Study Offers New Perspective On Nitric Oxide Signaling In Rheumatoid Arthritis

Published in the November 2006 issue of Arthritis and Rheumatism, results from the study could help answer questions that have puzzled scientists for more than 20 years:

Why do nearly 95 percent of RA patients have a common sequence of DNA, which scientists call a shared epitope, and why do patients with this DNA sequence have more severe forms of the disease than patients without it?

Most researchers believe 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.

Antigens are like little name tags on the surfaces of cells. They help the immune system recognize what belongs in our bodies and what doesn't. The immune system will attack foreign antigens. For example, without closely matched antigens, a transplant patient's immune system will reject a donated organ.

"Although the hypothesis that RA is an autoimmune disorder is widely accepted, there is no convincing evidence that it is correct," says Joseph Holoshitz, M.D., associate professor of internal medicine at U-M Medical School who directed the study. "We see this same type of association with HLA genes in other diseases, which we know are not autoimmune diseases."

Holoshitz and his colleagues discovered that the shared epitope can trigger a signaling cascade that leads to increased production of nitric oxide in other cells. A gas produced by several types of cells in the body, nitric oxide is an important signaling molecule.

"Our findings suggest this activity is unrelated to antigen presentation," says Holoshitz. "This is the first direct evidence that the shared epitope may be responsible for the overproduction of nitric oxide seen in patients with RA."

Overproduction of NO inhibits apoptosis -- the natural process that leads to cell death. Resistance to apoptosis is a common trait found in cells lining the joints of RA patients, and is believed to lead to disease symptoms.

In the U-M study, cells from individuals with the shared epitope were completely resistant to cell death when compared to samples from individuals without the shared epitope.

"It was previously postulated that nitric oxide plays a role in RA, since patients have higher levels of it in their joint tissue. When we looked at the rate of NO generation in these patients, we found that it was significantly higher for people with the shared epitope," says Holoshitz.

The findings offer scientists a new way of viewing other diseases, in addition to RA. For example, narcolepsy and certain types of leukemia are strongly associated with HLA genes, yet there is no convincing evidence that they are autoimmune diseases. According to Holoshitz, further research into HLA genes and their function could offer new insights into the cause of these diseases.

Holoshitz cautions that, although the association between the shared epitope and RA is consistently found among many ethnic groups, five to 10 percent of all RA patients are shared epitope-negative. Further studies are needed to examine other possible causes of nitric oxide overproduction in RA.

The research was supported by the National Institutes of Health, the Arthritis Foundation, and the University of Michigan Biotechnology Development Fund.

Contributing authors include first author Song Ling, Ph.D., a research investigator in the departmental of internal medicine, U-M Medical School; Angela Lai, a U-M undergraduate student; and Olga Borschukova and Paul Pumpens from the Biomedical Research and Study Center, University of Latvia.