Medical Discovery News
By Norbert Herzog and David Niesel

For the 1.5 million people in the United States who suffer from rheumatoid arthritis, there may be new hope. Scientists have discovered an inflammatory stress response that drives the development of RA and a specific inhibitor that could be used to block it.

While the immune system normally protects us from infections, autoimmune disorders like RA cause the immune system to attack its own body. RA produces chronic inflammation that can damage many organs, especially flexible joints. It mostly affects women between the ages of 40 and 60, although it can develop at any age. There appears to be a genetic component as well as an environmental trigger that contributes to RA.

In RA, the immune system attacks cells such as those in the synovium, the thin membrane lining joint and tendon sheaths that is only a few cells thick. The synovium holds a lubricating liquid called synovial fluid that cushions joints. That fluid also delivers oxygen and nutrients to the cartilage that provides a slippery coating to the ends of bones. In RA, the immune system attacks and destroys collagen, a protein that is the primary component of cartilage. RA is a progressive disease, so eventually the cartilage in joints wears away and then bones erode, causing loss of mobility, disfiguration and pain. Such attacks can also inflame the skin, heart, lungs and other tissues. Constant treatment is necessary to protect joints because the effects of cartilage and bone damage are irreversible.

Macrophages are one type of cell used by the immune systems to protect against infections and exist in every tissue of the body. Macrophages can engulf dead or damaged cells, as well as pathogens like bacteria and viruses. Though they normally protect the body, they can also contribute to inflammatory and degenerative diseases.

Macrophages from the synovial fluid of RA patients have elevated levels of a group of proteins called Toll-Like Receptors. TLRs have a critical role: They sense invading microorganisms in the body and send out danger signals. In a small-scale study, targeting the signals from TLRs was effective in treating RA.

A molecule called IRE1alpha processes signals from TLRs. Scientists discovered that mice engineered without this molecule do not have a problem with inflammatory arthritis and can’t develop RA. Additionally, normal mice treated with a drug called 4U8C that inhibits IRE1alpha were also protected from RA. High blood pressure, high cholesterol, heart disease, obesity and diabetes can contribute to the development of RA by activating the IRE1alpha molecule.

If this study produces the same results in people, these scientists may have found that suppressing IRE1alpha is the key to preventing and treating RA.

Professors Norbert Herzog and David Niesel are biomedical scientists at the University of Texas Medical Branch. Learn more at