Project Description Narrative:
The U.S. Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System estimates that in the United States, 46 million adults have been diagnosed with some type of arthritis, including osteoarthritis, rheumatoid arthritis, gout, or lupus. By the year 2030, it is projected that these types of rheumatic diseases will afflict 67 million Americans. In 2003, the total cost attributed to arthritis and other rheumatic conditions was $128 billion, which includes $81 billion in direct medical expenditures. In the state of Wisconsin, there are currently over 1,100,000 adults with arthritis, and more than 400,000 have functional limitations from their disease. A 20-39% increase in arthritis prevalence is expected by the year 2030.
While rheumatic diseases constitute the largest group of auto-inflammatory disorders, other autoimmune diseases such as type 1 diabetes are also on the rise, with over 2 million people affected. About 8-10% of those with type 1 diabetes are under the age of 20, including one in every 400-600 children and adolescents. Thus, despite significant advances in the treatment of autoimmune disease, the health impact of these disorders continues to increase.
Genetic deficiency of regulatory T cells expressing the transcription factor Foxp3 results in florid autoimmunity of multiple organs and premature death. Indeed, regulatory T cell dysfunction has been implicated in many autoimmune diseases. Foxp3 is one of only two genes whose deficiency is known to result in type 1 diabetes. Deficiency of the other gene (CD25) also affects regulatory T cell function, underscoring the essential role of regulatory T cells in preventing diabetes and other autoimmune diseases.
A complete understanding of how regulatory T cells maintain immunologic tolerance to self is essential, and therapies designed to target this crucial cell population are likely to have lasting impact on the function of the immune system. Thus, no single avenue of basic science investigation holds more promise for understanding and treating autoimmune disease than those studies that examine fundamental aspects of regulatory T cell biology.
A pressing and unresolved question is the role of ‘induced’ regulatory T cells in dominant tolerance. That question is the focus of this project. This research targets chronic diseases with genetic influences such as type 1 diabetes, arthritis, multiple sclerosis, and Crohn’s disease.