title: Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.
authors: Departments of Pharmacology.
authors: Raphael Sanches
authors: RS
authors: Peres
authors: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215006, China; f.y.liew@clinmed.gla.ac.uk shferrei@fmrp.usp.br plouzada@fmrp.usp.br fdqcunha@fmrp.usp.br.
authors: Foo Y
authors: FY
authors: Liew
authors: Departments of Pharmacology.
authors: Jhimmy
authors: J
authors: Talbot
authors: Biochemistry and Immunology, and.
authors: Vanessa
authors: V
authors: Carregaro
authors: Internal Medicine, School of Medicine of Ribeirão Preto, Center of Research in Inflammatory Diseases, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil;
authors: Rene D
authors: RD
authors: Oliveira
authors: Internal Medicine, School of Medicine of Ribeirão Preto, Center of Research in Inflammatory Diseases, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil;
authors: Sergio L
authors: SL
authors: Almeida
authors: Departments of Pharmacology.
authors: Rafael F O
authors: RF
authors: França
authors: Departments of Pharmacology.
authors: Paula B
authors: PB
authors: Donate
authors: Departments of Pharmacology.
authors: Larissa G
authors: LG
authors: Pinto
authors: Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil;
authors: Flavia I S
authors: FI
authors: Ferreira
authors: Biochemistry and Immunology, and.
authors: Diego L
authors: DL
authors: Costa
authors: Núcleo de Pesquisa em Produtos Naturais e Sintéticos, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil; and.
authors: Daniel P
authors: DP
authors: Demarque
authors: Núcleo de Pesquisa em Produtos Naturais e Sintéticos, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil; and.
authors: Dayana Rubio
authors: DR
authors: Gouvea
authors: Núcleo de Pesquisa em Produtos Naturais e Sintéticos, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil; and.
authors: Norberto P
authors: NP
authors: Lopes
authors: Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil;
authors: Regina Helena C
authors: RH
authors: Queiroz
authors: Biochemistry and Immunology, and.
authors: Joao Santana
authors: JS
authors: Silva
authors: Laboratory of Pathology, Faculty of Medicine, University of Brasilia, CEP 70910-900, Brasilia, Brazil.
authors: Florencio
authors: F
authors: Figueiredo
authors: Departments of Pharmacology.
authors: Jose Carlos
authors: JC
authors: Alves-Filho
authors: Departments of Pharmacology.
authors: Thiago M
authors: TM
authors: Cunha
authors: Departments of Pharmacology, f.y.liew@clinmed.gla.ac.uk shferrei@fmrp.usp.br plouzada@fmrp.usp.br fdqcunha@fmrp.usp.br.
authors: Sérgio H
authors: SH
authors: Ferreira
authors: Internal Medicine, School of Medicine of Ribeirão Preto, Center of Research in Inflammatory Diseases, University of São Paulo, Ribeirão Preto, CEP 14049-900, Sao Paulo, Brazil; f.y.liew@clinmed.gla.ac.uk shferrei@fmrp.usp.br plouzada@fmrp.usp.br fdqcunha@fmrp.usp.br.
authors: Paulo
authors: P
authors: Louzada-Junior
authors: Departments of Pharmacology, f.y.liew@clinmed.gla.ac.uk shferrei@fmrp.usp.br plouzada@fmrp.usp.br fdqcunha@fmrp.usp.br.
authors: Fernando Q
authors: FQ
authors: Cunha
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine; D008727:Methotrexate
keywords: adenosine; biomarker; ectonucleotidases; methotrexate; rheumatoid arthritis