Autoimmune diseases, such as Type I diabetes and rheumatoid arthritis, are caused by an immune system gone haywire, where the body's defense system assaults and destroys healthy tissues.
A mutant form of a protein called LYP has been implicated in multiple autoimmune diseases, but the precise molecular pathway involved has been unknown. Now, in a paper published March 18 in Nature Chemical Biology, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) show how the errant form of LYP can disrupt the immune system. In doing so, they also found a potential new therapy for autoimmune diseases—a chemical compound that appears to inhibit this mutant protein.
T cells and autoimmune disease
In Caucasian populations, a mutated form of LYP (short for lymphoid tyrosine phosphatase) is the third most common single-gene cause of Type 1 diabetes. It ranks second for rheumatoid arthritis.
Researchers have known that LYP and another protein called CSK (C-terminal Src kinase) work cooperatively to keep the immune system's destructive T cells from being activated. Because the uncontrolled activation of T cells is a hallmark of many autoimmune diseases, the proper functioning of LYP with CSK is thought to keep T cells in check.
While the normal form of LYP can bind CSK, the disease-associated mutant LYP cannot. In the new study, Sanford-Burnham researcher Lutz Tautz, Ph.D. led an international group of scientists in showing that normal LYP can disassociate itself from CSK, which paradoxically makes LYP better at dampening the signals that activate T cells. These findings explain why the mutant form of LYP is better at limiting T cell activation than normal LYP.
"It's still a mystery how a protein that impairs T cell signaling causes autoimmunity," said Tautz. "In a simple model of autoimmunity, you would think the opposite."
One possible explanation, Tautz said, is that the mutant LYP weakens the action of regulatory T cells, which control the other type of T cells, the kind that causes autoimmunity.
"If you have regulatory T cells that are not as active because they have inhibited signaling, then they might not be able to do their job properly," Tautz said.
Towards new therapeutics
In their study, the researchers also screened 50,000 drug-like chemical compounds and found 33 that have a specific effect on LYP activity. One compound, called LTV-1, blocked the action of the mutant LYP protein in human T cells. In fact, under physiological conditions, LTV-1 is the most potent LYP inhibitor reported to date.
Tautz said he plans to next develop the LTV-1 compound further, in part by modifying it chemically to make it more effective as a drug. Tests in mice, however, could be problematic because a separate study recently showed that mice with a corresponding LYP mutation don't get sick at all.
Developing new treatments for autoimmune diseases would help millions of people. Overall, autoimmune diseases affect more than 25 million individuals in the United States alone. According to the U.S. Department of Health and Human Services, autoimmune diseases are a leading cause of death and disability.
This research was funded by the National Cancer Institute, the Norwegian Cancer Society, the American Cancer Society, the Oxnard Foundation, the Belgian Research National Scientific Fund, and Liege University.
The study was co-authored by Torkel Vang, Sanford-Burnham and University of Oslo; Wallace H. Liu, Sanford-Burnham; Laurence Delacroix, Liege University; Shuangding Wu, Sanford-Burnham; Stefan Vasile, Sanford-Burnham; Russell Dahl, Sanford-Burnham; Li Yang, Sanford-Burnham; Lucia Musumeci, Liege University; Dana Francis, Brown University; Johannes Landskron, University of Oslo; Kjetil Tasken, University of Oslo; Michel L. Tremblay, McGill University; Benedicte A. Lie, University of Oslo; Rebecca Page, Brown University; Tomas Mustelin, Sanford-Burnham; Souad Rahmouni, Liege University; Robert C. Rickert, Sanford-Burnham; and Lutz Tautz, Sanford-Burnham.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham is a highly innovative organization, currently ranking second nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded, according to government statistics.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla) and Santa Barbara, California and Orlando (Lake Nona), Florida. For more information, please visit our website (www.sanfordburnham.org) or blog (http://beaker.sanfordburnham.org). You can also receive updates by following us on Facebook and Twitter.
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