Author | Menezes, Soraya Maria | |
Author | Leal, Fabio Eudes | |
Author | Dierckx, Tim | |
Author | Cunha, Antonio Ricardo Khouri | |
Author | Decanine, Daniele | |
Author | Santos, Gilvaneia Silva | |
Author | Schnitman, Saul V | |
Author | Kruschewsky, Ramon | |
Author | López, Giovanni | |
Author | Alvarez, Carolina | |
Author | Talledo, Michael | |
Author | Gotuzzo, Eduardo | |
Author | Nixon, Douglas F | |
Author | Vercauteren, Jurgen | |
Author | Brassat, David | |
Author | Liblau, Roland | |
Author | Vandamme, Anne Mieke | |
Author | Castro Filho, Bernardo Galvão | |
Author | Van Weyenbergh, Johan Josef Roza Maria | |
Access date | 2018-03-19T19:20:43Z | |
Available date | 2018-03-19T19:20:43Z | |
Document date | 2017 | |
Citation | MENEZES, S. M. et al. A FashiLymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation. Frontiers in Immunology, v. 8, p. 97, 2017. | pt_BR |
ISSN | 1664-3224 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/25404 | |
Sponsorship | Brazilian National Research Council (CNPq/Science Without Borders, PVE), Fonds voor Wetenschappelijk Onderzoek (FWO, grant G.0778.10N and G0D6817N). | pt_BR |
Language | eng | pt_BR |
Publisher | Frontiers Media | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Fas / CD95 | pt_BR |
Subject in Portuguese | Proliferação | pt_BR |
Subject in Portuguese | Mielopatia associada ao HTLV-1 / paraparesia espástica tropical | pt_BR |
Subject in Portuguese | Doença linfoproliferativa | pt_BR |
Subject in Portuguese | Apoptose | pt_BR |
Subject in Portuguese | Interferão | pt_BR |
Subject in Portuguese | NF-κB | pt_BR |
Subject in Portuguese | Esclerose múltipla | pt_BR |
Title | A FashiLymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation | pt_BR |
Type | Article | pt_BR |
DOI | 10.3389/fimmu.2017.00097 | |
Abstract | Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functionalFAS-670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. FashiT stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, bothFASandSTAT1have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashicells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation uponin vitroculture, but not to proviral load. This Fashiphenotype is HAM/TSP-specific, since bothex vivoandin vitroFas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptorin vitrowith antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating biased, but not defective Fas signaling in HAM/TSP.In silicoanalysis revealed biased Fas signaling toward proliferation and inflammation, driven by RelA/NF-κB. Correlation of Fas transcript levels with proliferation (but not apoptosis) was confirmed in HAM/TSPex vivotranscriptomes. In conclusion, we demonstrated a two-step increase in Fas expression, revealing a unique Fashilymphocyte phenotype in HAM/TSP, distinguishable from MS. Non-apoptotic Fas signaling might fuel HAM/TSP pathogenesis, through increased lymphoproliferation, inflammation, and early age of onset. | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium | pt_BR |
Affilliation | The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil | pt_BR |
Affilliation | Bahiana School of Medicine and Public Health. Salvador, BA, Brazil | pt_BR |
Affilliation | Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru | pt_BR |
Affilliation | Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru | pt_BR |
Affilliation | Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru / Hospital Cayetano Heredia. Departamento de Enfermedades Infecciosas,Tropicales y Dermatológicas. Lima, Peru | pt_BR |
Affilliation | The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium | pt_BR |
Affilliation | Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France | pt_BR |
Affilliation | Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidade Nova de Lisboa. Instituto de Higiene e Medicina Tropical. Center for Global Health and Tropical Medicine. Unidade de Microbiologia. Lisbon, Portugal | pt_BR |
Affilliation | Bahiana School of Medicine and Public Health. Salvador, BA, Brazil | pt_BR |
Affilliation | Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium | pt_BR |
Subject | Fas/CD95 | pt_BR |
Subject | Proliferation | pt_BR |
Subject | HTLV-1-associated myelopathy/tropical spastic paraparesis, | pt_BR |
Subject | Lymphoproliferative disease | pt_BR |
Subject | Apoptosis | pt_BR |
Subject | Interferon | pt_BR |
Subject | NF-κB | pt_BR |
Subject | Multiple sclerosis | pt_BR |