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Greiner-Tollersrud OK, Krausz M, Boehler V, Polyzou A, Seidl M, Spahiu A, Abdullah Z, Andryka-Cegielski K, Dominick FI, Huebscher K, Goschin A, Smulski CR, Trompouki E, Link R, Ebersbach H, Srinivas H, Marchant M, Sogkas G, Staab D, Vågbø C, Guerini D, Baasch S, Latz E, Hartmann G, Henneke P, Geiger R, Peng XP, Grimbacher B, Bartok E, Alseth I, Warncke M, Proietti M. ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA. Cell Rep 2024; 43:114899. [PMID: 39441717 DOI: 10.1016/j.celrep.2024.114899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 09/19/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024] Open
Abstract
Although adenosine deaminase 2 (ADA2) is considered an extracellular ADA, evidence questions the physiological relevance of this activity. Our study reveals that ADA2 localizes within the lysosomes, where it is targeted through modifications of its glycan structures. We show that ADA2 interacts with DNA molecules, altering their sequences by converting deoxyadenosine (dA) to deoxyinosine (dI). We characterize its DNA substrate preferences and provide data suggesting that DNA, rather than free adenosine, is its natural substrate. Finally, we demonstrate that dA-to-dI editing of DNA molecules and ADA2 regulate lysosomal immune sensing of nucleic acids (NAs) by modulating Toll-like receptor 9 (TLR9) activation. Our results describe a mechanism involved in the complex interplay between NA metabolism and immune response, possibly impacting ADA2 deficiency (DADA2) and other diseases involving this pathway, including autoimmune diseases, cancer, or infectious diseases.
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Affiliation(s)
| | - Máté Krausz
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
| | - Vincent Boehler
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Aikaterini Polyzou
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
| | - Maximilian Seidl
- Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Ambra Spahiu
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
| | - Zeinab Abdullah
- Institute of Experimental Immunology, Universitätsklinikum Bonn, Bonn, Germany
| | | | | | - Katrin Huebscher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institut für Forstentomologie und Waldschutz, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
| | - Andreas Goschin
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
| | - Cristian R Smulski
- Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Carlos de Bariloche, Río Negro, Argentina
| | - Eirini Trompouki
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
| | - Regina Link
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Hilmar Ebersbach
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Honnappa Srinivas
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Martine Marchant
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Georgios Sogkas
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; RESIST - Cluster of Excellence 2155, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Dieter Staab
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Cathrine Vågbø
- Proteomics and Modomics Experimental Core (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, Trondheim, Norway
| | - Danilo Guerini
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Sebastian Baasch
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institute for Infection Prevention and Control, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Eicke Latz
- Institute of Innate Immunity, Universitätsklinikum Bonn, Bonn, Germany
| | - Gunther Hartmann
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
| | - Philippe Henneke
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institute for Infection Prevention and Control, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roger Geiger
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; Institute of Oncology Research, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Xiao P Peng
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
| | - Eva Bartok
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
| | - Ingrun Alseth
- Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Max Warncke
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
| | - Michele Proietti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; RESIST - Cluster of Excellence 2155, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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Dong K, Wang Y, Yao Y, Yu W, Xu Z, Chen Y, Geng L, Wang S. The reduced frequency of CD39 +CD73 + B cell subsets in SLE patients is correlated with disease activity. Int Immunopharmacol 2024; 140:112743. [PMID: 39094356 DOI: 10.1016/j.intimp.2024.112743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by immune mechanisms dysregulation, leading to the production of diverse autoantibodies. However, the immune pathways underlying B-cell function and phenotypic abnormalities related to SLE pathogenesis remain incompletely understood. OBJECTIVE To explore new markers of SLE activity and potential targets for SLE immunotherapy. METHODS Collect peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls (HC). Use flow cytometry to detect CD39 and CD73 expression on B cell subsets and enzyme-linked immunosorbent assay (ELISA) to measure adenosine (ADO) concentrations in SLE patients' serum. Compare CD39+CD73+ B cell subsets frequency and ADO concentrations in SLE patients and HC group. Additionally, analyze the correlation between CD39+CD73+ B cell subsets frequency and clinical laboratory parameters. RESULTS CD39 and CD73 are simultaneously highly expressed on CD19+ B cell subsets, with significantly lower frequency of CD39+CD73+ B cell subsets in SLE patients compared to HC group. This frequency negatively correlates with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), C-reactive protein (CRP), and anti-double-stranded DNA (anti-dsDNA) antibodies, while positively correlating with IgM and prothrombin time (PT). Additionally, the frequency of CD39+CD73+ B cell subsets is significantly negatively correlated with IL-6 and IFN-α. In vitro cell experiments demonstrate that adenosine significantly inhibits R848-induced inflammatory cytokine production in a dose-dependent manner. CONCLUSION The frequency of CD39+CD73+ B cell subsets of SLE patients is decreased, correlating with clinical laboratory parameters and disease activity. Simultaneously, ADO concentration in the patients' serum is reduced. The CD39+CD73+ B cell/ADO pathway may represent a novel immunotherapy strategy for SLE.
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Affiliation(s)
- Kunzhan Dong
- Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Clinical College, Jiangsu University, Nanjing, Jiangsu 210008, China
| | - Ying Wang
- Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, China
| | - Yao Yao
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenhui Yu
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Zhiye Xu
- Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China
| | - Yan Chen
- Department of Nursing, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, China.
| | - Linyu Geng
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
| | - Sen Wang
- Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Clinical College, Jiangsu University, Nanjing, Jiangsu 210008, China; Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, China; Department of Clinical Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
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Brix A, Belleri L, Pezzotta A, Pettinato E, Mazzola M, Zoccolillo M, Marozzi A, Monteiro R, Del Bene F, Mortellaro A, Pistocchi A. ADA2 regulates inflammation and hematopoietic stem cell emergence via the A 2bR pathway in zebrafish. Commun Biol 2024; 7:615. [PMID: 38777862 PMCID: PMC11111730 DOI: 10.1038/s42003-024-06286-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients.
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Affiliation(s)
- Alessia Brix
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy
| | - Laura Belleri
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy
- Department of Development, Institut de la Vision, 17 Rue Moreau, 75012, Paris, France
| | - Alex Pezzotta
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy
| | - Emanuela Pettinato
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy
| | - Mara Mazzola
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy
| | - Matteo Zoccolillo
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy
| | - Anna Marozzi
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy
| | - Rui Monteiro
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, Edgbaston, B15 2TTB, UK
| | - Filippo Del Bene
- Department of Development, Institut de la Vision, 17 Rue Moreau, 75012, Paris, France
| | - Alessandra Mortellaro
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy.
| | - Anna Pistocchi
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, L.I.T.A., via Fratelli Cervi 93, Segrate, 20054, Milan, Italy.
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Bowers SM, Ng B, Abdossamadi S, Kariminia A, Cabral DA, Cuvelier GDE, Schultz KR, Brown KL. Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children. Transplant Cell Ther 2023; 29:303.e1-303.e9. [PMID: 36804932 DOI: 10.1016/j.jtct.2023.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/27/2023] [Accepted: 02/12/2023] [Indexed: 02/19/2023]
Abstract
Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.
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Affiliation(s)
- Sarah M Bowers
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Bernard Ng
- Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Sayeh Abdossamadi
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Amina Kariminia
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - David A Cabral
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplant, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Kirk R Schultz
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kelly L Brown
- British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
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Jia Q, Hao RJL, Lu XJ, Sun SQ, Shao JJ, Su X, Huang QF. Identification of hub biomarkers and immune cell infiltration characteristics of polymyositis by bioinformatics analysis. Front Immunol 2022; 13:1002500. [PMID: 36225941 PMCID: PMC9548705 DOI: 10.3389/fimmu.2022.1002500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Background Polymyositis (PM) is an acquirable muscle disease with proximal muscle involvement of the extremities as the main manifestation; it is a category of idiopathic inflammatory myopathy. This study aimed to identify the key biomarkers of PM, while elucidating PM-associated immune cell infiltration and immune-related pathways. Methods The gene microarray data related to PM were downloaded from the Gene Expression Omnibus database. The analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were performed on differentially expressed genes (DEGs). The hub genes of PM were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm, and the diagnostic accuracy of hub markers for PM was assessed using the receiver operating characteristic curve. In addition, the level of infiltration of 28 immune cells in PM and their interrelationship with hub genes were analyzed using single-sample GSEA. Results A total of 420 DEGs were identified. The biological functions and signaling pathways closely associated with PM were inflammatory and immune processes. A series of four expression modules were obtained by WGCNA analysis, with the turquoise module having the highest correlation with PM; 196 crossover genes were obtained by combining DEGs. Subsequently, six hub genes were finally identified as the potential biomarkers of PM using LASSO algorithm and validation set verification analysis. In the immune cell infiltration analysis, the infiltration of T lymphocytes and subpopulations, dendritic cells, macrophages, and natural killer cells was more significant in the PM. Conclusion We identified the hub genes closely related to PM using WGCNA combined with LASSO algorithm, which helped clarify the molecular mechanism of PM development and might have great significance for finding new immunotherapeutic targets, and disease prevention and treatment.
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Affiliation(s)
- Qi Jia
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Rui-Jin-Lin Hao
- Medical School of Nantong University, Nantong, China
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiao-Jian Lu
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Shu-Qing Sun
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jun-Jie Shao
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xing Su
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
| | - Qing-Feng Huang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
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Zeng T, Ling B, Hu X, Wang S, Qiao W, Gao L, Shen Y, Li D. The Value of Adenosine Deaminase 2 in the Detection of Tuberculous Pleural Effusion: A Meta-Analysis and Systematic Review. Can Respir J 2022; 2022:7078652. [PMID: 36124285 PMCID: PMC9482525 DOI: 10.1155/2022/7078652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Adenosine deaminase 2 (ADA2) is reported as a novel diagnostic biomarker for tuberculous pleural effusion (TPE) in many studies. This meta-analysis was conducted to systematically evaluate the general diagnostic performance of pleural ADA2 in TPE. After searching for relevant studies that investigated the diagnostic performance of pleural ADA2 in TPE in several databases, we assessed and selected eligible studies to calculate pooled parameters by STATA 16.0 software. A final set of thirteen studies entirely met the inclusion standards and were used to calculate pooled parameters in our meta-analysis. Among them, there were nine English studies and four Chinese studies. The pooled parameters of pleural ADA2 in diagnosing TPE were summarized as follows: sensitivity, 0.91 (95% CI: 0.86-0.95); specificity, 0.93 (95% CI: 0.92-0.95); positive likelihood ratio, 13.9 (95% CI: 10.6-18.3); negative likelihood ratio, 0.09 (95% CI:0.06-0.16); diagnostic odds ratio, 147 (95% CI: 76-284); and the area under the curve, 0.95 (95% CI: 0.93-0.97). Pleural ADA2 is a reliable indicator with excellent accuracy in TPE diagnosis. However, we need to combine pleural ADA2 with diverse examinations to diagnose TPE in clinical practice.
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Affiliation(s)
- Tingting Zeng
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Bing Ling
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Xueru Hu
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Shuyan Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Wenliang Qiao
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lijuan Gao
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Yongchun Shen
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu 610041, China
| | - Dajiang Li
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
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Li S, Yang J, Mohamed H, Wang X, Pang S, Wu C, López-García S, Song Y. Identification and Functional Characterization of Adenosine Deaminase in Mucor circinelloides: A Novel Potential Regulator of Nitrogen Utilization and Lipid Biosynthesis. J Fungi (Basel) 2022; 8:jof8080774. [PMID: 35893142 PMCID: PMC9332508 DOI: 10.3390/jof8080774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
Adenosine deaminase (ADA) is an enzyme distributed in a wide variety of organisms that cleaves adenosine into inosine. Since inosine plays an important role in nitrogen metabolism, ADA may have a critical function in the regulation of fatty acid synthesis. However, the role of ADA in oleaginous fungi has not been reported so far. Therefore, in this study, we identified one ada gene encoding ADA (with ID scaffold0027.9) in the high lipid-producing fungus, Mucor circinelloides WJ11, and investigated its role in cell growth, lipid production, and nitrogen metabolism by overexpressing and knockout of this gene. The results showed that knockout of the ada altered the efficiency of nitrogen consumption, which led to a 20% increment in the lipid content (25% of cell dry weight) of the engineered strain, while overexpression of the ada showed no significant differences compared with the control strain at the final growth stage; however, interestingly, it increased lipid accumulation at the early growth stage. Additionally, transcriptional analysis was conducted by RT-qPCR and our findings indicated that the deletion of ada activated the committed steps of lipid biosynthesis involved in acetyl-CoA carboxylase (acc1 gene), cytosolic malic acid enzyme (cme1 gene), and fatty acid synthases (fas1 gene), while it suppressed the expression of AMP-activated protein kinase (ampk α1 and ampk β genes), which plays a role in lipolysis, whereas the ada-overexpressed strain displayed reverse trends. Conclusively, this work unraveled a novel role of ADA in governing lipid biosynthesis and nitrogen metabolism in the oleaginous fungus, M. circinelloides.
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Affiliation(s)
- Shaoqi Li
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
| | - Junhuan Yang
- Department of Food Sciences, College of Food Science and Engineering, Lingnan Normal University, Zhanjiang 524048, China;
| | - Hassan Mohamed
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
| | - Xiuwen Wang
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
| | - Shuxian Pang
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
| | - Chen Wu
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
| | - Sergio López-García
- Department of Genetics and Microbiology (Associated Unit to IQFR-CSIC), Faculty of Biology, University of Murcia, 3100 Murcia, Spain;
| | - Yuanda Song
- Colin Ratledge Center for Microbial Lipids, School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255000, China; (S.L.); (H.M.); (X.W.); (S.P.); (C.W.)
- Correspondence: ; Tel.: +86-13964463099
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Gao ZW, Yang L, Liu C, Wang X, Guo WT, Zhang HZ, Dong K. Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis. Front Immunol 2022; 13:903461. [PMID: 35663977 PMCID: PMC9157497 DOI: 10.3389/fimmu.2022.903461] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Adenosine deaminase (ADA) plays an important role in immune response, which includes two isoenzymes: ADA1 and ADA2. This study aims to explore the roles of ADA1 and ADA2 in cancers. Methods Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were used to analyze the mRNA expression of ADA1 and ADA2 in human normal cells and tumor tissues. The enzyme assay was used to detect the ADA1 and ADA2 activities in serum from cancer patients. The Kaplan-Meier (KM) plotter was used to analyze the prognostic value of ADA1 and ADA2. TIMER2.0 was used to explore how ADA1 and ADA2 correlate with immune infiltration and immune checkpoints. cBioPortal database was used to investigate the mutations of ADA1 and ADA2. LinkedOmics was used to screen the ADA1 and ADA2 expression-related genes. Results ADA1 was significantly increased in several tumor tissues, including cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), thymoma (THYM), and uterine carcinosarcoma (UCS). ADA2 expression was significantly increased in esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), acute myeloid leukemia (LAML), OV, PAAD, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). There were no significant changes in serum ADA1 activities in most cancers, while serum ADA2 activities were increased in most cancers. For prognosis, high ADA1 expression was associated with the poor survival in several cancers, including esophageal squamous cell carcinoma (ESCC), HNSC, KIRC, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC). However, high ADA2 expression showed a favorable prognosis in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), HNSC, KIRC, KIRP, LUAD, OV, PAAD, sarcoma, and THYM. ADA1 showed a moderate positive correlation with multiple infiltrating immune cells in most cancers. ADA2 was positively correlated with B cells, CD8 T cells, monocytes/macrophages, and dendritic cells (DCs) and was strongly negatively correlated with myeloid-derived suppressor cells. Function analysis showed that ADA1 expression-related genes were mainly enriched in cell division biological progression. However, ADA2-related genes were mainly associated with immune response. Conclusion As isoenzymes, ADA1 and ADA2 showed opposite prognostic values and different correlative patterns with immune infiltrating. These data demonstrated the distinct roles of ADA1 and ADA2 in cancer. ADA2 might act as a protective factor in cancer.
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Affiliation(s)
| | | | | | | | | | | | - Ke Dong
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, China
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9
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Chen DY, Huang YH, Chen YM, Chen JJW, Yang TY, Chang GC, Tang KT. ANA positivity and complement level in pleural fluid are potential diagnostic markers in discriminating lupus pleuritis from pleural effusion of other aetiologies. Lupus Sci Med 2021; 8:8/1/e000562. [PMID: 34785570 PMCID: PMC8596033 DOI: 10.1136/lupus-2021-000562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 10/27/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Lupus pleuritis is the most common pulmonary manifestation of systemic lupus erythematosus (SLE). We aimed to compare various biomarkers in discriminating between pleural effusions due to lupus pleuritis and other aetiologies. METHODS We determined in 59 patients (16 patients with SLE and 43 patients without SLE) pleural fluid levels of high-mobility group box 1, soluble receptor for advanced glycation end products (sRAGE), adenosine deaminase (ADA), interleukin (IL) 17A, tumour necrosis factor-α, antinuclear antibodies (ANA), and complements C3 and C4. RESULTS We found significant differences in the pleural fluid level of sRAGE, ADA, IL-17A, C3 and C4, and in the proportion of ANA positivity, among lupus pleuritis and other groups with pleural effusion. Specifically, ANA positivity (titre ≥1: 80) achieved a high sensitivity of 91%, specificity of 83% and negative predictive value (NPV) of 97% in discriminating lupus pleuritis from non-lupus pleural effusion. A parallel combination of the level of C3 (<24 mg/dL) and C4 (<3 mg/dL) achieved a sensitivity of 82%, specificity of 89% and NPV of 93% in discriminating lupus pleuritis from non-lupus exudative pleural effusion. CONCLUSIONS In conclusion, ANA, C3 and C4 in pleural fluid are useful in discriminating lupus pleuritis from pleural effusion due to other aetiologies with high NPV.
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Affiliation(s)
- Der-Yuan Chen
- Translational Medicine Laboratory, China Medical University Hospital, Taichung, Taiwan.,Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Yen-Hsiang Huang
- Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Jeremy J W Chen
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Tsung-Ying Yang
- Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Gee-Chen Chang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Division of Pulmonary Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Kuo-Tung Tang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan .,Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
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10
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Gao ZW, Wang X, Zhang HZ, Lin F, Liu C, Dong K. The roles of adenosine deaminase in autoimmune diseases. Autoimmun Rev 2020; 20:102709. [PMID: 33197575 DOI: 10.1016/j.autrev.2020.102709] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Autoimmune diseases patients are characterized by the autoimmune disorders, whose immune system can't distinguish between auto- and foreign- antigens. Thus, Immune homeostasis disorder is the key factor for autoimmune diseases development. Adenosine deaminase (ADA) is the degrading enzyme for an immunosuppressive signal - adenosine, and play an important role in immune homeostasis regulation. Increasing evidences have shown that ADA is involved in various autoimmune diseases. ADA activity were changed in multiple autoimmune diseases patients and could be served as a biomarker for clinical diagnosis. In this study, we analyze the change of ADA activity in patients with autoimmune diseases, and we underline its potential diagnostic value for autoimmune diseases patients.
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Affiliation(s)
- Zhao-Wei Gao
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China
| | - Xi Wang
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China
| | - Hui-Zhong Zhang
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China
| | - Fang Lin
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China
| | - Chong Liu
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China
| | - Ke Dong
- Department of Clinical Diagnose, Tangdu Hospital, Airforce military medical university, Xi'an City, Shannxi Province, China.
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11
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Bowers SM, Gibson KM, Cabral DA, Brown KL. Adenosine deaminase 2 activity negatively correlates with age during childhood. Pediatr Rheumatol Online J 2020; 18:54. [PMID: 32650798 PMCID: PMC7350767 DOI: 10.1186/s12969-020-00446-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 06/30/2020] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Human adenosine deaminase 2 (ADA2) is an extracellular enzyme that negatively regulates adenosine-mediated cell signaling by converting adenosine to inosine. Altered ADA2 enzyme activity has been associated with some viral infections and rheumatic diseases. The potential utility of ADA2 as a biomarker is, however, limited by the absence of established ranges of ADA2 concentration and enzyme activity in the healthy population. It is known that ADA2 enzyme activity is lower in adults, but when (and why) this decline happens is not known. The purpose of this study was to establish normative ranges of ADA2 enzyme activity and protein concentration in the healthy pediatric population. METHODS We modified a commercially available ADA2 enzyme activity assay to enable higher throughput analysis of fresh, frozen and hemolyzed blood samples. With this assay and ADA2 protein immunoblotting, we analyzed ADA2 enzyme activity and protein concentration in blood plasma from a cohort of children and adolescents (n = 94) aged 5 months to 18 years. One-way ANOVA with subsequent Tukey multiple comparison test was used to analyze group differences. Reference intervals were generated using the central 95% of the population (2-97.5 percentiles). RESULTS ADA2 enzyme activity was consistent in fresh, frozen, and hemolyzed sera and plasma as measured by our modified assay. Analysis of plasma samples from the healthy pediatric cohort revealed that ADA2 enzyme activity is significantly lower in older children than in younger children (p < 0.0001). In contrast, there was no significant correlation between ADA2 protein concentration and either age or ADA2 enzyme activity. CONCLUSION We observed that ADA2 enzyme activity, but not ADA2 protein concentration, negatively correlates with age in a cohort of children and adolescents. Our findings stress the importance of appropriate age-matched controls for assessing ADA2 enzyme activity in the clinical setting.
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Affiliation(s)
- Sarah M Bowers
- British Columbia Children's Hospital Research Institute, Rm A4-145, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada
- Centre for Blood Research, The University of British Columbia, Vancouver, BC, Canada
| | - Kristen M Gibson
- British Columbia Children's Hospital Research Institute, Rm A4-145, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada
- Centre for Blood Research, The University of British Columbia, Vancouver, BC, Canada
- Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
| | - David A Cabral
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
- Division of Rheumatology, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Kelly L Brown
- British Columbia Children's Hospital Research Institute, Rm A4-145, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada.
- Centre for Blood Research, The University of British Columbia, Vancouver, BC, Canada.
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada.
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12
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Moens L, Hershfield M, Arts K, Aksentijevich I, Meyts I. Human adenosine deaminase 2 deficiency: A multi-faceted inborn error of immunity. Immunol Rev 2019; 287:62-72. [PMID: 30565235 DOI: 10.1111/imr.12722] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 09/23/2018] [Indexed: 12/15/2022]
Abstract
Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small- and medium-size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro-inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti-TNF therapy with etanercept and that is the first-line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients' refractory to anti-cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine-tune and steer future therapeutic strategies.
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Affiliation(s)
- Leen Moens
- Department of Microbiology and Immunology, Laboratory for Childhood Immunology, KU Leuven, Leuven, Belgium
| | - Michael Hershfield
- Department of Medicine, School of Medicine, Duke University, Durham, North Carolina
| | - Katrijn Arts
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Ivona Aksentijevich
- Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland
| | - Isabelle Meyts
- Department of Microbiology and Immunology, Laboratory for Childhood Immunology, KU Leuven, Leuven, Belgium.,Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
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13
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Zhao-wei G, Zhao GH, Li RC, Wang HP, Liu C, Zhang HZ, Dong K. Activities of Serum Adenosine Deaminase and its Isoenzymes in
Patients with Systemic Lupus Erythematosus, Rheumatoid Arthritis, Ankylosing
Spondylitis and Myasthenia Gravis. AKTUEL RHEUMATOL 2019. [DOI: 10.1055/a-1024-3495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Abstract
Objective The aim of this study was to evaluate the changes and
diagnostic value of serum ADA activity in autoimmune diseases, including
systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing
spondylitis (AS), and myasthenia gravis (MG).
Methods Serum ADA activity, including total ADA (tADA) and its isoenzymes
(ADA1 and ADA2), was determined in patients with different autoimmune diseases
(144 RA, 114 SLE, 55 AS, 68 MG). The changes in serum ADA activity in patients
were analysed. A receiver operating characteristic (ROC) curve analysis was
applied to evaluate the diagnostic performance of serum ADA activity.
Results Compared with healthy controls, the serum tADA activity in SLE
patients was significantly increased (p<0.001), while the serum tADA
activity in patients with RA, AS and MG did not change (p>0.05). The ROC
analysis showed that the optimal cut-off value of serum tADA activity for SLE
diagnosis was 10.5 U/L (79.8% specificity and
74.6% sensitivity; likelihood ratio (LR): 3.693; p<0.001).
Moreover, our results showed that there were no significant changes of ADA1 and
ADA2 activity in RA, AS and MG patients, while the serum ADA2 activity was
significantly increased in SLE patients. The ROC analysis showed that ADA2
activity could be used in diagnosing SLE with 75.4% specificity and
78.1% sensitivity (LR: 3.175). Based on the ROC curve analysis, serum
tADA activity (79.8% specificity and 74.6% sensitivity;
likelihood ratio (LR): 3.693) and ADA2 activity (75.4% specificity and
78.1% sensitivity; LR: 3.175) are unlikely to be used in diagnosing SLE.
Furthermore, there was a positive correlation between tADA activity and SLE
disease activity (r=0.303, p=0.010). Notably, serum tADA
activity in SLE patients with arthritis was higher than in patients without
arthritis (p=0.005), which suggests that tADA activity might be related
to lupus arthritis.
Conclusion These findings suggest that serum tADA and ADA2 activity might
play an important role in SLE progression.
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Affiliation(s)
- Gao Zhao-wei
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Guan-hua Zhao
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Rui-cheng Li
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Hui-ping Wang
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Chong Liu
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Hui-zhong Zhang
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
| | - Ke Dong
- Fourth Military Medical University, Department of Clinical Diagnosis,
Tangdu Hospital, Xi'an, China
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14
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Bagheri S, Saboury AA, Haertlé T. Adenosine deaminase inhibition. Int J Biol Macromol 2019; 141:1246-1257. [PMID: 31520704 DOI: 10.1016/j.ijbiomac.2019.09.078] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022]
Abstract
Adenosine deaminase is a critical enzyme in purine metabolism that regulates intra and extracellular adenosine concentrations by converting it to inosine. Adenosine is an important purine that regulates numerous physiological functions by interacting with its receptors. Adenosine and consequently adenosine deaminase can have pro or anti-inflammatory effects on tissues depending on how much time has passed from the start of the injury. In addition, an increase in adenosine deaminase activity has been reported for various diseases and the significant effect of deaminase inhibition on the clinical course of different diseases has been reported. However, the use of inhibitors is limited to only a few medical indications. Data on the increase of adenosine deaminase activity in different diseases and the impact of its inhibition in various cases have been collected and are discussed in this review. Overall, the evidence shows that many studies have been done to introduce inhibitors, however, in vivo studies have been much less than in vitro, and often have not been expanded for clinical use.
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Affiliation(s)
- S Bagheri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - A A Saboury
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
| | - T Haertlé
- Institut National de la Recherche Agronomique, Nantes, France
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15
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Antonioli L, Blandizzi C, Pacher P, Haskó G. The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases. Pharmacol Rev 2019; 71:345-382. [PMID: 31235653 PMCID: PMC6592405 DOI: 10.1124/pr.117.014878] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.
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Affiliation(s)
- Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (L.A., C.B.); Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (P.P.); and Department of Anesthesiology, Columbia University, New York, New York (G.H.)
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (L.A., C.B.); Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (P.P.); and Department of Anesthesiology, Columbia University, New York, New York (G.H.)
| | - Pál Pacher
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (L.A., C.B.); Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (P.P.); and Department of Anesthesiology, Columbia University, New York, New York (G.H.)
| | - György Haskó
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (L.A., C.B.); Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (P.P.); and Department of Anesthesiology, Columbia University, New York, New York (G.H.)
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16
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Activity and expression of E-NTPDase is altered in peripheral lymphocytes of systemic lupus erythematosus patients. Clin Chim Acta 2018; 488:90-97. [PMID: 30409763 DOI: 10.1016/j.cca.2018.10.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 09/26/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease, where there is irreversible breakdown of immunological self-tolerance. Extracellular adenosine triphosphate (ATP) and adenosine are signaling molecules that play an important part in the immune response. During inflammation and the immune response, a group of enzymes control these molecules, including ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'-nucleotidase, and ecto-adenosine deaminase (E-ADA). We determined the activity and expression of E-NTPDase, the expression of E-5'-nucleotidase, the activity of E-ADA in lymphocytes and serum of SLE patients. METHODS This study involved 35 patients with SLE and 30 healthy subjects as a control group. E-NTPDase activity and expression were increased in lymphocytes from SLE patients (31% and 37% for activity and expression, respectively) compared with the control group. RESULTS An approximately 42% increase in E-ADA activity in lymphocytes was observed in SLE patients compared with the control group, in serum the ADA activity was decreased by 57% in SLE patients. Expression of E-5'-nucleotidase was not changed in SLE patients. CONCLUSIONS E-NTPDase and E-ADA perform key functions in the modulation of the immune and inflammatory response in SLE.
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17
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Tvarijonaviciute A, Zamora C, Martinez-Subiela S, Tecles F, Pina F, Lopez-Jornet P. Salivary adiponectin, but not adenosine deaminase, correlates with clinical signs in women with Sjögren's syndrome: a pilot study. Clin Oral Investig 2018; 23:1407-1414. [PMID: 30030617 DOI: 10.1007/s00784-018-2570-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/12/2018] [Indexed: 01/13/2023]
Abstract
OBJECTIVES To evaluate salivary adiponectin and adenosine deaminase (ADA) in women suffering from Sjögren's syndrome (SS). METHODS Salivary adiponectin and ADA were measured in patients with SS (n = 17) and compared to their values in healthy controls (n = 13) and patients suffering from drug-induced xerostomia (non-SS sicca group; n = 19). A clinical history was made for each patient, patients were examined clinically, and xerostomia inventory (XI) was performed. RESULTS Salivary adiponectin corrected by total protein was higher in patients with SS than in healthy individuals (P < 0.05) or patients with non-SS sicca (P < 0.01) and correlated with XI (r = 0.555; P < 0.05). Salivary ADA was higher in patients with SS and non-SS sicca compared to controls (P < 0.05 in both cases). CONCLUSION The results of the present study indicate that adiponectin and ADA are increased in the saliva of patients with SS. CLINICAL RELEVANCE Salivary adiponectin corrected by total protein can be a potential biomarker of SS. TRIAL REGISTRATION NCT03156569.
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Affiliation(s)
- Asta Tvarijonaviciute
- Interdisciplinary Laboratory of Clinical Analysis Interlab-UMU, Faculty of Veterinary Medicine, Regional Campus of International Excellence 'Campus Mare Nostrum', University of Murcia, Espinardo, 30100, Murcia, Spain.
| | - Carmen Zamora
- Department of Oral Medicine, Faculty of Medicine, Regional Campus of International Excellence 'Campus Mare Nostrum', University of Murcia, Espinardo, 30100, Murcia, Spain
| | - Silvia Martinez-Subiela
- Interdisciplinary Laboratory of Clinical Analysis Interlab-UMU, Faculty of Veterinary Medicine, Regional Campus of International Excellence 'Campus Mare Nostrum', University of Murcia, Espinardo, 30100, Murcia, Spain
| | - Fernando Tecles
- Interdisciplinary Laboratory of Clinical Analysis Interlab-UMU, Faculty of Veterinary Medicine, Regional Campus of International Excellence 'Campus Mare Nostrum', University of Murcia, Espinardo, 30100, Murcia, Spain
| | - Francisca Pina
- Department of Rheumatology, Morales Meseguer General University Hospital, AV Marques de los Velez S/N, 30008, Murcia, Spain
| | - Pia Lopez-Jornet
- Department of Oral Medicine, Faculty of Medicine, Regional Campus of International Excellence 'Campus Mare Nostrum', University of Murcia, Espinardo, 30100, Murcia, Spain
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18
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Knight JS, Mazza LF, Yalavarthi S, Sule G, Ali RA, Hodgin JB, Kanthi Y, Pinsky DJ. Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction. Front Immunol 2018; 9:1322. [PMID: 29942314 PMCID: PMC6004379 DOI: 10.3389/fimmu.2018.01322] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 05/28/2018] [Indexed: 12/23/2022] Open
Abstract
Objectives CD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells' "purinergic halo" in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus. Methods Lupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39-/-, and CD73-/-. After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized. Results As compared with WT mice, CD39-/- mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39-/- and CD73-/- mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73-/- mice, while deficiency of either ectonucleotidase led to expansion of TH17 cells. CD39-/- and CD73-/- mice demonstrated exaggerated neutrophil extracellular trap release, while CD73-/- mice additionally had higher levels of plasma cell-free DNA. Conclusion These data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus.
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Affiliation(s)
- Jason S Knight
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Levi F Mazza
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Srilakshmi Yalavarthi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Gautam Sule
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Ramadan A Ali
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Yogendra Kanthi
- Division of Cardiology, Ann Arbor Veterans Administration Healthcare System, Ann Arbor, MI, United States.,Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - David J Pinsky
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
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19
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Zhu C, Mustafa D, Zheng PP, van der Weiden M, Sacchetti A, Brandt M, Chrifi I, Tempel D, Leenen PJM, Duncker DJ, Cheng C, Kros JM. Activation of CECR1 in M2-like TAMs promotes paracrine stimulation-mediated glial tumor progression. Neuro Oncol 2018; 19:648-659. [PMID: 28453746 DOI: 10.1093/neuonc/now251] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background The majority of glioma-associated microglia/macrophages have been identified as M2-type macrophages with immune suppressive and tumor supportive action. Recently, the extracellular adenosine deaminase protein Cat Eye Syndrome Critical Region Protein 1 (CECR1) was shown to regulate macrophage maturation. In this study, we investigate the role of CECR1 in the regulation of the glioma-associated macrophage response. Methods Expression of CECR1 was assessed in human glioma samples. CECR1-mediated macrophage response was studied in vitro, using donor derived CD14+ monocytes and the THP-1 monocytic cell line. The response of the human glioma cell line U87 to conditioned medium of macrophages preconditioned with recombinant human CECR1 or CECR1 silencing was also assessed. Results CECR1 was strongly expressed in high-grade gliomas (P < .001) and correlated positively with the M2 phenotype markers in tumor-associated microglia/macrophages (TAMs) (overall, P < .05). In vitro studies confirmed the presence of a significantly higher level of CECR1 expression in M2-like macrophages exposed to U87 conditioned medium (P < .001). CECR1 knockdown or stimulation of macrophages affected differentiation toward the M2-like phenotype. Stimulation of U87 cells with conditioned medium of CECR1 knockdown or stimulated macrophages affected tumor cell proliferation and migration, coinciding with altered intracellular signaling of mitogen-activated protein kinase (MAPK). In glioma tissue samples, CECR1 expression correlated with Ki67 and MAPK signaling protein. Conclusions CECR1 is a potent regulator of TAM polarization and is consistently highly expressed by M2-type TAMs, particularly in high-grade glioma. Paracrine effects induced by CECR1 in M2-like TAMs activate MAPK signaling and stimulate the proliferation and migration of glioma cells.
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Affiliation(s)
- Changbin Zhu
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.,Department of Pediatric Neurosurgery, Shanghai Xinhua Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dana Mustafa
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Andrea Sacchetti
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Maarten Brandt
- Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ihsan Chrifi
- Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Pieter J M Leenen
- Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Dirk Jan Duncker
- Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Caroline Cheng
- Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands.,Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Johan M Kros
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
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20
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Serum adenosine deaminase activity is increased in systemic lupus erythematosus patients and correlated with disease activity. Immunol Res 2018; 66:299-304. [DOI: 10.1007/s12026-018-8984-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Autoimmune diseases are characterized by the abnormal immune response against self-tissue, which are caused by the failure of nature immune homeostasis. Nature immune homeostasis represents the normal state of appropriate immune response to nonself-antigen and unresponsiveness to self-antigens. In normal situation, immune homeostasis is regulated by immunosuppressive signal and immunostimulating signal together. Accumulating data have demonstrated that the adenosinergic pathway played key roles in immune suppression and shield body from an excessive inflammatory response. The deficiency of adenosinergic pathway results in the imbalance between the pro- and anti-inflammatory activities. Thus, researchers pay much attention to the role of adenosinergic pathway in autoimmune diseases development. To date, accumulating data have suggested an important role of adenosinergic pathway-related molecules (i.e., CD39, CD73, ADA, adenosine receptors, etc.) in many types of human autoimmune diseases. More importantly, these findings have presented potential value of adenosinergic pathway analysis to be used for autoimmune diseases diagnosis, monitoring and treatment. In this review, we will provide a comprehensive description of the role of adenosinergic pathway in human autoimmune diseases.
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Affiliation(s)
- Ke Dong
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
| | - Zhao-Wei Gao
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Hui-Zhong Zhang
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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22
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Changes in CD73, CD39 and CD26 expression on T-lymphocytes of ANCA-associated vasculitis patients suggest impairment in adenosine generation and turn-over. Sci Rep 2017; 7:11683. [PMID: 28916770 PMCID: PMC5601951 DOI: 10.1038/s41598-017-12011-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/31/2017] [Indexed: 01/03/2023] Open
Abstract
Extracellular adenosine, generated via the concerted action of CD39 and CD73, contributes to T-cell differentiation and function. Adenosine concentrations are furthermore influenced by adenosine deaminase binding protein CD26. Because aberrant T-cell phenotypes had been reported in anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitis (AAV) patients, an impaired expression of these molecules on T-cells of AAV patients was hypothesized in the present study. While in AAV patients (n = 29) CD26 was increased on CD4+ lymphocytes, CD39 and CD73 were generally reduced on patients’ T-cells. In CD4+ cells significant differences in CD73 expression were confined to memory CD45RA- cells, while in CD4- lymphocytes differences were significant in both naïve CD45RA+ and memory CD45RA- cells. The percentage of CD4-CD73+ cells correlated with micro-RNA (miR)−31 expression, a putative regulator of factor inhibiting hypoxia-inducible factor 1 alpha (FIH-1), inversely with serum C-reactive protein (CRP) and positively with estimated glomerular filtration rate (eGFR). No correlation with disease activity, duration, and ANCA profile was found. It remains to be assessed if a decreased CD73 and CD39 expression underlies functional impairment of lymphocytes in AAV patients. Likewise, the relations between frequencies of CD4-CD73+ cells and serum CRP or eGFR require further functional elucidation.
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Gutiérrez AM, De La Cruz-Sánchez E, Montes A, Sotillo J, Gutiérrez-Panizo C, Fuentes P, Tornel PL, Cabezas-Herrera J. Easy and non-invasive disease detection in pigs by adenosine deaminase activity determinations in saliva. PLoS One 2017; 12:e0179299. [PMID: 28594948 PMCID: PMC5464646 DOI: 10.1371/journal.pone.0179299] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 05/26/2017] [Indexed: 12/24/2022] Open
Abstract
The quantification of adenosine deaminase (ADA) in porcine saliva samples has been analyzed for its use as a marker of disease. First, an analytical validation of the enzymatic assay used for ADA measurements was performed. Afterwards, saliva samples were collected from 50 healthy animals and 64 animals with different symptoms of disease, which were divided into local inflammation, gastrointestinal disorder, respiratory disorder and growth retardation. To optimize ADA measurements, total ADA (tADA), specific ADA (sADA) and ADA isoforms 1 and 2 activities were calculated. Moreover, to preliminarily estimate the diagnostic value of tADA activity measurements for disease detection, receiver operating characteristic (ROC) analyses was performed and compared to the results obtained for salivary acute phase proteins, haptoglobin (Hp) and C-reactive protein (CRP). The salivary levels of tADA activity were significantly elevated in animals with local inflammation, gastrointestinal disorder and respiratory disorder. The calculation of the different ADA activities did not provide additional information to tADA activity quantification for disease detection. The diagnostic value of tADA activity was superior to those observed for Hp and CRP measurements in the present study. It might be concluded that ADA analysis in saliva could be used as a simple, rapid, economic and non-invasive diagnostic tool in porcine production in field conditions.
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Affiliation(s)
- Ana María Gutiérrez
- Department of Animal Medicine and Surgery, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, Espinardo, Murcia, Spain
- * E-mail:
| | - Ernesto De La Cruz-Sánchez
- Department of Physical Activity and Sport, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, San Javier, Murcia, Spain
| | - Ana Montes
- Department of Animal Medicine and Surgery, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, Espinardo, Murcia, Spain
| | - Juan Sotillo
- Department of Animal Medicine and Surgery, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, Espinardo, Murcia, Spain
| | - Cándido Gutiérrez-Panizo
- Department of Animal Medicine and Surgery, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, Espinardo, Murcia, Spain
| | | | - Pedro Luis Tornel
- Clinical Analysis Service, University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain
| | - Juan Cabezas-Herrera
- Molecular Therapy and Biomarkers Research Group, Clinical Analysis Service, University Hospital Virgen de la Arrixaca, IMIB-Arrixaca, El Palmar, Murcia, Spain
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Torgutalp M, Efe C, Babaoglu H, Kav T. Relationship between serum adenosine deaminase levels and liver histology in autoimmune hepatitis. World J Gastroenterol 2017; 23:3876-3882. [PMID: 28638227 PMCID: PMC5467073 DOI: 10.3748/wjg.v23.i21.3876] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 03/13/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the relationship between serum adenosine deaminase (ADA) levels and histological features in patients with autoimmune hepatitis (AIH). METHODS A total of 80 subjects (52 AIH cases and 28 healthy controls) were included in the study. Patients were diagnosed according to the simplified criteria suggested by the International Autoimmune Hepatitis Group. All of the cases had been diagnosed with AIH between 2010-2015 at Hacettepe University, Department of Gastroenterology. Serum blood samples were collected and stored at -80 °C until the biochemical estimation of ADA activity. The diagnosis of patients was confirmed by liver biopsy. Serum ADA > 20 U/L was considered to be high level. RESULTS Mean serum ADA levels were significantly higher in AIH patients than those in healthy controls (25.4 ± 9.6 U/L vs 12.8 ± 2.2 U/L, P < 0.001). Serum ADA levels > 20 U/L were found in 63.5% AIH patients and in 0% healthy controls (P < 0.001). Mean serum ADA levels were significantly increased in each stage of histological activity: 15.2 ± 3.5 U/L for patients with mild interface hepatitis, 23.1 ± 10.0 U/L for patients with moderate interface hepatitis and 30.9 ± 7.0 U/L for patients with severe interface hepatitis (P < 0.001). Correlation analysis showed that there was a positive association between serum ADA levels and histological activity (r = 0.71, P < 0.001). Receiver operating characteristic analysis suggested that 24.5 U/L was the optimum cut-off point of ADA level for severe interface hepatitis (sensitivity 88%, specificity 85.2%, area under the curve: 0.88). CONCLUSION Because of the positive correlation with inflammatory activity, serum ADA level may be a potential biomarker for predicting or monitoring histological activity in patients with AIH.
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Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV. Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci 2017; 74:555-570. [PMID: 27663683 PMCID: PMC11107696 DOI: 10.1007/s00018-016-2357-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 08/29/2016] [Accepted: 09/02/2016] [Indexed: 11/29/2022]
Abstract
At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity. Here, we found that ADA2 binds to neutrophils, monocytes, NK cells and B cells that do not express CD26, a receptor for ADA1. Moreover, the analysis of CD4+ T-cell subset revealed that ADA2 specifically binds to regulatory T cells expressing CD39 and lacking the receptor for ADA1. Also, it was found that ADA1 binds to CD16- monocytes, while CD16+ monocytes preferably bind ADA2. A study of the blood samples from ADA2-deficient patients showed a dramatic reduction in the number of lymphocyte subsets and an increased concentration of TNF-α in plasma. Our results suggest the existence of a new mechanism, where the activation and survival of immune cells is regulated through the activities of ADA2 or ADA1 anchored to the cell surface.
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Affiliation(s)
- Yuliia Kaljas
- Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, 9 Jinsui Road, Tianhe, Guangzhou, 510623, Guangdong, China
- Turku Centre for Biotechnology, University of Turku, Tykistokatu 6, 20520, Turku, Finland
| | - Chengqian Liu
- Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, 9 Jinsui Road, Tianhe, Guangzhou, 510623, Guangdong, China
- Turku Centre for Biotechnology, University of Turku, Tykistokatu 6, 20520, Turku, Finland
| | - Maksym Skaldin
- Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, 9 Jinsui Road, Tianhe, Guangzhou, 510623, Guangdong, China
- Turku Centre for Biotechnology, University of Turku, Tykistokatu 6, 20520, Turku, Finland
| | - Chengxiang Wu
- Department of Public Health, John A. Burns School of Medicine, University of Hawaii at Manoa, 1960 East West Road, Biomed, Honolulu, HI, 96822, USA
- Division of Regenerative Medicine, Tulane National Primate Research Center, 18703 Three River Road, Covington, LA, 70433, USA
| | - Qing Zhou
- National Institutes of Health, National Human Genome Research Institute, Bldg. 10, Bethesda, MD, 20892, USA
| | - Yuanan Lu
- Department of Public Health, John A. Burns School of Medicine, University of Hawaii at Manoa, 1960 East West Road, Biomed, Honolulu, HI, 96822, USA
| | - Ivona Aksentijevich
- Department of Public Health, John A. Burns School of Medicine, University of Hawaii at Manoa, 1960 East West Road, Biomed, Honolulu, HI, 96822, USA
| | - Andrey V Zavialov
- Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, 9 Jinsui Road, Tianhe, Guangzhou, 510623, Guangdong, China.
- Turku Centre for Biotechnology, University of Turku, Tykistokatu 6, 20520, Turku, Finland.
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No association between serum adenosine deaminase activity and disease activity in Crohn's disease. Dig Dis Sci 2015; 60:1755-60. [PMID: 25652144 DOI: 10.1007/s10620-014-3510-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Adenosine deaminase activity is proposed as a marker of inflammation in some inflammatory conditions. AIMS To investigate the association of serum adenosine deaminase activity and disease activity in Crohn's disease patients. METHODS In a cross-sectional study, 30 consecutive known cases of Crohn's disease (15 with active disease and 15 in remission) referring to a university hospital in Tehran (Iran) and 15 age- and gender-matched healthy controls were studied. Disease activity was assessed using the Crohn's disease activity index (cutoff >150). Total serum adenosine deaminase activity, C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin were evaluated in patients. Serum adenosine deaminase activity was measured in controls. RESULTS Mean age of the patients was 36.8 ± 12.6 years, and 56.7 % were male. Serum adenosine deaminase activity in patients with active disease, patients in remission, and controls was 12.3 ± 5.9, 14.6 ± 6.2, and 11.9 ± 6.4 U/L, respectively (P = 0.458). Compared with patients in remission, those with active disease had higher erythrocyte sedimentation rate (40.4 ± 30.6 vs. 16.9 ± 16.0 mm/h, P = 0.014) and higher frequency of positive C-reactive protein (66.6 vs. 13.3 %, P = 0.004) and positive fecal calprotectin tests (86.6 vs. 33.3 %, P = 0.004). Serum adenosine deaminase activity was not correlated with erythrocyte sedimentation rate (r = 0.05, P = 0.761) and was not different between patients with positive and negative C-reactive protein (12.2 ± 5.4 vs. 14.2 ± 6.5 U/L, P = 0.393) and fecal calprotectin tests (11.7 ± 5.3 vs. 16.0 ± 6.5 U/L, P = 0.063). CONCLUSIONS In patients with Crohn's disease, serum adenosine deaminase activity is not associated with clinical disease activity or with other inflammation markers and cannot be suggested as an inflammation marker.
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Cortés A, Gracia E, Moreno E, Mallol J, Lluís C, Canela EI, Casadó V. Moonlighting Adenosine Deaminase: A Target Protein for Drug Development. Med Res Rev 2014; 35:85-125. [DOI: 10.1002/med.21324] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Antoni Cortés
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Eduard Gracia
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Estefania Moreno
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Josefa Mallol
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Carme Lluís
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Enric I. Canela
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
| | - Vicent Casadó
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED); Institute of Biomedicine of the University of Barcelona (IBUB); Department of Biochemistry and Molecular Biology; Faculty of Biology; University of Barcelona; Barcelona Spain
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Ferreiro L, San José E, Valdés L. Tuberculous pleural effusion. Arch Bronconeumol 2014; 50:435-43. [PMID: 24721286 DOI: 10.1016/j.arbres.2013.07.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 07/12/2013] [Accepted: 07/12/2013] [Indexed: 12/28/2022]
Abstract
Tuberculous pleural effusion (TBPE) is the most common form of extrapulmonary tuberculosis (TB) in Spain, and is one of the most frequent causes of pleural effusion. Although the incidence has steadily declined (4.8 cases/100,000population in 2009), the percentage of TBPE remains steady with respect to the total number of TB cases (14.3%-19.3%). Almost two thirds are men, more than 60% are aged between 15-44years, and it is more common in patients with human immunodeficiency virus. The pathogenesis is usually a delayed hypersensitivity reaction. Symptoms vary depending on the population (more acute in young people and more prolonged in the elderly). The effusion is almost invariably a unilateral exudate (according to Light's criteria), more often on the right side, and the tuberculin test is negative in one third of cases. There are limitations in making a definitive diagnosis, so various pleural fluid biomarkers have been used for this. The combination of adenosine deaminase and lymphocyte percentage may be useful in this respect. Treatment is the same as for any TB. The addition of corticosteroids is not advisable, and chest drainage could help to improve symptoms more rapidly in large effusions.
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Affiliation(s)
- Lucía Ferreiro
- Servicio de Neumología, Complejo Hospitalario Clínico-Universitario de Santiago, Santiago de Compostela, La Coruña, España
| | - Esther San José
- Servicio de Análisis Clínicos, Complejo Hospitalario Clínico-Universitario de Santiago, Santiago de Compostela, La Coruña, España; Grupo Interdisciplinar de Investigación en Neumología, Instituto de Investigaciones Sanitarias de Santiago (IDIS), Santiago de Compostela, La Coruña, España
| | - Luis Valdés
- Servicio de Neumología, Complejo Hospitalario Clínico-Universitario de Santiago, Santiago de Compostela, La Coruña, España; Grupo Interdisciplinar de Investigación en Neumología, Instituto de Investigaciones Sanitarias de Santiago (IDIS), Santiago de Compostela, La Coruña, España.
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Garca MF, Demir H, Turan M, Bozan N, Kozan A, Belli ŞB, Arslan A, Cankaya H. Assessment of adenosine deaminase (ADA) activity and oxidative stress in patients with chronic tonsillitis. Eur Arch Otorhinolaryngol 2013; 271:1797-802. [DOI: 10.1007/s00405-013-2843-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 11/05/2013] [Indexed: 11/24/2022]
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Ren TL, Yang CJ, Hang YX, Shi H, Zhou HX, Fang DY, Shi GX, Ji XJ. G-Quadruplex-Based DNAzyme as a Sensing Platform for Ultrasensitive Colorimetric Adenosine Deaminase Detection. ANAL LETT 2013. [DOI: 10.1080/00032719.2013.800543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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