New Study Challenges Theory that RA is an Autoimmune Disorder

Patient Expert

In a new study published in the November 2006 issue of Arthritis and Rheumatism, scientists at the University Of Michigan Medical School reported evidence that challenges longstanding theories about the cause of rheumatoid arthritis.
The focus of the study was to discover why almost 95 percent of RA patients have a common sequence of DNA (called a shared epitope), and why these patients tend to have more severe forms of the disease than patients without it. The current prevailing theory is that RA is an autoimmune disorder because the shared epitope is located in an area of the human genome that codes for proteins involved in the immune system's recognition of antigens. The researchers believed that there is no solid evidence of RA being an autoimmune disorder, even though it is the most accepted theory, because other diseases have a similar association between HLA genes and yet they are not considered autoimmune diseases. HLA stands for "Human Leukocyte Antigens". HLA antigens are molecules produced by the HLA genes. HLA molecules are expressed on the surface of white blood cells to coordinate the immune response.

The researchers found that the shared epitope can cause a signaling cascade that leads to increased production of nitric oxide in other cells. Nitric oxide is a gas produced by several different types of cells and it is thought to be a type of signal for cells. The study concluded that the shared epitope may cause overproduction of nitric oxide in patients with RA. They also suggested that this cascade action is unrelated to antigens and the body's recognition of them. People with the shared epitope had a significantly higher rate of NO generation than people without the shared epitope.

This information is important because nitric oxide inhibits apoptosis, the natural process of programmed cell death. For example, when a cell is damaged beyond repair, or infected with a virus, apoptosis is programmed to occur. It can be triggered within the cell itself, by the surrounding tissue, or by immune cells. Apoptosis is the complementary action to cell renewal and part of normal functioning, as compared to necrosis which is a form of cell death that results from acute cellular injury.

This study found that cells from individuals with the shared epitope were completely resistant to cell death when compared to samples from individuals without the shared epitope. If a cell's capability of apoptosis is damaged (e.g. mutation), or if the initiation of apoptosis is blocked (e.g. a virus), a damaged cell can continue dividing without restrictions. This damage causes build up of damaged tissue, cancer, and other problems.

The authors suggested that further research should be conducted on HLA genes and their effect on the causes of diseases including RA. They also suggest that further studies are needed to examine other possible causes of nitric oxide overproduction in RA.

Citation: Arthritis & Rheumatism: (54) 11, pp. 3423-3432, November 2006