Researchers with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered a new mechanism of inflammation in the TNF receptor 1(TNFR1)-associated periodic fever syndrome (TRAPS). Their investigation in mice revealed that having one mutant gene and one normal gene for TNFR1 caused greater disease inflammation than having two mutant TNFR1 genes. The researchers concluded that mutant TNFR1 and normal TNFR1 must both be present to cause an increased inflammatory response in TRAPS. The study appears in the Proceedings of the National Academy of Sciences (PNAS).
TNF, or tumor necrosis factor, acting through the TNF receptor 1 is a key cytokine (molecular messenger) that promotes inflammation and is important in a number of common rheumatic diseases, such as rheumatoid arthritis and ankylosing spondylitis. In 1999, a team led by NIAMS Clinical Director Dr. Daniel L. Kastner discovered that mutations in the gene coding for TNFR1 caused TRAPS, an autosomal dominant periodic fever syndrome characterized by recurrent, prolonged episodes of fever and inflammation. Since then, researchers from around the world have identified more than fifty mutations in TNFR1 linked to TRAPS. But how these mutations cause the inflammation in the skin, eyes, peritoneum (the tissue lining the abdominal cavity), and other sites in the body that characterize the disease remains a mystery.
Normal TNFR1 protein is made within a cell and travels to the cell surface where it resides in the membrane. TNF from outside of the cell then binds to TNFR1, triggering a cascade within the cell that leads to inflammation. Most genetic mutations associated with TRAPS cause the TNFR1 protein to misfold within the cell, so that it never reaches its destination on the cell surface. Since the protein is unable to carry out its normal function, it is said to result in a loss of function. However, a loss of function should result in TRAPS patients having less inflammation, not more. The NIAMS researchers set out to discover why mutations in the TNFR1 gene resulted in a gain of function, meaning more inflammation, rather than a loss of function.
Using mice genetically altered to produce TNFR1 with mutations identical to those in TRAPS, the researchers in the NIAMS Laboratory of Clinical Investigationand the NIAMS Autoimmunity Branch found that the mutant receptor was able to provoke enhanced inflammation from within the cell. The researchers went on to show that mice with two mutant copies of the receptor did not display any signs of abnormal inflammation, indicating that the mutant receptor relies on the co-existence of the normal copy of the receptor to cause disease. This is in line with what scientists know about TRAPS, where only one copy of the TNFR1 gene is usually mutated. Cooperation between a protein altered by a genetic mutation and its functional counterpart is a newly-identified mechanism in human genetic disease and also has implications for the therapy of this condition. Traditionally, treatment for TRAPS has involved blocking the action of TNF outside of the cell. However, this therapy does not completely eliminate symptoms of the disease. These findings suggest that strategies to combat inflammation caused by the mutant receptor within the cell may also be necessary. The studies of this rare disease have also opened a window into the secret life of this receptor inside the cell, which may have different functions than it does in its normal location on the cell surface.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
Simon A, Park H, Maddipati R, Lobito AA, Bulua AC, Jackson AJ, Chae JJ, Ettinger R, de Koning HD, Cruz AC, Kastner DL, Komarow H, Siegel RM. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010 May 10. [Epub ahead of print] PubMed PMID: 20457915.