Abstract:SummaryAnti-endothelial cell antibodies (AECA) have been frequently detected in systemic vasculitis, which affects blood vessels of various sizes. To understand the pathogenic roles of AECA in systemic vasculitis, we attempted to identify target antigens for AECA comprehensively by a proteomic approach. Proteins extracted from human umbilical vein endothelial cells (HUVEC) were separated by two-dimensional electrophoresis, and Western blotting was subsequently conducted using sera from patients with systemic v… Show more
“…In addition to its role in diseases associated with increased ROS, autoantibodies against Prxs have been associated with autoimmune diseases such as Kawasaki disease, systemic sclerosis, and systemic vasculitis (84,125,139). In these studies, sera from patients with and without autoimmune diseases were screened for autoantibodies against different isoforms of Prx.…”
The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes.
“…In addition to its role in diseases associated with increased ROS, autoantibodies against Prxs have been associated with autoimmune diseases such as Kawasaki disease, systemic sclerosis, and systemic vasculitis (84,125,139). In these studies, sera from patients with and without autoimmune diseases were screened for autoantibodies against different isoforms of Prx.…”
The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes.
“…Recognition of autoantigens by antiendothelial cell antibodies has been reported [8,9]. We previously demonstrated a marked elevation of a B-cell-activating factor belonging to the TNF family (BAFF) [10] before intravenous immunoglobulin therapy (IVIG), and its steep drop after the therapy [11], which suggest that B-cell activation in the acute phase might be involved in the pathogenesis of KD.…”
Background: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. Although endothelial cell damage associated with vasculitis might lead to the hypercoagulability that is involved in coronary artery disease, the changes in coagulation after intravenous immunoglobulin therapy (IVIG) have not been well investigated in KD. The aims of this study were to address the changes in coagulation before and after IVIG in KD, and to further elucidate the coagulation-inflammation axis, with special attention to endothelial damage. Methods: We retrospectively collected the laboratory data before and after IVIG in 26 pediatric KD patients treated at the Nara Prefecture Western Medical Center between May 2010 and April 2012. Prothrombin time (PT), activated partial thromboplastin time (APTT) and levels of fibrin/fibrinogen degradation products (FDP) and D-dimer were assessed as coagulation markers. Fibrinogen, ferritin, serum amyloid A, procalcitonin and urine F2 microglobulin were assessed as inflammation markers. Thrombomodulin, antithrombin, factor VIII activity (FVIII:C), and von Willebrand factor antigen (VWF:Ag) were used to assess endothelial damage. Results: Prolonged PT and APTT before IVIG were significantly shortened after IVIG, and elevated levels of FDP and D-dimer were significantly decreased. Elevated levels of inflammation markers had decreased significantly after IVIG, but levels of FVIII:C and VWF:Ag remained high, even after IVIG. Conclusions: Ameliorated inflammation by IVIG might improve the hypercoagulable state. Nevertheless, our results suggest that endothelial damage might be prolonged in IVIG-treated patients. Control of endothelial damage in KD is critical. i 2014 S. Karger AG, Basel
“…Currently, we have detected more than 150 candidate antigenic spots, and identified more than 50 protein spots. In our earlier study, we identified Peroxiredoxin-2 (Prx2), a member of the Peroxiredoxin (Prx) family of peroxidases, as a target antigen for AECA [9]. In mammalian cells, the Prx family has at least six members (Table 1), and Prx2 is one of the most rapid and potent responders to oxidative stress.…”
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confidence: 99%
“…To evaluate the roles of AECA in detail, it is essential that their target antigens are identified and that the role of individual target antigens is assessed. Various approaches, such as expression libraries and proteomic, have been developed to identify biomarkers [6][7][8][9][10][11]. In KD, two target antigens for the AECA, tropomyosin and T-plastin, were identified using serological analysis of a recombinant cDNA expression library [11].…”
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confidence: 99%
“…These kinds of analyses may lead to clinical applications. To identify the target proteins for AECA in patients with vasculitis, we used a proteomics approach that included 2-dimensional electrophoresis and Western Blotting, followed by mass spectrometry [9]. Briefly, we extracted the proteins from HUVEC and HeLa cells (control), and separated them by 2-dimensional electrophoresis to detect AECA antigens specific for ECs.…”
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