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A Fas(hi) Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation

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dc.contributor.author Menezes, Soraya Maria
dc.contributor.author Leal, Fabio E.
dc.contributor.author Dierckx, Tim
dc.contributor.author Khouri, Ricardo
dc.contributor.author Decanine, Daniele
dc.contributor.author Silva-Santos, Gilvaneia
dc.contributor.author Schnitman, Saul V.
dc.contributor.author Kruschewsky, Ramon
dc.contributor.author Lopez, Giovanni
dc.contributor.author Alvarez, Carolina
dc.contributor.author Talledo, Michael
dc.contributor.author Gotuzzo, Eduardo
dc.contributor.author Nixon, Douglas F.
dc.contributor.author Vercauteren, Jurgen
dc.contributor.author Brassat, David
dc.contributor.author Liblau, Roland
dc.contributor.author Vandamme, Anne Mieke
dc.contributor.author Galvao-Castro, Bernardo
dc.contributor.author Van Weyenbergh, Johan
dc.date.accessioned 2019-01-25T15:02:14Z
dc.date.available 2019-01-25T15:02:14Z
dc.date.issued 2017
dc.identifier.uri https://hdl.handle.net/20.500.12866/4585
dc.description.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 functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fashi T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have 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 Fashi cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fashi phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas 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 receptor in vitro with 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 silico analysis 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/TSP ex vivo transcriptomes. In conclusion, we demonstrated a two-step increase in Fas expression, revealing a unique Fashi lymphocyte 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. en_US
dc.language.iso eng
dc.publisher Frontiers Media
dc.relation.ispartof urn:issn:1664-3224
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject apoptosis en_US
dc.subject Fas/CD95 en_US
dc.subject HTLV-1-associated myelopathy/tropical spastic paraparesis en_US
dc.subject interferon en_US
dc.subject lymphoproliferative disease en_US
dc.subject multiple sclerosis en_US
dc.subject NF-kappaB en_US
dc.subject proliferation en_US
dc.title A Fas(hi) Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.3389/fimmu.2017.00097
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE


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