Juvenile rheumatoid (or idiopathic) arthritis (JRA/JIA) is the most common cause of childhood disability. Even the mildest form of the disease carries a significant risk of joint deformation and loss of function that foreshadows lifelong discomfort and disability. The disease affects 1 child in every 200 under the age of 16. Controlling the disease in early childhood is important to prevent the deformity and later disability in children with JRA/JIA. However, the current treatment paradigm mandating earlier use of aggressive, anti-inflammatory drugs has potential harmful side effects making it imperative that we develop measures that can detect impending disease flares and develop better drugs for treatment with fewer side effects. In order to achieve these goals we need to better understand the development of the disease. Presently, we do not know what triggers the abnormal immune activity in JIA that can lead to serious damage to joints, eyes, and other vital organs, and there are no markers in the blood or genes of children with arthritis that can help us to follow disease activity or to predict JIA outcome. Recent discovery of an antibody to the DEK protein in some children with JIA and related diseases holds great promise for improving our knowledge of how these conditions begin and how they might be treated more effectively. We recently identified DEK protein and antibodies in synovial fluids from patients. We also found that DEK protein is secreted by activated human macrophages by a process that is capable of eliciting antibodies against the DEK protein. The secretion of DEK is stimulated by Interleukin-8, a protein that helps to recruit immune cells to an area of inflammation. In addition, dexamethasone and cyclosporin, two powerful anti-inflammatory medications used to treat autoimmune diseases, can block DEK secretion. We have also seen that the DEK protein itself can attract immune cells to an area of inflammation and, in this way may, increase the severity of the immune reaction. Now we suggest to investigate in details the way DEK attracts immune cells by identifying the potential binding receptor/s for DEK. To identify the binding receptor/s to DEK we will perform in vitro migration assays using specific receptors inhibitors, immunoprecipitation and co-localization assays. To investigate DEK contribution to the development of the disease will use several known animal models for arthritis assess the effect of DEK protein and antibodies on the development of the disease. These insights are very important to our ability to develop a new strategy to the diagnosis/treatment of JIA, and to improve the present and future health of children with arthritis and related diseases.
Relevance of this research to public health: Juvenile idiopathic arthritis (JIA) affects 1 child in every 200 under the age of 16 and is the most common cause of childhood disability. Currently, we do not know what triggers the disease, and there are no specific markers or drugs for controlling/treatment of the disease other than the common aggressive anti-inflammatory drugs. Since we recently identified DEK protein and antibodies in patients'synovial fluids, we suggest investigating the role of DEK in the development of JIA and its potential as a new target for future diagnosis/treatment.
| Mor-Vaknin, Nirit; Saha, Anjan; Legendre, Maureen et al. (2017) DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis. Nat Commun 8:14252 |
| Logan, Gemma E; Mor-Vaknin, Nirit; Braunschweig, Till et al. (2015) DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML). Blood Cells Mol Dis 54:123-31 |
| Saha, Anjan K; Kappes, Ferdinand; Mundade, Amruta et al. (2013) Intercellular trafficking of the nuclear oncoprotein DEK. Proc Natl Acad Sci U S A 110:6847-52 |
| Mor-Vaknin, Nirit; Legendre, Maureen; Yu, Yue et al. (2013) Murine colitis is mediated by vimentin. Sci Rep 3:1045 |
| Broxmeyer, Hal E; Kappes, Ferdinand; Mor-Vaknin, Nirit et al. (2012) DEK regulates hematopoietic stem engraftment and progenitor cell proliferation. Stem Cells Dev 21:1449-54 |
| Mor-Vaknin, Nirit; Kappes, Ferdinand; Dick, Amalie E et al. (2011) DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum 63:556-67 |
