High Levels of <scp>DEK</scp> Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti–Tumor Necrosis Factor Therapy

Mor‐Vaknin, Nirit; Rivas, Miguel; Legendre, Maureen; Mohan, Smriti; Ye, Yuanfan; Mau, Theresa; Johnson, Anne; Huang, Bin; Zhao, Lili; Kimura, Yukiko; Spalding, Steven J.; Morris, Paula; Gottlieb, Beth S.; Onel, Karen; Olson, Judyann C.; Edelheit, Barbara; Shishov, Michael; Jung, Lawrence; Cassidy, Elaine; Prahalad, Sampath; Passo, Murray H.; Beukelman, Timothy; Mehta, Jay; Giannini, Edward H.; Adams, Barbara S.; Lovell, Daniel J.; Markovitz, David M.

doi:10.1002/art.40404

Cited by 13 publications

(8 citation statements)

References 31 publications

(62 reference statements)

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“…2,3 In the synovial fluid of JIA patients, DEK is actively secreted by inflammatory macrophages and acts as a chemotactic factor for recruiting neutrophils, CD8 + T cells, and NK cells. 4,5 Recently, Mor-Vaknin et al proposed that DEK is crucial to the formation of neutrophil extracellular traps (NETs) in mice and humans. 6 The excess production of NETs is a potential source of autoantibodies in rheumatic diseases.…”

Section: Introductionmentioning

confidence: 99%

Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis

Cao

et al. 2020

Mol. Pharmaceutics

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DEK protein is critical to the formation of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA). Blocking DEK using the aptamer DTA via articular injection has been shown to have robust anti-inflammatory efficacy in a previous study. However, DTA is prone to nuclease degradation and renal clearance in vivo. RA is a systemic disease that involves multiple joints, and local injection is impractical in clinical settings. In this study, DTA was modified with methoxy groups on all deoxyribose sugar units and inverted deoxythymidine on the 3′ end (DTA4) to enhance its stability against nuclease. DTA4 is stable for 72 h in 90% mouse serum and maintains a high binding affinity to DEK. DTA4 effectively inhibits the formation of NETs and the migration of HUVECs in vitro. DTA4 was then modified with cholesterol on its 5′ end to form DTA6. DTA6 dramatically reduces DEK expression in inflammatory RAW264.7 cells. A hydrogel microneedle (hMN) was then fabricated for the transdermal delivery of DTA6. The hMN maintains morphological integrity after absorbing the aptamer solution, effectively pierces the skin, and rapidly releases DTA6 into the dermis. The DTA6-loaded hMN significantly attenuates inflammation and protects joints from cartilage/bone erosion in collagen-induced arthritis (CIA) mice.

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Section: Introductionmentioning

confidence: 99%

Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis

Cao

et al. 2020

Mol. Pharmaceutics

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“…Intriguingly, a number of these biomarkers that were found to be significantly related to SLE disease activity and recent disease flares recognize antigens that function to regulate the cell cycle and transcription and translation of genes. For instance, antigens including DEK which has previously been found to be elevated in pediatric patients with juvenile inflammatory arthritis and SLE, 15,16 as well as CCNB1 are involved in chromatin organization, 17 CCNB1 and HMG20B control cell cycle at the G2/M transition. 18 HMGB2 encodes non-histone chromosomal HBG protein family that promotes DNA flexibility by facilitating cooperative interaction between cis-acting protein and involving the final ligation step in DNA double strand break repair and V(D)J recombination.…”

Section: Discussionmentioning

confidence: 99%

Detection of putative autoantibodies in systemic lupus erythematous using a novel native-conformation protein microarray platform

Mak

Kow

Ismail³

et al. 2020

Lupus

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Objective Conventional immunoassays detect autoantibodies related to systemic lupus erythematosus (SLE) via recognition of epitopes on autoantigens expressed in their denatured rather than native conformational state, casting difficulty in evaluating the genuine pathogenicity of the autoantibodies. We aimed to use a novel high-throughput protein microarray platform to identify autoantibodies against native autoantigens in SLE sera. Methods Sera from SLE patients and those of gender-, age-, and ethnicity-matched healthy controls (HC) were screened against more than 1,600 immune-related antigens of native conformation. The relative fluorescent unit readout from post-assay imaging were subjected to bioinformatics pre-processing and composite normalization. A penetrance fold change (pFC) analysis between SLE and HC samples shortlisted 50 autoantigens that were subjected to an unsupervised cluster analysis. Correlations between the pFC of putative autoantigens and clinical parameters including SLE disease activity index (SLEDAI-2K) and recent SLE flares were explored. Results 381 autoantigens were identified when 15 SLE and 15 HC serum samples were compared. The top 20 autoantigens which elicited autoantibody responses in SLE sera filtered based on the highest pFC were further analyzed. Autoantigens which the putative autoantibodies reacted against are those involved in chromatin organization such as DEK, regulation of transcription activity including REOX4 and ELF4, and negative regulation of NFkB activity such as TRIB3. Additionally, the pFC of these autoantibodies significantly and positively correlated with SLEDAI-2K and recent SLE flares. Conclusion A high-throughput protein microarray platform allows detection and quantification of putative lupus-related autoantibodies which are of potential pathophysiological and prognostic significance in SLE patients.

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“…Furthermore, involvement of DEK in several signaling pathways, including p53, NF-κB, Wnt, mTOR, and Rho, has been reported [28,32,34,35], although the precise signaling mechanism underlying its expression remains to be established. DEK is actively secreted in both free form (non-classical) and exosome (classical) [8], which could be detectable in urine (bladder cancer) [11], plasma (oropharyngeal) [36], synovial fluid (juvenile idiopathic arthritis (JIA)) [26,37], and the HepG2 cell line (conditioned medium) [22,23]. Macrophages are not the only cells that secrete DEK in association with poor prognosis [26].…”

Section: Discussionmentioning

confidence: 99%

DEK Is a Potential Biomarker Associated with Malignant Phenotype in Gastric Cancer Tissues and Plasma

Lee

Tsai

et al. 2019

IJMS

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Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative and absolute quantitation (iTRAQ), a human plasma proteome database, and public Oncomine datasets to search for aberrantly expressed oncogene-associated proteins in GC tissues and plasma. One of the most significantly upregulated biomarkers, DEK, was selected and its expression validated. Our immunohistochemistry (IHC) (n = 92) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 72) analyses disclosed a marked increase in DEK expression in tumor tissue, compared with paired nontumor mucosa. Importantly, significantly higher preoperative plasma DEK levels were detected in GC patients than in healthy controls via enzyme-linked immunosorbent assay (ELISA). In clinicopathological analysis, higher expression of DEK in both tissue and plasma was significantly associated with advanced stage and poorer survival outcomes of GC patients. Data from receiver operating characteristic (ROC) curve analysis disclosed a better diagnostic accuracy of plasma DEK than carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), and C-reactive protein (CRP), highlighting its potential as an effective plasma biomarker for GC. Plasma DEK is also more sensitive in tumor detection than the other three biomarkers. Knockdown of DEK resulted in inhibition of GC cell migration via a mechanism involving modulation of matrix metalloproteinase MMP-2/MMP-9 level and vice versa. Our results collectively support plasma DEK as a useful biomarker for making diagnosis and prognosis of GC patients.

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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

Cited by 13 publications

References 31 publications

Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis

Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis

Detection of putative autoantibodies in systemic lupus erythematous using a novel native-conformation protein microarray platform

DEK Is a Potential Biomarker Associated with Malignant Phenotype in Gastric Cancer Tissues and Plasma

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