86 results on '"Banki K"'
Search Results
2. Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
- Author
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Oaks, Z., Patel, A., Huang, N., Choudhary, G., Winans, T., Faludi, T., Krakko, D., Duarte, M., Lewis, J., Beckford, M., Blair, S., Kelly, R., Landas, S. K., Middleton, F. A., Asara, J. M., Chung, S. K., Fernandez, D. R., Banki, K., and Perl, A.
- Published
- 2023
- Full Text
- View/download PDF
3. Publisher Correction: Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
- Author
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Oaks, Z., Patel, A., Huang, N., Choudhary, G., Winans, T., Faludi, T., Krakko, D., Duarte, M., Lewis, J., Beckford, M., Blair, S., Kelly, R., Landas, S. K., Middleton, F. A., Asara, J. M., Chung, S. K., Fernandez, D. R., Banki, K., and Perl, A.
- Published
- 2023
- Full Text
- View/download PDF
4. Human T-Cell Lymphotropic Virus (HTLV)-Related Endogenous Sequence, HRES-1, Encodes a 28-kDa Protein: A Possible Autoantigen for HTLV-I Gag-Reactive Autoantibodies
- Author
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Banki, K., Maceda, J., Hurley, E., Ablonczy, E., Mattson, D. H., Szegedy, L., Hung, C., and Perl, A.
- Published
- 1992
5. Human Transaldolase and Cross-Reactive Viral Epitopes Identified by Autoantibodies of Multiple Sclerosis Patients
- Author
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Esposito, M., Venkatesh, V., Otvos, L., Weng, Z., Vajda, S., Banki, K., and Andras Perl
- Subjects
Models, Molecular ,Multiple Sclerosis ,Sequence Homology, Amino Acid ,Immunodominant Epitopes ,Molecular Mimicry ,Molecular Sequence Data ,Immunology ,Cross Reactions ,Autoantigens ,Peptide Mapping ,Transaldolase ,Epitopes, B-Lymphocyte ,Humans ,Immunology and Allergy ,Computer Simulation ,Amino Acid Sequence ,Antigens, Viral ,Autoantibodies - Abstract
Multiple sclerosis is mediated by an autoimmune process causing selective destruction of oligodendrocytes. Transaldolase, which is expressed in the brain selectively in oligodendrocytes, is a target of high affinity autoantibodies in serum and cerebrospinal fluid of multiple sclerosis patients. A three-dimensional model of human transaldolase was developed based on the crystal structure of the enzyme from Escherichia coli. To identify immunodominant epitopes, 33 peptides overlapping human transaldolase by 5 amino acids were synthesized. Ab 12484, raised against enzymatically active human transaldolase, recognized antigenic determinants corresponding to linear epitopes (residues 27–31 and 265–290) and α helices (residues 75–98 and 302–329). Four immunodominant peptides harboring charged amino acid residues with topographically exposed side chains were identified by sera from 13 multiple sclerosis patients with predetermined autoreactivity to transaldolase. Autoantibodies binding to the most prominent human transaldolase epitope, between residues 271 and 285, showed cross-reactivity with Epstein-Barr and herpes simplex virus type 1 capsid-derived peptides. Molecular mimicry between immunodominant autoepitopes and viral Ags may be a decisive factor in directing autoimmunity to transaldolase in multiple sclerosis patients.
- Published
- 1999
6. Detection of lupus anticoagulant and successful anticoagulation in familial Sneddon syndrome
- Author
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Tily, H., primary, Banki, K., additional, Hoffman, G. S., additional, and Perl, A., additional
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- 2010
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7. Sensitivity to apoptosis is regulated by changes in transaldolase expression
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Banki, K., primary, Hutter, E., additional, Colombo, E., additional, Gonchoroff, N.J., additional, and Perl, A., additional
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- 1997
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8. Comparative analysis of antibody and cell-mediated autoimmunity to transaldolase and myelin basic protein in patients with multiple sclerosis.
- Author
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Colombo, E, primary, Banki, K, additional, Tatum, A H, additional, Daucher, J, additional, Ferrante, P, additional, Murray, R S, additional, Phillips, P E, additional, and Perl, A, additional
- Published
- 1997
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9. Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood
- Author
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Hutchison, R.E., primary, Banki, K., additional, Shuster, J.J., additional, Barrett, D., additional, Dieck, C., additional, Berard, C.W., additional, Murphy, S.B., additional, Link, M.P., additional, Pick, T.E., additional, Laver, J., additional, Schwenn, M., additional, Mathew, P., additional, and Morris, S.W., additional
- Published
- 1997
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10. Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis.
- Author
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Banki, K, primary, Colombo, E, additional, Sia, F, additional, Halladay, D, additional, Mattson, D H, additional, Tatum, A H, additional, Massa, P T, additional, Phillips, P E, additional, and Perl, A, additional
- Published
- 1994
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11. Cloning and expression of the human gene for transaldolase. A novel highly repetitive element constitutes an integral part of the coding sequence.
- Author
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Banki, K., primary, Halladay, D., additional, and Perl, A., additional
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- 1994
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12. Human transaldolase-associated repetitive elements are transcribed by RNA polymerase III.
- Author
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Perl, A, Colombo, E, Samoilova, E, Butler, M C, and Banki, K
- Abstract
Repetitive elements flanked by exons 2 and 3 of the human transaldolase gene, thus termed transaldolase-associated repetitive elements, TARE, were identified in human DNA. Nonpolyadenylated TARE transcripts were detected by Northern blot analysis and cloned by reverse transcriptase-mediated polymerase chain reaction from human T lymphocytes. A dominant 1085-nucleotide long transcript, TARE-6, contained two adjacent Alu elements, a right monomer and a complete dimer, oriented opposite to the direction of transcription of the transaldolase gene. Reverse transcriptase-polymerase chain reaction and in vitro transcription analyses showed that transcription of TARE-6 proceeded in the orientation of the RNA pol III promoter of the Alu dimer and opposite to the orientation of the TAL-H gene. TAREs lacking RNA polymerase III promoter showed no transcriptional activity. In vitro transcription of TARE-6 was resistant to 1 microg/ml alpha-amanitin but sensitive to 100 microg/ml alpha-amanitin and tagetitoxin, suggesting involvement of RNA polymerase III. TAREs in both the transaldolase and HSAG-1 genomic loci were surrounded by TA target site duplications. Homologies between transaldolase and HSAG-1 break off internally at splice donor and acceptor sites. The results suggest RNA polymerase III-mediated transcription of TARE may be a source of repetitive elements, contributing to distinct genes and thus shaping the human genome.
- Published
- 2000
13. The three-dimensional structure of human transaldolase
- Author
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Thorell, S., Jr., P. Gergely, Banki, K., Perl, A., and Schneider, G.
- Published
- 2000
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14. Leukemoid reaction.
- Author
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Mukhopadhyay S, Banki K, and Mahajan S
- Abstract
We report on 2 patients who were initially suspected to have classic Hodgkin lymphoma because of lymphadenopathy and the presence of Reed-Sternberg-like cells. Both patients had an associated leukemoid reaction (using a threshold leukocyte count of 50 000/pt) and were eventually diagnosed with metastatic carcinoma. Disseminated carcinoma can mimic Hodgkin lymphoma clinically, radio- logically, and histologically. Reed-Sternberg-like cells may be found in carcinomas, and they represent a particularly challenging diagnostic pitfall for the unwary. When these cells lead to a suspicion of Hodgkin lymphoma, the presence of a leukemoid reaction should prompt the pathologist to question the diagnosis. Misdiagnosis can be avoided by the use of cytokeratin whenever a leukemoid reaction is present in a suspected case of Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]
- Published
- 2004
15. Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase.
- Author
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Banki, K, Hutter, E, Gonchoroff, N J, and Perl, A
- Abstract
Dysregulated apoptosis may underlie the etiology of T cell depletion by human immunodeficiency virus type 1 (HIV-1). We show that HIV-induced apoptosis is preceded by an exponential increase in reactive oxygen intermediates (ROIs) produced in mitochondria. This leads to caspase-3 activation, phosphatidylserine (PS) externalization, and GSH depletion. Since mitochondrial ROI levels are regulated by the supply of NADPH from the pentose phosphate pathway (PPP), the effect of transaldolase (TAL), a key enzyme of PPP, was investigated. Jurkat and H9 human CD4+ T cells were transfected with TAL expression vectors oriented in the sense or antisense direction. TAL overexpression down-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. Alternatively, decreased TAL expression up-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. HIV-induced 1) mitochondrial ROI production, 2) caspase-3 activation, 3) proteolysis of poly(ADP-ribose) polymerase, and 4) PS externalization were accelerated in cells overexpressing TAL. In contrast, suppression of TAL abrogated these four activities. Thus, susceptibility to HIV-induced apoptosis can be regulated by TAL through controlling the balance between mitochondrial ROI production and the metabolic supply of reducing equivalents by the PPP. The dominant effect of TAL expression on oxidative stress, caspase activation, PS externalization, and cell death suggests that this balance plays a pivotal role in HIV-induced apoptosis.
- Published
- 1998
16. Glutathione levels and sensitivity to apoptosis are regulated by changes in transaldolase expression.
- Author
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Banki, K, Hutter, E, Colombo, E, Gonchoroff, N J, and Perl, A
- Abstract
Transaldolase (TAL) is a key enzyme of the reversible nonoxidative branch of the pentose phosphate pathway (PPP) that is responsible for the generation of NADPH to maintain glutathione at a reduced state (GSH) and, thus, to protect cellular integrity from reactive oxygen intermediates (ROIs). Formation of ROIs have been implicated in certain types of apoptotic cell death. To evaluate the role of TAL in this process, Jurkat human T cells were permanently transfected with TAL expression vectors oriented in the sense or antisense direction. Overexpression of TAL resulted in a decrease in glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities and NADPH and GSH levels and rendered these cells highly susceptible to apoptosis induced by serum deprivation, hydrogen peroxide, nitric oxide, tumor necrosis factor-alpha, and anti-Fas monoclonal antibody. In addition, reduced levels of TAL resulted in increased glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities and increased GSH levels with inhibition of apoptosis in all five model systems. The effect of TAL expression on susceptibility to apoptosis through regulating the PPP and GSH production is consistent with an involvement of ROIs in each pathway tested. Production of ROIs in Fas-mediated cell death was further substantiated by measurement of intracellular ROI production with oxidation-sensitive fluorescent probes, by the protective effects of GSH precursor, N-acetyl cysteine, free radical spin traps 5,5-dimethyl-1-pyrroline-1-oxide and 3,3,5,5-tetramethyl-1-pyrroline-1-oxide, the antioxidants desferrioxamine, nordihydroguaiaretic acid, and Amytal, and by the enhancing effects of GSH depletion with buthionine sulfoximine. The results provide definitive evidence that TAL has a role in regulating the balance between the two branches of PPP and its overall output as measured by GSH production and thus influences sensitivity to cell death signals.
- Published
- 1996
17. Elevation of Mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling
- Author
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Banki, K., Hutter, E., Gonchoroff, N. J., and Andras Perl
- Subjects
Immunology ,Immunology and Allergy - Abstract
Stimulation of the CD95/Fas/Apo-1 receptor leads to apoptosis through activation of the caspase family of cysteine proteases and disruption of the mitochondrial transmembrane potential (Δψm). We show that, in Jurkat human T cells and peripheral blood lymphocytes, Fas-induced apoptosis is preceded by 1) an increase in reactive oxygen intermediates (ROI) and 2) an elevation of Δψm. These events are followed by externalization of phosphatidylserine (PS), disruption of Δψm, and cell death. The caspase inhibitor peptides, DEVD-CHO, Z-VAD.fmk, and Boc-Asp.fmk, blocked Fas-induced PS externalization, disruption of Δψm, and cell death, suggesting that these events are sequelae of caspase activation. By contrast, in the presence of caspase inhibitors, ROI levels and Δψm of Fas-stimulated cells remained elevated. Because ROI levels and Δψm are regulated by the supply of reducing equivalents from the pentose phosphate pathway (PPP), we studied the impact of transaldolase (TAL), a key enzyme of the PPP, on Fas signaling. Overexpression of TAL accelerated Fas-induced mitochondrial ROI production, Δψm elevation, activation of caspase-8 and caspase-3, proteolysis of poly(A)DP-ribose polymerase, and PS externalization. Additionally, suppression of TAL diminished these activities. Therefore, by controlling the balance between mitochondrial ROI production and metabolic supply of reducing equivalents through the PPP, TAL regulates susceptibility to Fas-induced apoptosis. Early increases in ROI levels and Δψm as well as the dominant effect of TAL expression on activation of caspase-8/Fas-associated death domain-like IL-1β-converting enzyme, the most upstream member of the caspase cascade, suggest a pivotal role for redox signaling at the initiation of Fas-mediated apoptosis.
18. Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
- Author
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Huang N, Winans T, Wyman B, Oaks Z, Faludi T, Choudhary G, Lai ZW, Lewis J, Beckford M, Duarte M, Krakko D, Patel A, Park J, Caza T, Sadeghzadeh M, Morel L, Haas M, Middleton F, Banki K, and Perl A
- Subjects
- Animals, Mice, CD8-Positive T-Lymphocytes metabolism, Endosomes metabolism, Kynurenine metabolism, Mitochondria metabolism, Mitophagy, TOR Serine-Threonine Kinases metabolism, rab4 GTP-Binding Proteins metabolism, Glomerulonephritis metabolism, Lupus Erythematosus, Systemic
- Abstract
Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4A
Q72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+ CD4- CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis., (© 2024. The Author(s).)- Published
- 2024
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19. IL-17A inhibitor-induced leucocytoclastic vasculitis is responsive to IL-23 blockade in a psoriatic arthritis patient.
- Author
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Binod KC, Jabbour A, Poudel P, Banki K, and Perl A
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- Humans, Interleukin-17, Antibodies, Monoclonal, Humanized pharmacology, Interleukin-23, Arthritis, Psoriatic drug therapy, Vasculitis, Leukocytoclastic, Cutaneous chemically induced, Psoriasis
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2024
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20. Primary CNS ALK-negative anaplastic large cell lymphoma: A case report and review of the literature.
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Brady AL, Fuller CE, Patel S, Hall W, Banki K, and Ghimire KB
- Abstract
Primary central nervous system (CNS) ALK-negative anaplastic large cell lymphoma (ALCL) is a rare and enigmatic disease, with limited data available in the literature. This case report adds to the existing body of knowledge by describing a unique case of a 68-year-old, immunocompetent male who presented with a single ring-enhancing lesion, which upon further analysis proved to be an ALK-negative ALCL that was primary to the CNS. A comprehensive review of the existing literature is provided, highlighting the genetic characteristics and diverse neuroimaging findings of this disease entity. This report adds valuable information to the understanding of this rare disorder, and highlights the need for further research in the field of primary CNS ALK-negative ALCL., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
- Published
- 2023
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21. Liposomal Daunorubicin and Cytarabine, a Potential Therapy for Blastic Plasmacytoid Dendritic Cell Neoplasm.
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Ashok Kumar P, Ombada M, Pemmasani G, Tambe A, Banki K, and Gentile T
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- Male, Humans, Middle Aged, Cytarabine, Dendritic Cells pathology, Daunorubicin, Acute Disease, Hematologic Neoplasms pathology, Skin Neoplasms pathology, Myeloproliferative Disorders
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignancy with poor outcomes. Although novel options like tagraxofusp, a CD123-directed cytotoxin, has emerged and is promising, treatment options are very limited in the relapsed and recurrent setting. We present a case of refractory BPDCN in a 62-year-old man who showed a complete bone marrow response to liposomal daunorubicin and cytarabine (vyxeos).
- Published
- 2022
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22. Pfizer-biontech COVID-19 RNA vaccination induces phosphatidylserine autoantibodies, cryoglobulinemia, and digital necrosis in a patient with pre-existing autoimmunity.
- Author
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Nasr S, Khalil S, Poiesz BJ, Banki K, and Perl A
- Abstract
We describe a 64-year-old Caucasian female with a history of Raynaud's disease, hand arthritis, photosensitivity, Sjogren's syndrome and leukocytoclastic vasculitis who presented with progressively worsening fingertip necrosis that began three days after receiving a first dose of Pfizer-BioNTech COVID-19 RNA vaccine. Our workup revealed cryoglobulinemia, hypocomplementemia, elevated antinuclear antibodies (ANA) and IgM antiphospholipid autoantibodies (aPL) directed against phosphatidylserine (aPL-PS), suggesting a diagnosis of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The patient failed to develop anti-spike IgG antibodies up to two months following vaccination. Disease progression was halted by plasmapheresis, anticoagulation, and immune suppression. We conclude that the vaccine RNA moiety may induce SLE manifesting in APS, cryoglobulinemia, hypocomplementemia, and digital necrosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)
- Published
- 2021
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23. Successful treatment of secondary macrophage activation syndrome with emapalumab in a patient with newly diagnosed adult-onset Still's disease: case report and review of the literature.
- Author
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Gabr JB, Liu E, Mian S, Pillittere J, Bonilla E, Banki K, and Perl A
- Abstract
Here, we present a 22-year-old female patient with adult-onset Still's disease (AOSD) who was newly diagnosed in the setting of secondary macrophage activation syndrome (MAS), a rare, life-threatening inflammatory disease with 50% mortality due to multi-organ failure. She met the diagnostic criteria of AOSD and MAS, while genetic testing excluded primary causes of MAS. She had high fevers, anemia, thrombocytopenia, splenomegaly, hematophagocytosis, and elevated serum ferritin (37,950 ng/mL) and CD25 levels (11,870 pg/mL), which remained unresponsive to corticosteroids and anakinra. Her serum interferon gamma (IFN-γ) levels were elevated (7 pg/mL). She was markedly responsive to IFN-γ blockade with emapalumab that eliminated her fevers and all MAS-associated laboratory abnormalities. This report provides initial evidence for therapeutic efficacy for IFN-γ blockade in AOSD and secondary MAS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3127). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)
- Published
- 2020
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24. Nine-test panel has superior sensitivity to detect antiphospholipid antibody syndrome in patients with or without SLE.
- Author
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Dziamski K, Sharmeen S, Banki K, and Perl A
- Subjects
- Antibodies, Antiphospholipid blood, Antiphospholipid Syndrome blood, Antiphospholipid Syndrome etiology, Humans, Lupus Coagulation Inhibitor blood, Lupus Erythematosus, Systemic blood, Platelet Function Tests, Predictive Value of Tests, Prothrombin Time, Retrospective Studies, Sensitivity and Specificity, Thrombosis prevention & control, beta 2-Glycoprotein I blood, Antiphospholipid Syndrome diagnosis, Lupus Erythematosus, Systemic complications
- Abstract
Anti-phospholipid antibodies (aPL) and lupus anticoagulant (LAC) represent diagnostic criteria for systemic lupus erythematosus (SLE) and underlie anti-phospholipid syndrome (APS) in patients with and without SLE. 526 healthy controls and 1633 SLE and 1835 primary APS (PAPS) patients were evaluated. LAC was assessed by hexagonal phase phospholipid neutralization assay (HPPNA), diluted Russell viper venom test (dRVVT), and platelet neutralization procedure (PNP). β2-glycoprotein-I and cardiolipin IgG, IgM, and IgA antibodies (aCL-IgG, aCL-IgM, aCL-IgA) were measured. 222/1633 SLE patients had APS based on the nine-test panel, which afforded the highest sensitivity (74%) and negative predictive value (90%) but lowest specificity (52%). HPPNA was the most sensitive individual test at 52%. The nine-test panel yielded the greatest sensitivity for aPL detection (70%) relative to HPPNA, the most sensitive individual test (36%) in PAPS. Superior sensitivity of a nine-test aPL panel has major implications for preventing potentially fatal thrombotic events in SLE and PAPS., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
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25. Transaldolase haploinsufficiency in subjects with acetaminophen-induced liver failure.
- Author
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Oaks Z, Jimah J, Grossman CC, Beckford M, Kelly R, Banerjee S, Niland B, Miklossy G, Kuloglu Z, Kansu A, Lee W, Szonyi L, Banki K, and Perl A
- Subjects
- Adult, Animals, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Female, Humans, Liver Cirrhosis pathology, Liver Cirrhosis prevention & control, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms prevention & control, Male, Mice, Mice, Knockout, Mitochondria metabolism, Oxidative Stress drug effects, Pentose Phosphate Pathway, Transaldolase metabolism, Young Adult, Acetylcysteine pharmacology, Haploinsufficiency drug effects, Liver Failure chemically induced, Transaldolase deficiency
- Abstract
Transaldolase (TAL) is an enzyme in the pentose phosphate pathway (PPP) that generates NADPH for protection against oxidative stress. While deficiency of other PPP enzymes, such as transketolase (TKT), are incompatible with mammalian cell survival, mice lacking TAL are viable and develop progressive liver disease attributed to oxidative stress. Mice with homozygous or heterozygous TAL deficiency are predisposed to cirrhosis, hepatocellular carcinoma (HCC) and acetaminophen (APAP)-induced liver failure. Both mice and humans with complete TAL deficiency accumulate sedoheptulose 7-phosphate (S7P). Previous human studies relied on screening patients with S7P accumulation, thus excluding potentially pathogenic haploinsufficiency. Of note, mice with TAL haploinsufficiency are also predisposed to HCC and APAP-induced liver failure which are preventable with oral N-acetylcysteine (NAC) administration. Based on TALDO1 DNA sequencing, we detected functional TAL deficiency due to novel, heterozygous variations in two of 94 healthy adults and four of 27 subjects with APAP-induced liver failure (P = .022). The functional consequences of these variations were individually validated by site-directed mutagenesis of normal cDNA and loss of activity by recombinant enzyme. All four patients with TAL haplo-insufficiency with APAP-induced liver failure were successfully treated with NAC. We also document two novel variations in two of 15 children with previously unexplained liver cirrhosis. Examination of the National Center for Biotechnology Information databases revealed 274 coding region variations have been documented in 1125 TALDO1 sequences relative to 25 variations in 2870 TKT sequences (P < .0001). These findings suggest an unexpected prevalence and variety of genetic changes in human TALDO1 with relevance for liver injury that may be preventable by treatment with NAC., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2020
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26. Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting promote HRES-1/RAB4 expression and mTOR activation.
- Author
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Godavarthy A, Kelly R, Jimah J, Beckford M, Caza T, Fernandez D, Huang N, Duarte M, Lewis J, Fadel HJ, Poeschla EM, Banki K, and Perl A
- Subjects
- Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Alleles, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, Female, HCT116 Cells, HeLa Cells, Humans, Middle Aged, Nuclear Respiratory Factor 1, Receptors, Antigen, T-Cell, T-Lymphocytes, Terminal Repeat Sequences physiology, Transcription Factors, Young Adult, Endogenous Retroviruses genetics, Epigenesis, Genetic, Lupus Erythematosus, Systemic genetics, TOR Serine-Threonine Kinases genetics, Terminal Repeat Sequences genetics
- Abstract
Overexpression and long terminal repeat (LTR) polymorphism of the HRES‑1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine-119 is hypermethylated while cytosine-51 of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine-119 but not cytosine-51 was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype- and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele-dependent transducer of environmental stress and controller of T cell activation.
- Published
- 2020
- Full Text
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27. Systemic lupus erythematosus-myasthenia gravis overlap syndrome: Presentation and treatment depend on prior thymectomy.
- Author
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Minchenberg SB, Chaparala G, Oaks Z, Banki K, and Perl A
- Subjects
- Female, Humans, Male, Middle Aged, Thymectomy methods, Undifferentiated Connective Tissue Diseases diagnosis, Lupus Erythematosus, Systemic diagnosis, Myasthenia Gravis diagnosis
- Abstract
In this study, we investigated four patients who met the diagnostic criteria for overlapping systemic lupus erythematosus (SLE) and myasthenia gravis (MG) but responded differently to treatment. All patients were acetylcholine receptor (AChR) and antinuclear antibody positive at the time of SLE diagnosis. Two patients presented with SLE who have been effectively treated with cholinesterase inhibitors for MG. These patients developed SLE with photosensitivity, rash, and arthritis post thymectomy, which had been performed 29 years and 40 years earlier, respectively. Two other patients were found to have AChR antibodies and MG in the context on new-onset SLE. These subjects were responsive to hydroxychloroquine and immunosuppression but failed cholinesterase inhibitors. The evolution of these cases is relevant for the role of thymus in lupus pathogenesis during aging and for treatment selection in SLE-MG overlap patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
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28. Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years.
- Author
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Oaks Z, Winans T, Huang N, Banki K, and Perl A
- Subjects
- Acetylcysteine therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Lupus Erythematosus, Systemic drug therapy, Sirolimus therapeutic use, B-Lymphocytes metabolism, Lupus Erythematosus, Systemic metabolism, T-Lymphocytes metabolism, TOR Serine-Threonine Kinases metabolism
- Abstract
The mechanistic target of rapamycin (mTOR) is a central regulator in cell growth, activation, proliferation, and survival. Activation of the mTOR pathway underlies the pathogenesis of systemic lupus erythematosus (SLE). While mTOR activation and its therapeutic reversal were originally discovered in T cells, recent investigations have also uncovered roles in other cell subsets including B cells, macrophages, and "non-immune" organs such as the liver and the kidney. Activation of mTOR complex 1 (mTORC1) precedes the onset of SLE and associated co-morbidities, such as anti-phospholipid syndrome (APS), and may act as an early marker of disease pathogenesis. Six case reports have now been published that document the development of SLE in patients with genetic activation of mTORC1. Targeting mTORC1 over-activation with N-acetylcysteine, rapamycin, and rapalogs provides an opportunity to supplant current therapies with severe side effect profiles such as prednisone or cyclophosphamide. In the present review, we will discuss the recent explosion of findings in support for a central role for mTOR activation in SLE.
- Published
- 2016
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29. Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.
- Author
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Oaks Z, Winans T, Caza T, Fernandez D, Liu Y, Landas SK, Banki K, and Perl A
- Subjects
- Animals, Antibodies, Anticardiolipin biosynthesis, Antibodies, Anticardiolipin drug effects, Antibodies, Anticardiolipin immunology, Antibodies, Antiphospholipid drug effects, Antibodies, Antiphospholipid immunology, Antibody Formation drug effects, Antibody Formation immunology, Blotting, Western, Disease Models, Animal, Dynamins metabolism, Electron Transport Chain Complex Proteins drug effects, Enzyme-Linked Immunosorbent Assay, Female, Immunosuppressive Agents pharmacology, Lupus Erythematosus, Systemic chemically induced, Lupus Erythematosus, Systemic metabolism, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, Mitochondria, Liver drug effects, Oxidative Stress drug effects, Oxygen Consumption drug effects, Sirolimus pharmacology, Transaldolase genetics, beta 2-Glycoprotein I immunology, Antibodies, Antiphospholipid biosynthesis, Electron Transport Chain Complex Proteins metabolism, Lupus Erythematosus, Systemic immunology, Mitochondria, Liver metabolism, Multiprotein Complexes metabolism, Oxidative Stress immunology, Oxygen Consumption immunology, TOR Serine-Threonine Kinases metabolism
- Abstract
Objective: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis., Methods: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-β
2 -glycoprotein I (anti-β2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control., Results: Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-β2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-β2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice., Conclusion: In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE., (© 2016, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)- Published
- 2016
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30. Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus.
- Author
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Liu Y, Yu J, Oaks Z, Marchena-Mendez I, Francis L, Bonilla E, Aleksiejuk P, Patel J, Banki K, Landas SK, and Perl A
- Subjects
- Acetylcysteine therapeutic use, Adult, Alanine Transaminase blood, Aspartate Aminotransferases blood, Azathioprine therapeutic use, Biomarkers, Cohort Studies, Complement System Proteins immunology, Cyclosporine therapeutic use, Diabetes Mellitus epidemiology, Female, Free Radical Scavengers therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Liver Diseases drug therapy, Liver Diseases epidemiology, Longitudinal Studies, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic epidemiology, Male, Middle Aged, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Prednisone therapeutic use, Prevalence, Retrospective Studies, Severity of Illness Index, Sex Distribution, Sirolimus therapeutic use, Antibodies, Antinuclear immunology, Liver Diseases immunology, Lupus Erythematosus, Systemic immunology
- Abstract
Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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31. HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE.
- Author
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Caza TN, Fernandez DR, Talaber G, Oaks Z, Haas M, Madaio MP, Lai ZW, Miklossy G, Singh RR, Chudakov DM, Malorni W, Middleton F, Banki K, and Perl A
- Subjects
- Animals, Autophagy physiology, Case-Control Studies, Cells, Cultured, Diphosphonates therapeutic use, Dynamins blood, Dynamins physiology, Female, GTP Phosphohydrolases physiology, Homeostasis physiology, Humans, Jurkat Cells, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic immunology, Lysosomes metabolism, Mice, Inbred MRL lpr, Microtubule-Associated Proteins physiology, Mitochondrial Proteins physiology, Mitophagy immunology, Molecular Targeted Therapy methods, Pyridines therapeutic use, T-Lymphocytes metabolism, GTP Phosphohydrolases blood, Lupus Erythematosus, Systemic blood, Microtubule-Associated Proteins blood, Mitochondria metabolism, Mitochondrial Proteins blood, rab4 GTP-Binding Proteins physiology
- Abstract
Objective: Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice., Methods: Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 μg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology., Results: Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (-49%; p=0.01) and mouse lymphocytes (-41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (-86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001)., Conclusions: These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2014
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32. HRES-1/Rab4 promotes the formation of LC3(+) autophagosomes and the accumulation of mitochondria during autophagy.
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Talaber G, Miklossy G, Oaks Z, Liu Y, Tooze SA, Chudakov DM, Banki K, and Perl A
- Subjects
- Amino Acid Sequence, Cell Line, Gene Expression, Genes, Reporter, Humans, Intracellular Membranes metabolism, Macrolides pharmacology, Microtubule-Associated Proteins chemistry, Microtubule-Associated Proteins genetics, Mitochondria drug effects, Molecular Sequence Data, Protein Binding, Protein Transport drug effects, rab4 GTP-Binding Proteins genetics, Autophagy physiology, Microtubule-Associated Proteins metabolism, Mitochondria metabolism, Phagosomes metabolism, rab4 GTP-Binding Proteins metabolism
- Abstract
HRES-1/Rab4 is a small GTPase that regulates endocytic recycling. It has been colocalized to mitochondria and the mechanistic target of rapamycin (mTOR), a suppressor of autophagy. Since the autophagosomal membrane component microtubule-associated protein light chain 3 (LC3) is derived from mitochondria, we investigated the impact of HRES-1/Rab4 on the formation of LC3(+) autophagosomes, their colocalization with HRES-1/Rab4 and mitochondria, and the retention of mitochondria during autophagy induced by starvation and rapamycin. HRES-1/Rab4 exhibited minimal baseline colocalization with LC3, which was enhanced 22-fold upon starvation or 6-fold upon rapamycin treatment. Colocalization of HRES-1/Rab4 with mitochondria was increased >2-fold by starvation or rapamycin. HRES-1/Rab4 overexpression promoted the colocalization of mitochondria with LC3 upon starvation or rapamycin treatment. A dominant-negative mutant, HRES-1/Rab4(S27N) had reduced colocalization with LC3 and mitochondria upon starvation but not rapamycin treatment. A constitutively active mutant, HRES-1/Rab4(Q72L) showed diminished colocalization with LC3 but promoted the partitioning of mitochondria with LC3 upon starvation or rapamycin treatment. Phosphorylation-resistant mutant HRES-1/Rab4(S204Q) showed diminished colocalization with LC3 but increased partitioning to mitochondria. A newly discovered C-terminally truncated native isoform, HRES-1/Rab4(1-121), showed enhanced localization to LC3 and mitochondria without starvation or rapamycin treatment. HRES-1/Rab4(1-121) increased the formation of LC3(+) autophagosomes in resting cells, while other isoforms promoted autophagosome formation upon starvation. HRES-1/Rab4, HRES-1/Rab4(1-121), HRES-1/Rab4(Q72L) and HRES-1/Rab4(S204Q) promoted the accumulation of mitochondria during starvation. The specificity of HRES-1/Rab4-mediated mitochondrial accumulation is indicated by its abrogation by dominant-negative HRES-1/Rab4(S27N) mutation. The formation of interconnected mitochondrial tubular networks was markedly enhanced by HRES-1/Rab4(Q72L) upon starvation, which may contribute to the retention of mitochondria during autophagy. The present study thus indicates that HRES-1/Rab4 regulates autophagy through promoting the formation of LC3(+) autophagosomes and the preservation of mitochondria.
- Published
- 2014
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33. Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients.
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Niland B, Miklossy G, Banki K, Biddison WE, Casciola-Rosen L, Rosen A, Martinvalet D, Lieberman J, and Perl A
- Subjects
- Amino Acid Sequence, Autoantibodies blood, Autoantibodies immunology, Autoantigens metabolism, Blotting, Western, CD8-Positive T-Lymphocytes immunology, Cytotoxicity, Immunologic immunology, Enzyme-Linked Immunosorbent Assay, Humans, Leukocytes, Mononuclear immunology, Lymphocyte Activation immunology, Molecular Sequence Data, Mutagenesis, Site-Directed, Oligodendroglia immunology, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Transaldolase metabolism, Autoantigens immunology, Granzymes metabolism, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Transaldolase immunology
- Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8(+) CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8(+) T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major C-terminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8(+) T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.
- Published
- 2010
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34. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
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Hanczko R, Fernandez DR, Doherty E, Qian Y, Vas G, Niland B, Telarico T, Garba A, Banerjee S, Middleton FA, Barrett D, Barcza M, Banki K, Landas SK, and Perl A
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, JNK Mitogen-Activated Protein Kinases metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms prevention & control, Male, Mice, Mice, Knockout, Mitochondria metabolism, Phosphorylation, Transaldolase metabolism, alpha-Fetoproteins metabolism, beta Catenin metabolism, fas Receptor metabolism, Acetylcysteine pharmacology, Carcinoma, Hepatocellular enzymology, Carcinoma, Hepatocellular prevention & control, Cell Transformation, Neoplastic metabolism, Liver Failure chemically induced, Liver Neoplasms enzymology, Transaldolase deficiency
- Abstract
Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
- Published
- 2009
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35. Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.
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Qian Y, Banerjee S, Grossman CE, Amidon W, Nagy G, Barcza M, Niland B, Karp DR, Middleton FA, Banki K, and Perl A
- Subjects
- Cell Line, Transformed, Cells, Cultured, Female, Glucose-6-Phosphate metabolism, Humans, Microscopy, Electron, Signal Transduction, Sugar Phosphates metabolism, Transaldolase genetics, Apoptosis physiology, Homeostasis physiology, Mitochondria physiology, Pentose Phosphate Pathway physiology, Transaldolase deficiency
- Abstract
TAL (transaldolase) was originally described in the yeast as an enzyme of the PPP (pentose phosphate pathway). However, certain organisms and mammalian tissues lack TAL, and the overall reason for its existence is unclear. Recently, deletion of Ser(171) (TALDeltaS171) was found in five patients causing inactivation, proteasome-mediated degradation and complete deficiency of TAL. In the present study, microarray and follow-up Western-blot, enzyme-activity and metabolic studies of TALDeltaS171 TD (TAL-deficient) lymphoblasts revealed co-ordinated changes in the expression of genes involved in the PPP, mitochondrial biogenesis, oxidative stress, and Ca(2+) fluxing. Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP. Nucleotide analysis showed depletion of NADPH and NAD(+) and accumulation of ADP-ribose. TD cells have diminished Deltapsi(m) (mitochondrial transmembrane potential) and increased mitochondrial mass associated with increased production of nitric oxide and ATP. TAL deficiency resulted in enhanced spontaneous and H(2)O(2)-induced apoptosis. TD lymphoblasts showed increased expression of CD38, which hydrolyses NAD(+) into ADP-ribose, a trigger of Ca(2+) release from the endoplasmic reticulum that, in turn, facilitated CD20-induced apoptosis. By contrast, TD cells were resistant to CD95/Fas-induced apoptosis, owing to a dependence of caspase activity on redox-sensitive cysteine residues. Normalization of TAL activity by adeno-associated-virus-mediated gene transfer reversed the elevated CD38 expression, ATP and Ca(2+) levels, suppressed H(2)O(2)- and CD20-induced apoptosis and enhanced Fas-induced cell death. The present study identified the TAL deficiency as a modulator of mitochondrial homoeostasis, Ca(2+) fluxing and apoptosis.
- Published
- 2008
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36. Regulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection.
- Author
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Nagy G, Ward J, Mosser DD, Koncz A, Gergely P Jr, Stancato C, Qian Y, Fernandez D, Niland B, Grossman CE, Telarico T, Banki K, and Perl A
- Subjects
- Antigens, CD metabolism, Apoptosis, Base Sequence, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Chloramphenicol O-Acetyltransferase metabolism, Dependovirus genetics, Disease Susceptibility, Exons genetics, Flow Cytometry, Gene Products, tat pharmacology, Genes, Dominant, HIV Core Protein p24 metabolism, HIV Infections virology, HIV Long Terminal Repeat genetics, HeLa Cells, Humans, Introns genetics, Jurkat Cells, Lysosomes, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation genetics, Receptors, Transferrin metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Homology, Nucleic Acid, Transfection, rab4 GTP-Binding Proteins genetics, tat Gene Products, Human Immunodeficiency Virus, CD4 Antigens metabolism, Gene Expression Regulation, Viral, Gene Products, tat genetics, HIV Infections metabolism, HIV-1 pathogenicity, rab4 GTP-Binding Proteins metabolism
- Abstract
A novel 2986-base transcript encoded by the antisense strand of the HRES-1 human endogenous retrovirus was isolated from peripheral blood lymphocytes. This transcript codes for a 218-amino acid protein, termed HRES-1/Rab4, based on homology to the Rab4 family of small GTPases. Antibody 13407 raised against recombinant HRES-1/Rab4 detected a native protein of identical molecular weight in human T cells. HRES-1 nucleotides 2151-1606, located upstream of HRES-1/Rab4 exon 1, have promoter activity when oriented in the direction of HRES-1/Rab4 transcription. The human immunodeficiency virus, type 1 (HIV-1), tat gene stimulates transcriptional activity of the HRES-1/Rab4 promoter via trans-activation of the HRES-1 long terminal repeat. Transfection of HIV-1 tat into HeLa cells or infection of H9 and Jurkat cells by HIV-1 increased HRES-1/Rab4 protein levels. Overexpression of HRES-1/Rab4 in Jurkat cells abrogated HIV infection, gag p24 production, and apoptosis, whereas dominant-negative HRES-1/Rab4(S27N) had the opposite effects. HRES-1/Rab4 inhibited surface expression of CD4 and targeted it for lysosomal degradation. HRES-1/Rab4(S27N) enhanced surface expression, recycling, and total cellular CD4 content. Infection by HIV elicited a coordinate down-regulation of CD4 and up-regulation of HRES-1/Rab4 in PBL. Moreover, overexpression of HRES-1/Rab4 reduced CD4 expression on peripheral blood CD4+ T cells. Stimulation by HIV-1 of HRES-1/Rab4 expression and its regulation of CD4 recycling reveal novel coordinate interactions between an infectious retrovirus and the human genome.
- Published
- 2006
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37. Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa.
- Author
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Perl A, Qian Y, Chohan KR, Shirley CR, Amidon W, Banerjee S, Middleton FA, Conkrite KL, Barcza M, Gonchoroff N, Suarez SS, and Banki K
- Subjects
- Animals, Calcium Signaling physiology, Epididymis enzymology, Epididymis ultrastructure, Gene Expression, Gene Silencing, Heterozygote, Homozygote, Infertility, Male, Male, Membrane Potentials physiology, Mice, Mice, Knockout, Mitochondria pathology, Mitochondria ultrastructure, Molecular Sequence Data, NAD metabolism, Reactive Oxygen Species metabolism, Recombination, Genetic, Sperm Motility physiology, Spermatozoa cytology, Spermatozoa ultrastructure, Sugar Phosphates metabolism, Transaldolase deficiency, Fertility physiology, Mitochondrial Membranes enzymology, Spermatozoa enzymology, Spermatozoa physiology, Transaldolase metabolism
- Abstract
Fertility of spermatozoa depends on maintenance of the mitochondrial transmembrane potential (Deltapsi(m)), which is generated by the electron-transport chain and regulated by an oxidation-reduction equilibrium of reactive oxygen intermediates, pyridine nucleotides, and glutathione (GSH). Here, we report that male mice lacking transaldolase (TAL)(-/-) are sterile because of defective forward motility. TAL(-/-) spermatozoa show loss of Deltapsi(m) and mitochondrial membrane integrity because of diminished NADPH, NADH, and GSH. Mitochondria constitute major Ca(2+) stores; thus, diminished mitochondrial mass accounts for reduced Ca(2+) fluxing, defective forward motility, and infertility. Reduced forward progression of TAL-deficient spermatozoa is associated with diminished mitochondrial reactive oxygen intermediate production and Ca(2+) levels, intracellular acidosis, and compensatory down-regulation of carbonic anhydrase IV and overexpression of CD38 and gamma-glutamyl transferase. Microarray analyses of gene expression in the testis, caput, and cauda epididymidis of TAL(+/+), TAL(+/-), and TAL(-/-) littermates confirmed a dominant impact of TAL deficiency on late stages of sperm-cell development, affecting the electron-transport chain and GSH metabolism. Stimulation of de novo GSH synthesis by oral N-acetyl-cysteine normalized the low fertility rate of TAL(+/-) males without affecting the sterility of TAL(-/-) males. Whereas TAL(-/-) sperm failed to fertilize TAL(+/+) oocytes in vitro, sterility of TAL(-/-) sperm was circumvented by intracytoplasmic sperm injection, indicating that TAL deficiency influenced the structure and function of mitochondria without compromising the nucleus and DNA integrity. Collectively, these data reveal an essential role of TAL in sperm-cell mitochondrial function and, thus, male fertility.
- Published
- 2006
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38. CD8+ T cell-mediated HLA-A*0201-restricted cytotoxicity to transaldolase peptide 168-176 in patients with multiple sclerosis.
- Author
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Niland B, Banki K, Biddison WE, and Perl A
- Subjects
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Female, HLA-A2 Antigen, Humans, Male, Middle Aged, Multiple Sclerosis pathology, Oligodendroglia enzymology, Peptide Fragments immunology, T-Cell Antigen Receptor Specificity, CD8-Positive T-Lymphocytes immunology, Cytotoxicity, Immunologic, HLA-A Antigens immunology, Multiple Sclerosis immunology, Transaldolase immunology
- Abstract
Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes and targeted by autoreactive T cells of patients with multiple sclerosis (MS). Among 14 TAL peptides with predicted HLA-A2 binding, TAL 168-176 (LLFSFAQAV, TALpep) exhibited high affinity for HLA-A2. Prevalence of HLA-A2-restricted CD8+ T cells specific for TALpep was increased in PBMC of HLA-A2+ MS patients, as compared with HLA-A2- MS patients, HLA-A2+ other neurological disease patients, and HLA-A2+ healthy donors. HLA-A*0201/TALpep tetramers detected increased frequency of TAL-specific CD8+ T cells, and precursor frequency of TAL-specific IFN-gamma-producing T cells was increased in each of seven HLA-A2+ MS patients tested. Stimulation by TALpep or rTAL of PBMC from HLA-A2+ MS patients elicited killing of TALpep-pulsed HLA-A2-transfected HmyA2.1 lymphoma cells, but not HLA-A3-transfected control HmyA3.1 targets. Without peptide pulsing of targets, HLA-A2-transfected, but not control MO3.13 oligodendroglial cells, expressing high levels of endogenous TAL, were also killed by CD8+ CTL of MS patients, indicating recognition of endogenously processed TAL. TCR Vbeta repertoire analysis revealed use of the TCR Vbeta14 gene by T cell lines (TCL) of MS patients generated via stimulation by TAL- or TALpep-pulsed APCs. All TAL-specific TCL-binding HLA-A*0201/TALpep tetramers expressed TCR Vbeta14 on the cell surface. Moreover, Ab to TCR Vbeta14 abrogated cytotoxicity by HLA-A2-restricted TAL-specific TCL. Therefore, TAL-specific CTL may serve as a novel target for therapeutic intervention in patients with MS.
- Published
- 2005
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39. Leukemoid reaction: a diagnostic clue in metastatic carcinoma mimicking classic Hodgkin lymphoma.
- Author
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Mukhopadhyay S, Mukhopadhyay S, Banki K, and Mahajan S
- Subjects
- Adult, Aged, Diagnosis, Differential, Fatal Outcome, Humans, Kidney Neoplasms pathology, Lung Neoplasms pathology, Male, Adrenal Gland Neoplasms secondary, Carcinoma diagnosis, Carcinoma secondary, Hodgkin Disease diagnosis, Leukemoid Reaction diagnosis, Retroperitoneal Neoplasms secondary
- Abstract
We report on 2 patients who were initially suspected to have classic Hodgkin lymphoma because of lymphadenopathy and the presence of Reed-Sternberg-like cells. Both patients had an associated leukemoid reaction (using a threshold leukocyte count of 50 000/microL) and were eventually diagnosed with metastatic carcinoma. Disseminated carcinoma can mimic Hodgkin lymphoma clinically, radiologically, and histologically. Reed-Sternberg-like cells may be found in carcinomas, and they represent a particularly challenging diagnostic pitfall for the unwary. When these cells lead to a suspicion of Hodgkin lymphoma, the presence of a leukemoid reaction should prompt the pathologist to question the diagnosis. Misdiagnosis can be avoided by the use of cytokeratin whenever a leukemoid reaction is present in a suspected case of Hodgkin lymphoma.
- Published
- 2004
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40. Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.
- Author
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Grossman CE, Niland B, Stancato C, Verhoeven NM, Van Der Knaap MS, Jakobs C, Brown LM, Vajda S, Banki K, and Perl A
- Subjects
- Cells, Cultured, Child, Enzyme Activation genetics, Enzyme Activation physiology, Enzyme Inhibitors pharmacology, Female, Fibroblasts chemistry, Fibroblasts enzymology, Fibroblasts metabolism, Gene Expression Regulation, Bacterial genetics, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Humans, Liver Cirrhosis enzymology, Liver Cirrhosis genetics, Lymphocytes chemistry, Lymphocytes enzymology, Lymphocytes metabolism, Models, Molecular, Mutagenesis, Site-Directed genetics, Proteasome Endopeptidase Complex physiology, Protein Conformation, RNA metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins genetics, Sequence Deletion physiology, Serine physiology, Transaldolase biosynthesis, Transaldolase metabolism, Proteasome Endopeptidase Complex genetics, Sequence Deletion genetics, Serine genetics, Transaldolase deficiency, Transaldolase genetics
- Abstract
Homozygous deletion of three nucleotides coding for Ser-171 (S171) of TAL-H (human transaldolase) has been identified in a female patient with liver cirrhosis. Accumulation of sedoheptulose 7-phosphate raised the possibility of TAL (transaldolase) deficiency in this patient. In the present study, we show that the mutant TAL-H gene was effectively transcribed into mRNA, whereas no expression of the TALDeltaS171 protein or enzyme activity was detected in TALDeltaS171 fibroblasts or lymphoblasts. Unlike wild-type TAL-H-GST fusion protein (where GST stands for glutathione S-transferase), TALDeltaS171-GST was solubilized only in the presence of detergents, suggesting that deletion of Ser-171 caused conformational changes. Recombinant TALDeltaS171 had no enzymic activity. TALDeltaS171 was effectively translated in vitro using rabbit reticulocyte lysates, indicating that the absence of TAL-H protein in TALDeltaS171 fibroblasts and lymphoblasts may be attributed primarily to rapid degradation. Treatment with cell-permeable proteasome inhibitors led to the accumulation of TALDeltaS171 in whole cell lysates and cytosolic extracts of patient lymphoblasts, suggesting that deletion of Ser-171 led to rapid degradation by the proteasome. Although the TALDeltaS171 protein became readily detectable in proteasome inhibitor-treated cells, it displayed no appreciable enzymic activity. The results suggest that deletion of Ser-171 leads to inactivation and proteasome-mediated degradation of TAL-H. Since TAL-H is a regulator of apoptosis signal processing, complete deficiency of TAL-H may be relevant for the pathogenesis of liver cirrhosis.
- Published
- 2004
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41. Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity.
- Author
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Perl A, Gergely P Jr, Nagy G, Koncz A, and Banki K
- Subjects
- Adenosine Triphosphate metabolism, Apoptosis immunology, Apoptosis physiology, Dendritic Cells immunology, Dendritic Cells physiology, Humans, Inflammation etiology, Inflammation metabolism, Inflammation physiopathology, Interferon-alpha metabolism, Lupus Erythematosus, Systemic etiology, Lupus Erythematosus, Systemic metabolism, Lupus Erythematosus, Systemic physiopathology, Lymphocyte Activation physiology, Membrane Potentials physiology, Mitochondria metabolism, Models, Biological, Models, Immunological, Reactive Oxygen Species metabolism, Signal Transduction physiology, T-Lymphocytes metabolism, Autoimmunity physiology, Mitochondria physiology, T-Lymphocytes physiology
- Published
- 2004
- Full Text
- View/download PDF
42. Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus.
- Author
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Perl A, Gergely P Jr, and Banki K
- Subjects
- Adenosine Triphosphate biosynthesis, Apoptosis, Humans, Interleukin-10 physiology, Interleukin-12 physiology, Lupus Erythematosus, Systemic metabolism, Lymphocyte Activation, Membrane Potentials, Mitochondria immunology, Reactive Oxygen Species metabolism, Signal Transduction, T-Lymphocytes cytology, T-Lymphocytes metabolism, Lupus Erythematosus, Systemic immunology, Mitochondria metabolism, T-Lymphocytes immunology
- Abstract
Activation, proliferation, or programmed cell death of T lymphocytes are dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta Psi(m)) also plays a decisive role in cell survival by controlling activity of redox-sensitive caspases. T lymphocytes of patients with systemic lupus erythematosus (SLE) exhibit mitochondrial hyperpolarization, increased ROI production, diminished intracellular glutathione levels, cytoplasmic alkalinization, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. These redox and metabolic checkpoints represent novel targets for pharmacological intervention in SLE.
- Published
- 2004
- Full Text
- View/download PDF
43. ZNF143 mediates basal and tissue-specific expression of human transaldolase.
- Author
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Grossman CE, Qian Y, Banki K, and Perl A
- Subjects
- Amino Acid Motifs, Apoptosis, Base Sequence, Binding Sites, Binding, Competitive, Blotting, Western, Cell Differentiation, Cell Line, Cell Line, Tumor, Cell Survival, Chloramphenicol O-Acetyltransferase metabolism, Chromatin metabolism, DNA chemistry, DNA-Binding Proteins metabolism, Deoxyribonuclease I metabolism, Gene Deletion, Genes, Dominant, Genes, Reporter, HeLa Cells, Humans, Jurkat Cells, Kruppel-Like Transcription Factors, Molecular Sequence Data, Mutation, Oligonucleotides chemistry, Oligonucleotides metabolism, Oxidation-Reduction, Plasmids metabolism, Precipitin Tests, Promoter Regions, Genetic, Signal Transduction, Tissue Distribution, Trans-Activators metabolism, Transaldolase metabolism, Transcription Factor AP-2, Transcription Factors metabolism, Transcription, Genetic, Transfection, Up-Regulation, DNA-Binding Proteins physiology, Trans-Activators physiology, Transaldolase biosynthesis
- Abstract
Transaldolase regulates redox-dependent apoptosis through controlling NADPH and ribose 5-phosphate production via the pentose phosphate pathway. The minimal promoter sufficient to drive chloramphenicol acetyltransferase reporter gene activity was mapped to nucleotides -49 to -1 relative to the transcription start site of the human transaldolase gene. DNase I footprinting with nuclear extracts of transaldolase-expressing cell lines unveiled protection of nucleotides -29 to -16. Electrophoretic mobility shift assays identified a single dominant DNA-protein complex that was abolished by consensus sequence for transcription factor ZNF143/76 or mutation of the ZNF76/143 motif within the transaldolase promoter. Mutation of an AP-2alpha recognition sequence, partially overlapping the ZNF143 motif, increased TAL-H promoter activity in HeLa cells, without significant impact on HepG2 cells, which do not express AP-2alpha. Cooperativity of ZNF143 with AP-2alpha was supported by supershift analysis of HeLa cells where AP-2 may act as cell type-specific repressor of TAL promoter activity. However, overexpression of full-length ZNF143, ZNF76, or dominant-negative DNA-binding domain of ZNF143 enhanced, maintained, or abolished transaldolase promoter activity, respectively, in HepG2 and HeLa cells, suggesting that ZNF143 initiates transcription from the transaldolase core promoter. ZNF143 overexpression also increased transaldolase enzyme activity. ZNF143 and transaldolase expression correlated in 21 different human tissues and were coordinately upregulated 14- and 34-fold, respectively, in lactating mammary glands compared with nonlactating ones. Chromatin immunoprecipitation studies confirm that ZNF143/73 associates with the transaldolase promoter in vivo. Thus, ZNF143 plays a key role in basal and tissue-specific expression of transaldolase and regulation of the metabolic network controlling cell survival and differentiation.
- Published
- 2004
- Full Text
- View/download PDF
44. Apoptosis and mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus.
- Author
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Perl A, Nagy G, Gergely P, Puskas F, Qian Y, and Banki K
- Subjects
- Adenosine Triphosphate analysis, Adenosine Triphosphate metabolism, Blotting, Western, Caspases analysis, Caspases metabolism, Chromatography, High Pressure Liquid, Flow Cytometry, Glutathione analysis, Glutathione metabolism, Humans, In Vitro Techniques, Lupus Erythematosus, Systemic etiology, Lupus Erythematosus, Systemic immunology, Lymphocyte Activation, Membrane Potentials, Models, Biological, Reactive Oxygen Species metabolism, T-Lymphocytes immunology, Apoptosis, Lupus Erythematosus, Systemic metabolism, Lupus Erythematosus, Systemic pathology, Mitochondria metabolism, T-Lymphocytes metabolism, T-Lymphocytes pathology
- Abstract
Systemic lupus erythematosus (SLE) is characterized by abnormal activation and cell death signaling within the immune system. Activation, proliferation, or death of cells of the immune system are dependent on controlled reactive oxygen intermediate (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta(Psi)m) reflects the energy stored in the electrochemical gradient across the inner mitochondrial membrane, which in turn is used by F0F1-ATPase to convert adenosine 5'-diphosphate to ATP during oxidative phosphorylation. Mitochondrial hyperpolarization and transient ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit elevated Delta(Psi)m, that is, persistent mitochondrial hyperpolarization, cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Oxidative stress affects signaling through the T-cell receptor as well as the activity of redox-sensitive caspases. ATP depletion may be responsible for diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Mitochondrial dysfunction is identified as a key mechanism in the pathogenesis of SLE.
- Published
- 2004
- Full Text
- View/download PDF
45. Metabolic switches of T-cell activation and apoptosis.
- Author
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Perl A, Gergely P Jr, Puskas F, and Banki K
- Subjects
- Adenosine Triphosphate metabolism, Animals, Antigens, CD metabolism, Ascorbic Acid metabolism, Glucose metabolism, HIV-1 metabolism, Humans, Membrane Potentials physiology, Mitochondria metabolism, Oxidation-Reduction, Pentose Phosphate Pathway, Reactive Oxygen Species metabolism, Receptors, Antigen, T-Cell metabolism, Apoptosis physiology, Lymphocyte Activation physiology, Signal Transduction physiology, T-Lymphocytes physiology
- Abstract
The signaling networks that mediate activation, proliferation, or programmed cell death of T lymphocytes are dependent on complex redox and metabolic pathways. T lymphocytes are primarily activated through the T-cell receptor and co-stimulatory molecules. Although activation results in lymphokine production, proliferation, and clonal expansion, it also increases susceptibility to apoptosis upon crosslinking of cell-surface death receptors or exposure to toxic metabolites. Activation signals are transmitted by receptor-associated protein tyrosine kinases and phosphatases through calcium mobilization to a secondary cascade of kinases, which in turn activate transcription factors initiating cell proliferation and cytokine production. Initiation and activity of cell death-mediating proteases are redox-sensitive and dependent on energy provided by ATP. Mitochondria play crucial roles in providing ATP for T-cell activation through the electron transport chain and oxidative phosphorylation. The mitochondrial transmembrane potential (DeltaPsi(m)) plays a decisive role not only by driving ATP synthesis, but also by controlling reactive oxygen species production and release of cell death-inducing factors. DeltaPsi(m) and reactive oxygen species levels are regulated by the supply of reducing equivalents, glutathione and thioredoxin, as well as NADPH generated in the pentose phosphate pathway. This article identifies redox and metabolic checkpoints controlling activation and survival of T lymphocytes.
- Published
- 2002
- Full Text
- View/download PDF
46. Differential regulation of hydrogen peroxide and Fas-dependent apoptosis pathways by dehydroascorbate, the oxidized form of vitamin C.
- Author
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Puskas F, Gergely P, Niland B, Banki K, and Perl A
- Subjects
- Animals, Antioxidants chemistry, Ascorbic Acid chemistry, Dehydroascorbic Acid pharmacology, Flow Cytometry, Free Radical Scavengers chemistry, Free Radical Scavengers metabolism, Glucosephosphate Dehydrogenase metabolism, Glutathione metabolism, Humans, Jurkat Cells drug effects, Jurkat Cells metabolism, Membrane Potentials drug effects, Membrane Potentials physiology, Mitochondria metabolism, Oxidation-Reduction, Phosphogluconate Dehydrogenase metabolism, Reactive Oxygen Species metabolism, Transaldolase metabolism, Tumor Cells, Cultured, Antioxidants metabolism, Apoptosis physiology, Ascorbic Acid metabolism, Dehydroascorbic Acid metabolism, Hydrogen Peroxide metabolism, Oxidants metabolism, fas Receptor metabolism
- Abstract
Dehydroascorbate (DHA), the oxidized form of vitamin C (ascorbate), enhanced antioxidant defenses of human T cells preferentially importing DHA over ascorbate. In itself, DHA did not affect cytosolic or mitochondrial reactive oxygen intermediate levels as monitored by flow cytometry using oxidation-sensitive fluorescent probes. DHA at 200-1,000 microM stimulated activity of pentose phosphate pathway enzymes glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transaldolase, elevated intracellular glutathione levels, and inhibited H(2)O(2)-induced changes in mitochondrial transmembrane potential and cell death. With respect to the CD4 antigen, DHA selectively enhanced cell-surface expression of the Fas receptor and increased susceptibility of Jurkat and H9 human T cells to Fas-mediated cell death. The data identify DHA as a selective regulator of H(2)O(2)- and Fas-dependent apoptosis pathways.
- Published
- 2002
- Full Text
- View/download PDF
47. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.
- Author
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Gergely P Jr, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, and Perl A
- Subjects
- Adolescent, Adult, Apoptosis immunology, CD28 Antigens metabolism, CD3 Complex metabolism, Female, Flow Cytometry, Glutathione metabolism, Glutathione Disulfide metabolism, Humans, Hydrogen Peroxide pharmacology, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic pathology, Lymphocyte Activation physiology, Male, Membrane Potentials drug effects, Membrane Potentials immunology, Middle Aged, Necrosis, Oxidants pharmacology, Reactive Oxygen Species metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, Adenosine Triphosphate metabolism, Lupus Erythematosus, Systemic metabolism, Mitochondria physiology, T-Lymphocytes metabolism
- Abstract
Objective: Peripheral blood lymphocytes (PBLs) from systemic lupus erythematosus (SLE) patients exhibit increased spontaneous and diminished activation-induced apoptosis. We tested the hypothesis that key biochemical checkpoints, the mitochondrial transmembrane potential (deltapsim) and production of reactive oxygen intermediates (ROIs), mediate the imbalance of apoptosis in SLE., Methods: We assessed the deltapsim with potentiometric dyes, measured ROI production with oxidation-sensitive fluorochromes, and monitored cell death by annexin V and propidium iodide staining of lymphocytes, using flow cytometry. Intracellular glutathione levels were measured by high-performance liquid chromatography, while ATP and ADP levels were assessed by the luciferin-luciferase assay., Results: Both deltapsim and ROI production were elevated in the 25 SLE patients compared with the 25 healthy subjects and the 10 rheumatoid arthritis patients. Intracellular glutathione contents were diminished, suggesting increased utilization of reducing equivalents in SLE. H2O2, a precursor of ROIs, increased deltapsim and caused apoptosis in normal PBLs. In contrast, H2O2-induced apoptosis and deltapsim elevation were diminished, particularly in T cells, and the rate of necrotic cell death was increased in patients with SLE. The intracellular ATP content and the ATP:ADP ratio were reduced and correlated with the deltapsim elevation in lupus. CD3:CD28 costimulation led to transient elevation of the deltapsim, followed by ATP depletion, and sensitization of normal PBLs to H2O2-induced necrosis. Depletion of ATP by oligomycin, an inhibitor of F0F1-ATPase, had similar effects., Conclusion: T cell activation and apoptosis are mediated by deltapsim elevation and increased ROI production. Mitochondrial hyperpolarization and the resultant ATP depletion sensitize T cells for necrosis, which may significantly contribute to inflammation in patients with SLE.
- Published
- 2002
- Full Text
- View/download PDF
48. Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease.
- Author
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Perl A and Banki K
- Subjects
- Humans, Models, Biological, Oxidation-Reduction, T-Lymphocytes metabolism, Transcription, Genetic, Virus Replication, HIV Infections metabolism, Membrane Potentials, Mitochondria metabolism, Reactive Oxygen Species
- Abstract
Redox mechanims play important roles in replication of human immunodeficiency virus type 1 (HIV-1) and cellular susceptibility to apoptosis signals. Viral replication and accelerated turnover of CD4+ T cells occur throughout a prolonged asymptomatic phase in patients infected by HIV-1. Disease development is associated with steady loss of CD4+ T cells by apoptosis, increased rate of opportunistic infections and lymphoproliferative diseases, disruption of energy metabolism, and generalized wasting. Such pathological states are preceded by: (i) depletion of intracellular antioxidants, glutathione (GSH) and thioredoxin (TRX), (ii) increased reactive oxygen species (ROS) production, and (iii) changes in mitochondrial transmembrane potential (deltapsi(m)). Disruption of deltapsi(m) appears to be the point of no return in the effector phase of apoptosis. Viral proteins Tat, Nef, Vpr, protease, and gp120, have been implicated in initiation and/or intensification of oxidative stress and disruption of deltapsi(m). Redox-sensitive transcription factors, NF-kappaB, AP-1, and p53, support expression of viral genes and proinflammatory lymphokines. ROS regulate apoptosis signaling through Fas, tumor necrosis factor (TNF), and related cell death receptors, as well as the T-cell receptor. Oxidative stress in HIV-infected donors is accompanied by increased glucose utilization both on the cellular and organismal levels. Generation of GSH and TRX from their corresponding oxidized forms is dependent on NADPH provided through the pentose phosphate pathway of glucose metabolism. This article seeks to delineate the genetic and metabolic bases of HIV-induced oxidative stress. Such understanding should lead to development of effective antioxidant therapies in HIV disease.
- Published
- 2000
- Full Text
- View/download PDF
49. Stimulation of the pentose phosphate pathway and glutathione levels by dehydroascorbate, the oxidized form of vitamin C.
- Author
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Puskas F, Gergely P Jr, Banki K, and Perl A
- Subjects
- Antioxidants pharmacology, Apoptosis drug effects, Ascorbic Acid metabolism, Cell Line, Dehydroascorbic Acid metabolism, Glucosephosphate Dehydrogenase metabolism, Humans, Hydrogen Peroxide toxicity, Jurkat Cells, Phosphogluconate Dehydrogenase metabolism, Transaldolase metabolism, Dehydroascorbic Acid pharmacology, Glutathione metabolism, Pentose Phosphate Pathway drug effects
- Abstract
Ascorbic acid, or vitamin C, generally functions as an antioxidant by directly reacting with reactive oxygen intermediates and has a vital role in defenses against oxidative stress. However, ascorbic acid also has pro-oxidant properties and may cause apoptosis of lymphoid and myeloid cells. The present study shows that dehydroascorbate, the oxidized form of vitamin C, stimulates the antioxidant defenses of cells, preferentially importing dehydroascorbate over ascorbate. While 200-800 microM vitamin C caused apoptosis of Jurkat and H9 human T lymphocytes, pretreatment with 200-1000 microM dehydroascorbate stimulated activity of pentose phosphate pathway enzymes glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transaldolase, elevated intracellular glutathione levels, and inhibited H(2)O(2)-induced changes in mitochondrial transmembrane potential and cell death. A 3. 3-fold maximal glutathione elevation was observed after 48 h stimulation with 800 microM dehydroascorbate. In itself, dehydroascorbate did not affect cytosolic or mitochondrial reactive oxygen intermediate levels as monitored by flow cytometry using oxidation-sensitive fluorescent probes. The data reveal a novel mechanism for increasing glutathione levels through stimulation of the pentose phosphate pathway and identify dehydroascorbate as an antioxidant for cells susceptible to the pro-oxidant and proapoptotic properties of vitamin C.
- Published
- 2000
- Full Text
- View/download PDF
50. Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.
- Author
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Magistrelli C, Samoilova E, Agarwal RK, Banki K, Ferrante P, Vladutiu A, Phillips PE, and Perl A
- Subjects
- Adolescent, Adult, Alleles, Antibodies, Antinuclear blood, Autoantigens genetics, Autoimmunity genetics, Base Sequence, Case-Control Studies, DNA Primers genetics, Endogenous Retroviruses immunology, Endogenous Retroviruses pathogenicity, Female, Genotype, Humans, Lupus Erythematosus, Systemic genetics, Male, Middle Aged, Molecular Mimicry, Pedigree, Retroviridae Proteins genetics, Retroviridae Proteins immunology, Terminal Repeat Sequences, Antigens, Nuclear, Endogenous Retroviruses genetics, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic virology, Polymorphism, Genetic
- Abstract
Antinuclear autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Autoantibodies to HRES-1/p28, a 28 000 M(r) nuclear protein, commonly occur in patients with SLE. HRES-1 is a single-copy endogenous retroviral element mapped to human Chromosome 1 at q42. A polymorphic Hin dIII site defines two different allelic forms of the genomic locus. The HRES-1/1 probe [5.5 kilobases (kb)] anneals to three polymorphic fragments and three genotypes can be differentiated: I, 5.5 kb fragment only; II, 3.7 kb and 1.8 kb fragments only; and III, all three polymorphic fragments. By cloning of the HRES-1 locus from homozygous type I and type II human DNA samples, the polymorphic Hin dIII site was identified as a G to C transition at position 653 of the long terminal repeat region. Family studies showed that Hin dIII genotypes of the HRES-1 locus are inherited in a Mendelian pattern. The relative frequency of genotype I with respect to genotype III was 3.1-fold lower in patients with SLE (14:40=0.35) in comparison to 100 ethnically matched control donors (47:43=1.09; P=0.0084). Frequency of genotype I vs genotype II alleles was lower in SLE (68/52) than in normal donors (137/63; P=0.033), suggesting that a genotype I allele of the HRES-1 locus may be protective against SLE. Western blot seroreactivity with recombinant HRES-1/p28 was noted in 4/14 (29%) of genotype I patients and 13/19 (68%) of genotype III patients (P<0.025). These data raise the possibility that the HRES-1 element or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE.
- Published
- 1999
- Full Text
- View/download PDF
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