Juvenile Idiopathic Arthritis (JIA) is a common, debilitating disease of childhood that is very poorly understood at the molecular level, and for which useful biomarkers to guide clinical management are generally lacking. A recent advance in the therapy of JIA has been the initiation of anti-TNF therapy, which has been clinically quite efficacious. However, these therapies are very expensive and predispose to infections, and the long-range side effects in children are not yet clear. Therefore, when to stop anti-TNF therapy in children with JIA is a major question. Five centers, under the direction of Dr. Daniel Lovell at the Cincinnati Children's Hospital Medical Center, are commencing a clinical trial in which, with careful monitoring of potential biomarkers, anti-TNF therapy will be discontinued in children with polyarticular or extended oligoarticular JIA when disease has remained inactive for six months. The subsequent clinical and laboratory course of these patients will then be followed. Here we propose to exploit this important clinical trial to understand the role of the DEK protein in the pathogenesis, exacerbation, and management of JIA. As good serological tests are currently not available to monitor treatment in JIA, it is significant that several groups have shown a strong correlation between JIA and auto-antibodies to the biochemically distinct DEK protein, a protein that undergoes significant post-translational modifications including phosphorylation, acetylation, and polyribosylation. We have now begun to understand the post-translational modifications and domains of DEK that the autoantibodies recognize. We also find DEK protein in the blood and synovial fluids of patients, and have made the observation that DEK, which is normally a nuclear protein, can actually be secreted by monocytic cells and released by apoptotic T cells, and serve as a chemoattractant for neutrophils, CD8+ T cells, and natural killer cells. As DEK expression has been found to be stimulated by TNF, and we can inhibit DEK secretion with TNF blockade, we hypothesize that DEK and/or antibodies to DEK are potential biomarkers for predicting which patients can safely stop anti-TNF therapy. In addition, we suggest that DEK may play a direct role in the autoimmunity of JIA, and will study that hypothesis in the context of this clinical trial. We propose to assess the quantity and nature of DEK antigen and antibody in the blood of patients drawn at regular intervals during and after anti-TNF therapy, and to examine whether these parameters change with TNF blockade or allow us to ascertain whether DEK or DEK antibodies can be used to predict who can be taken off of anti-TNF therapy. We will also delineate which post-translational modifications enhance the autoantigenicity of DEK and its ability to function as a chemoattractant for inflammatory cells. Thus, the proposed studies will use an important clinical trial to address whether DEK can be used as a biomarker in JIA, as well as to understand the immunobiology of DEK. These studies therefore have the potential to increase our understanding of the biology of JIA and to improve management of this very important disease of children. Public Health Relevance: Juvenile Idiopathic Arthritis (JIA) is a common and debilitating disease, the pathogenesis of which is understudied and poorly understood, and for which biomarkers to guide diagnostic and therapeutic decisions are lacking. Recent findings suggest that the DEK protein, and antibodies to this protein, may be important in the pathogenesis of JIA, and might serve as a useful biomarker. Within the context of a clinical trial that will address the key issue of when it is appropriate to discontinue anti-TNF therapy in patients with JIA, we propose to study the role of DEK in the pathogenesis and management of JIA.

Public Health Relevance

Juvenile Idiopathic Arthritis (JIA) is a common and debilitating disease, the pathogenesis of which is understudied and poorly understood, and for which biomarkers to guide diagnostic and therapeutic decisions are lacking. Recent findings suggest that the DEK protein, and antibodies to this protein, may be important in the pathogenesis of JIA, and might serve as a useful biomarker. Within the context of a clinical trial that will address the key issue of when it is appropriate to discontinue anti-TNF therapy in patients with JIA, we propose to study the role of DEK in the pathogenesis and management of JIA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087128-04
Application #
8311059
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Program Officer
Peyman, John A
Project Start
2009-09-01
Project End
2013-12-31
Budget Start
2012-09-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$378,564
Indirect Cost
$133,539
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mor-Vaknin, Nirit; Rivas, Miguel; Legendre, Maureen et al. (2018) High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol 70:594-605
Broxmeyer, Hal E; Mor-Vaknin, Nirit; Kappes, Ferdinand et al. (2013) Concise review: role of DEK in stem/progenitor cell biology. Stem Cells 31:1447-53
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
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
Kappes, Ferdinand; Waldmann, Tanja; Mathew, Veena et al. (2011) The DEK oncoprotein is a Su(var) that is essential to heterochromatin integrity. Genes Dev 25:673-8
Kappes, Ferdinand; Khodadoust, Michael S; Yu, Limin et al. (2011) DEK expression in melanocytic lesions. Hum Pathol 42:932-8
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
Fahrer, Jörg; Popp, Oliver; Malanga, Maria et al. (2010) High-affinity interaction of poly(ADP-ribose) and the human DEK oncoprotein depends upon chain length. Biochemistry 49:7119-30