Research sheds light on autoimmune disease

A paper by an MUSC researcher published in the Aug. 1 issue of the Journal of Experimental Medicine has important implications for the treatment of autoimmune diseases such as rheumatoid arthritis, lupus and vasculitis.

Gary Gilkeson, MD, associate professor in the Division of Rheumatology and Immunology, along with colleagues from Duke University, the University of California at Davis, the University of Miami Medical Center and Merck Research Laboratories, found that by genetically knocking out inducible nitric oxide production in mice, the animals were prevented from developing vasculitis. Their findings indicate that nitric oxide production is critical for the development of vasculitis.

Gilkeson explained that vasculitis is an inflammation of the blood vessels that can be a very serious and even fatal disease. "When vessels are inflamed, the result is inadequate blood flow to whatever organ is involved," said Gilkeson. "Common manifestations are necrosis of digits, stroke, heart attack and kidney failure."

Nitric oxide is important in maintaining blood pressure and some brain functions. In the immune system, it is produced by immune cells in response to inflammation and is important in killing off various microorganisms such as bacteria and parasites. "As with anything we have naturally, if made in the wrong place, at the wrong time or in excess quantity, it can be harmful rather than beneficial," said Gilkeson. In his earlier research at Duke University and in other research projects at MUSC, Gilkeson has demonstrated that nitric oxide overproduction is associated with the development of autoimmune disease.

Gilkeson explained that there are two types of enzymes that produce nitric oxide. One type produces nitric oxide all the time, and that is what is associated with several normal functions, including maintaining blood pressure and brain function. But the inducible typeśresponsible for the immune responseśwhen overproduced is associated with autoimmune diseases.

Several major drug companies are very interested in nitric oxide, with Merck cooperating with this research. Compounds have already been developed to block all nitric oxide production. There are limitations in these for long-term use in humans because of their effect on normal functioning. Merck, Monsanto and Glaxo Wellcome are all working to develop agents to block the production of only the inducible type of nitric oxide. They are interested in simulating pharmacologically what Gilkeson has accomplished by knocking out the specific gene to curb inducible nitric oxide production.