, ICA512-a tyrosine-phosphatase-like protein, proinsulin, ICA12-a potential transcription factor)
• primary biliary cirrhosis, the small bile ducts of the liver (pyruvate dehydrogenase complex)

Autoimmune diseases, once established, usually progress to the point where the target tissue becomes totally destroyed, and the only option for treatment is replacement- by artificial joints in severe rheumatoid arthritis, by life-long insulin injections in diabetes mellitus, and by a liver transplant in primary biliary cirrhosis. Often, the autoimmune response can go on undetected for long periods, sometimes for many years, before any symptoms become apparent. For example, the autoimmune response to the islet cells of the pancreas can be detected up to ten years prior to the development of diabetes. In fact, detection of an autoimmune response to components of the islet cells, such as glutamic acid decarboxylase, proinsulin, and ICA512, are predictive markers of the future development of diabetes. This opens up the possibility of intervening to stop the disease process and so prevent further islet cell destruction. Research in the autoimmunity laboratory seeks to understand how the damaging immune response is initiated, how it causes the progressive tissue damage, and to develop diagnostic assays for the early detection and treatment of autoimmune diseases.

Techniques of analytical biochemistry, cell biology, immunology and molecular biology are being applied to: identify and characterise autoantigens, determine the subcellular localisation of autoantigens in cells and tissues, examine the effects of environmental agents on autoantigen expression, and to identify the antigenic epitopes recognised by disease associated autoantibodies.

The studies encompass the following areas:

• molecular characterisation of autoantigens, their isoforms and structurally related molecules, in particular cartilage and tissue collagens, glutamic acid decarboxylase, ICA512, ICA12, and constituents of the pyruvate dehydrogenase complex,
• identification of autoepitopes on proteins and the use of random peptide phage display libraries to identify polypeptides that mimic disease-associated epitopes
• analysis of structural and functional aspects of antigens in order to understand the role of autoantibodies in the development of the disease
• analysis of the expression and cell biology of antigens in order to identify factors that alter their pattern of expression and exposure to the immune system
• analysis of genetic and environmental effects in autoimmunity from variations in autoantibody responses from different ethnic groups
• development of novel diagnostic assays, including the use of structurally modified recombinant antigens prepared from yeast, bacterial and mammalian expression systems
  

Project areas

1. Cell biology and neuroendocrine associations of autoantigens in insulin dependent diabetes mellitus. (Dr. M.A. Myers, Dr. M.J. Rowley, Dr. I.R. Mackay, Prof. P.Z. Zimmet
   
   
2. Structural and functional analysis of disease-related determinants of collagen molecules (Dr. M.J. Rowley, Dr. J.A. Davies, Dr. I.R. Mackay)
   
   
3. The analysis of molecular interactions using "phage display" (Dr. M.J. Rowley, Dr. J. Davies, Dr. M.A. Myers, Dr. I.R. Mackay