U.S.-AUSTRIAN SCIENTISTS IDENTIFY MOLECULE'S CRITICAL ROLE IN ARTHRITIS

Research Could Lead to Future Treatment Advances for Arthritis, Diabetes and Other Autoimmune Diseases

SAN DIEGO - August 18, 2004 -  A research team of scientists from the U.S. and Austria have discovered that the molecule (Cbl-b) plays a critical role in preventing the development of arthritis and other autoimmune diseases. In autoimmune disease, the immune system, which normally wards off invading diseases, instead mistakenly attacks normal body tissues, leading to illness. The research team's finding, based on controlled laboratory studies of mice, may have important implications for the future development of therapies for autoimmune disorders such as arthritis and diabetes.

In a paper (Essential Role of the E3 Ubiquitin Ligase Cbl-b in T Cell Anergy Induction, Immunity, August 2004) to be published Wednesday in the scientific journal Immunity, researchers from the La Jolla Institute for Allergy & Immunology (LIAI) in San Diego, Calif. and from the Institute for Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, found that the presence or absence of the Cbl-b molecule had a direct impact on whether the mice developed arthritis.

In the study, led by Yun-Cai Liu, Ph.D., from LIAI, and Josef M. Penninger of the Austrian Academy, the researchers used two groups of mice. One group had been genetically-targeted to remove the Cbl-b molecule; the other were normal mice with the Cbl-b molecule. The researchers injected substances to induce arthritis into the two groups of mice. They found that, under these conditions, the normal group with the Cbl-b molecule did not react, while the group without the Cbl-b molecule developed severe arthritis.

"We concluded that the Cbl-b molecule was affecting the T cell's immune response, giving the immune system of the normal mice the ability to "tolerate" the arthritis antigens," said Liu. The mice without the Cbl-b molecule could not tolerate these substances and their T cells began attacking their own tissues, leading to the development of the autoimmune disease.

Mitchell Kronenberg, Ph.D., LIAI President and Scientific Director, said the finding is an important step forward in unraveling the mysteries of autoimmune disease. "By building on this research, we may one day be able to understand why some people develop arthritis and other autoimmune diseases and other people do not. This knowledge could lead to the development of drug therapies that would prevent or treat these diseases."

The study went further to define the molecular mechanisms for prevention of autoimmunity by Cbl-b. Tagging of protein targets with ubiquitin leads to the degradation of the target. Ubiquitin ligases are the critical players for the tagging process and Cbl-b is one of these ligases. Instead of protein degradation, however, the study discovered that Cbl-b helps tag ubiquitin to a critical signaling molecule and affects its function without causing degradation. Thus, the research elucidates a unique pathway for Cbl-b to regulate immune cell function.

About LIAI
Founded in 1988, the La Jolla Institute for Allergy and Immunology is a nonprofit medical research center dedicated to increasing knowledge and improving human health through studies of the immune system. Scientists at the institute carry out research searching for cures for cancer, allergy and asthma, infectious diseases, and autoimmune diseases such as diabetes, inflammatory bowel disease and arthritis. LIAI's research staff includes more than 100 Ph.Ds.

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