August 25, 2008

Protein Plays Role in Preventing Autoimmunity

Scanning electron micrograph of a T Cell Scanning electron micrograph of a T cell. NIAID

Eliminating a protein called furin from immune cells in mice can lead to development of autoimmune disease, a new study reports. The finding sheds light on the molecular processes that trigger autoimmunity. The research may also have implications for developing drugs to increase immune responses in treating cancer, infectious disease and other disorders.

Furin was discovered nearly 20 years ago as an enzyme that helps to snip apart and activate a variety of proteins. Since then, scientists have been gradually uncovering the enzyme's pivotal role in embryo development, immune system defenses and a broad range of diseases, including avian flu, anthrax, Alzheimer's disease and cancer.

Because of its complex activities in the cell, researchers have found it difficult to tease apart the functions of furin from those of other cellular enzymes with similar roles. In one effort to distinguish furin function, scientists tried to create mice that lacked the enzyme, but the animals could not survive beyond the embryo stage.

To zero in on furin's importance to immune cells called helper T cells, scientists from NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of Allergy and Infectious Diseases (NIAID) collaborated with other researchers to create mice that lacked furin only in their T cells. The results were reported in the advance online edition of Nature on August 13, 2008.

By about 6 months of age, the mice with furin-depleted T cells developed systemic autoimmune disease, meaning their immune systems attacked their own cells and tissues throughout their bodies. The mice became noticeably sick, with progressive weight loss.

The researchers found that deleting furin in helper T cells affected the function of 2 types of T cells: regulatory T cells, which promote immune tolerance to the body's own cells and tissues, and effector T cells. Further analysis showed that mice lacking furin in their regulatory T cells had lower levels of a specific protein, TGF-β1, which is produced by these cells and helps to preserve immune tolerance. However, the researchers noted that effector T cells also produce TGF-β1. They found that furin is needed for TGFβ-1 production by effector T cells, and that the absence of furin in effectors makes these cells more aggressive in causing autoimmune disease and tissue damage.

“We already know that furin seems to have roles in a variety of human diseases, such as cancer, cystic fibrosis and infectious diseases,” says lead author Dr. Marko Pesu of NIAMS. “These findings show that having no furin in certain immune system cells can increase the immune response and lead to autoimmune disease in mice.”

Because of furin's known role in a wide range of diseases, several research teams are exploring the therapeutic potential of furin-blocking drugs. “However,” adds study co-author and NIAMS Scientific Director Dr. John J. O'Shea, “these results suggest that the development of drug interventions could have an unexpected side effect of increasing the risk of developing autoimmune disease.”

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