Session Title: Pediatric Rheumatology - Pathogenesis and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: The nuclear oncoprotein DEK is a known autoantigen associated with juvenile idiopathic arthritis (JIA) and other autoimmune diseases. DEK is actively secreted by human macrophages and serves as chemoattractant for leukocytes, including neutrophils and T cells. We have previously demonstrated that DEK and anti-DEK autoantibodies are abundant in the inflamed synovia of JIA patients. Postranslational modification, particularly acetylation, of DEK markedly increases its autoantigenicity, suggesting an active role for DEK and DEK autoantibodies in the inflamed joint. Using zymosan induced arthritis (ZIA) mouse model, we demonstrate that DEK contributes to the development of inflammatory arthritis by recruiting neutrophils to the joint. Remarkably, DEK also appeared to be required for the formation of neutrophil extracellular traps (NETs) and is detected in association with known NET markers in human neutrophils from synovial fluids of JIA patients.
Methods: We investigated the role of DEK using the ZIA mouse model, comparing 129/B6 wild type (WT) to DEK knockout (DEK KO) mice. Zymosan A from Saccharomyces cerevisiae, or an equal amount of sterile saline, was injected through the suprapatellar ligament into the joint cavity of WT and DEK KO mice. Inflammatory cytokines in the joint tissue homogenates were detected by ELISA. Neutrophils from healthy volunteers were purified by centrifugation over a discontinuous Histopaque gradient. Synovial fluid neutrophils from JIA patients and mouse bone marrow neutrophils were isolated in a similar manner. The Transwell system was used for chemotaxis assays. The neutrophil markers Ly6G, elastase and DEK and were detected by immunoflorescence and confocal microscopy.
Results: Significant levels of DEK were found in NETs from JIA synovial neutrophils. In the ZIA mouse model, DEK KO mice displayed significantly less inflammation in the joints compare to WT. Substantially reduced levels of pro-inflammatory cytokines were detected in zymosan injected joints from DEK KO vs. WT mice. Neutrophil migration into the injected joints was markedly lower in DEK KO vs. WT mice and DEK KO neutrophils demonstrated defects in NETs formation in response to lipopolysaccharide (LPS) and Escherichia coli.
Conclusion: Extracellular DEK found in the supernatant of activated primary human neutrophils serves as a chemoattractant and is important for NET formation. DEK is also detected in NETs produced by synovial fluid neutrophils of JIA patients. These results demonstrate that the nuclear autoantigen DEK plays a major role in the development of inflammation in the joints, suggesting an active role for DEK in the development of JIA as well as other autoimmune diseases.
A. K. Saha,
M. J. Gonzalez-Hernandez,
M. A. Amin,
B. J. Rabquer,
J. M. Jorns,
M. J. Kaplan,
B. S. Adams,
D. A. Fox,
A. E. Koch,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-dek-autoantigen-regulates-formation-of-neutrophil-extracellular-traps-and-zymosan-induced-arthritis-in-mice/