Researchers at National Jewish Medical and Research Center who are studying a protein implicated in the development of lupus and rheumatoid arthritis have discovered a unique “flap” that is crucial to the protein’s function. When they created a flap-free version of the molecule, it engaged receptors but triggered no biological activity. The findings, reported in the February 8 issue of Cell, provide insight into an important immune-system protein and suggest that the flap-free version may one day serve as a treatment for various autoimmune diseases.
The molecule, known variously as Tall-1, BlyS, BAFF, THANK and zTNF4, has generated intense interest in the biomedical community because of its role in both autoimmunity and the normal immune response.
“Our studies have revealed the structural element crucial to Tall-1’s ability to trigger maturation of B cells and antibody production,” said Gongyi Zhang, Ph.D., Assistant Professor of Immunology at National Jewish. “By removing Tall-1’s unique flap, we have created a molecule that could have important therapeutic applications in lupus, rheumatoid arthritis and other autoimmune diseases.”
Tall-1 is an important regulator of the immune system. It spurs B cells to mature and produce antibodies, one of the body’s major defense mechanisms. Mice engineered to make too much Tall-1 develop lupus-like symptoms. People with lupus and rheumatoid arthritis have been shown to have high levels of Tall-1 in their blood. Lupus and rheumatoid arthritis are autoimmune diseases in which the body’s immune system mistakenly attacks its own tissues. Approximately 1.4 million people in the United States, mostly women, suffer from lupus. Rheumatoid arthritis afflicts approximately 2.1 million people in the U.S.
Hong-Bing Shu, Ph.D., Assistant Professor of Immunology at National Jewish, originally identified Tall-1 in 1999 and soon thereafter one its receptors, BCMA. He collaborated with Dr. Zhang to determine the protein’s unique shape.
Tall-1 has a flap, a loop of eight amino acids not found in related proteins in the tumor necrosis factor (TNF) family. While other TNF family members cluster into units of three molecules, Tall-1 clusters into a much larger, 60-molecule ball, which appears crucial to the protein’s biological activity.
Dr. Zhang’s analysis indicated that the flap is responsible for this unique clustering. When the researchers created a modified version of Tall-1 lacking the flap, it failed to assemble into the 60-molecule ball. It also failed to stimulate B cells, even though the modified Tall-1 did bind to one of its target receptors, BCMA.
“The flap region is essential for the proper function of Tall-1 in cell cultures,” said Dr. Shu. “We believe this region is a good target for development of small molecule drugs against lupus, rheumatoid arthritis, and other disorders involving the immune system and B cells. We are also investigating whether the flap-less Tall-1 mutant can be used to compete with the normal Tall-1 in vivo and inhibit its activity.”
National Jewish has applied for various patents on the potential uses of Tall-1, its modified version, and its receptor, BCMA.
Several groups, including Dr. Shu’s, identified Tall-1 at about the same time in 1999, which is why the molecule has so many names. Several companies, including Human Genome Sciences, Amgen, Biogen and Zymogenetics, are researching Tall-1 and related molecules as potential pharmaceuticals. Human Genome Sciences is currently conducting clinical trials of Tall-1, which it calls BlyS, and an antibody to Tall-1.