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

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August 17, 2004 12:00 PM US Eastern Timezone

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

BIOWIRE2K

SAN DIEGO--(BUSINESS WIRE)--Aug. 17, 2004--A research team of scientists

from the U.S. and Austria have discovered that the molecule (Cbl- 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 and 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 f 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.

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

non-profit medical research center dedicated to increasing knowledge and

improving human health through studies of the immune system. Researchers at

the institute carry out studies designed to understand and lead to the

development of cures for cancer, allergy and asthma, infectious diseases,

and autoimmune diseases such as diabetes, inflammatory bowel disease and

arthritis. The institute's research staff includes over 100 Ph.Ds.