A Fashi Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation

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

Human leukocyte antigen (HLA) class I frequencies in human T-cell lymphotropic virus type 1 (HTLV-1)-infected patients from Salvador-Brazil

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-06-19T16:50:26Z No. of bitstreams: 1 Olavarria VN Human leukocyte....pdf: 206537 bytes, checksum: 27a5689e5759f077c984c154143b088e (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-06-19T17:12:32Z (GMT) No. of bitstreams: 1 Olavarria VN Human leukocyte....pdf: 206537 bytes, checksum: 27a5689e5759f077c984c154143b088e (MD5)Made available in DSpace on 2017-06-19T17:12:32Z (GMT). No. of bitstreams: 1 Olavarria VN Human leukocyte....pdf: 206537 bytes, checksum: 27a5689e5759f077c984c154143b088e (MD5) Previous issue date: 2011Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, BrasilEscola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Avançado de Saúde Pública. Salvador, BA, BrasilEscola Bahiana de Medicina e Saúde Pública. Salvador, BA, BrasilNational Cancer Institute. Laboratory of Genomic Diversity. SAIC-Frederick, Inc. Frederick, Maryland, USAEscola Bahiana de Medicina e Saúde Pública. Salvador, BA, BrasilUniversity of Wisconsin–Madison. Wisconsin National Primate Center. Madison, Wisconsin, USANational Cancer Institute. Laboratory of Genomic Diversity. SAIC-Frederick, Inc. Frederick, Maryland, USAEscola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Avançado de Saúde Pública. Salvador, BA, Brasi

Comparação entre a escala para paraplegia espástica, escala de Kurtzke e escala de Osame, na paraparesia epástica tropical/mielopatia associada ao HTLV

O objetivo deste estudo foi comparar a escala de incapacidade motora de Osame e a escala expandida do estado de incapacidade de Kurtzke com a escala para avaliação da paraplegia espástica com o objetivo de avaliar a clinica dos pacientes com mielopatia associada a HTLV-I/paraparesia espastica tropical (PET/MAH). MÉTODOS: Foram incluídos pacientes com diagnóstico de infecção pelo HTLV-I/HTLV-II e a suspeita clinica de PET/MAH. RESULTADOS: Foram avaliados 45 pacientes. Ao analisar os resultados das escalas encontramos as seguintes médias de 21,08 pontos para a escala para paraplegia espástica, 4,35 pontos para a escala de Osame e 4,77 pontos para a de Kurtze. A relação entre a escala de paraplegia com a de Osame foi muito significativa com p < 0.0001, e com relação a escala de Kurtze obteve resultado semelhante com p < 0.0001, também significante. Comparando-se as escalas de Osame, Kurztze e escala para avaliação da paraplegia espástica com o tempo de doença obtivemos um resultado significante com p=0,0004, para a escala de paraplegia espastica, p = 0,0018 para a escala de Osame e p < 0,0001 para a escala de Kurtzke. CONCLUSÕES: A escala da paraplegia espástica possui boa relação com as escalas de Osame e Kurzte, mostrando um p muito significativo, indicando que apesar da escala não ter sido feita inicialmente para ser aplicada aos pacientes com PET/MAH devido à infecção pelo HLTV, ela se mostrou capaz de ser tão eficiente quanto às escalas de Osame e Kurtzke para avaliar o quadro neurológico dos pacientes.The objective of this study was to compare Osame's scale of motor incapacity and the expanded scale of the state of incapacity of Kurtzke with the spastic paraplegia rating scale for the clinical evaluation of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS: Patients with the diagnosis of infection by HTLV-I/HTLV-II and with the clinical suspicion of HAM/TSP were included in the study. RESULTS: There were 45 patients who were evaluated. When analyzing the results of the scales, the researchers found the following averages of 21.08 points for the spastic paraplegia rating scale, 4.35 points for Osame's scale, and 4.77 points for Kurtzke's scale. The relation between the scale of paraplegia with Osame's was very significant with p < 0.0001, and regarding Kurtzke's scale, there was a similar result of p < 0.0001. When comparing Osame's, Kurtze's, and the spastic paraplegia rating scale with the time of disease, the researchers found a significant result of p = 0.0004 for the scale of spastic paraplegia, p = 0.0018 for Osame's scale, and p < 0.0001 for Kurtzke's scale. CONCLUSION: The spastic paraplegia rating scale has a good relation with Osame's and Kurtzke's scales showing a p index that is very significant that indicates that, although the scale was not initially made to be applied to patients with HAM/TSP because of the infection by HLTV, it showed to be as efficient as Osame's and Kurtzke's scales in evaluating the patients' neurological conditions

Comparação entre a escala para paraplegia espástica, escala de Kurtzke e escala de Osame, na paraparesia epástica tropical/mielopatia associada ao HTLV

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2012-12-18T21:03:42Z No. of bitstreams: 1 Adry, Rodrigo Antonio Rocha da Cruz et al Comparison between the.pdf: 752143 bytes, checksum: f640e49a5270a7c2b971b48fe1f058de (MD5)Made available in DSpace on 2012-12-18T21:03:42Z (GMT). No. of bitstreams: 1 Adry, Rodrigo Antonio Rocha da Cruz et al Comparison between the.pdf: 752143 bytes, checksum: f640e49a5270a7c2b971b48fe1f058de (MD5) Previous issue date: 2012Faculdade de Medicina. Hospital de Base de São José do Rio Preto. São José do Rio Preto, SP, Brasil.Faculdade de Medicina. Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil.Faculdade de Tecnologia e Ciências. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.O objetivo deste estudo foi comparar a escala de incapacidade motora de Osame e a escala expandida do estado de incapacidade de Kurtzke com a escala para avaliação da paraplegia espástica com o objetivo de avaliar a clinica dos pacientes com mielopatia associada a HTLV-I/paraparesia espastica tropical (PET/MAH). MÉTODOS: Foram incluídos pacientes com diagnóstico de infecção pelo HTLV-I/HTLV-II e a suspeita clinica de PET/MAH. RESULTADOS: Foram avaliados 45 pacientes. Ao analisar os resultados das escalas encontramos as seguintes médias de 21,08 pontos para a escala para paraplegia espástica, 4,35 pontos para a escala de Osame e 4,77 pontos para a de Kurtze. A relação entre a escala de paraplegia com a de Osame foi muito significativa com p < 0.0001, e com relação a escala de Kurtze obteve resultado semelhante com p < 0.0001, também significante. Comparando-se as escalas de Osame, Kurztze e escala para avaliação da paraplegia espástica com o tempo de doença obtivemos um resultado significante com p=0,0004, para a escala de paraplegia espastica, p = 0,0018 para a escala de Osame e p < 0,0001 para a escala de Kurtzke. CONCLUSÕES: A escala da paraplegia espástica possui boa relação com as escalas de Osame e Kurzte, mostrando um p muito significativo, indicando que apesar da escala não ter sido feita inicialmente para ser aplicada aos pacientes com PET/MAH devido à infecção pelo HLTV, ela se mostrou capaz de ser tão eficiente quanto às escalas de Osame e Kurtzke para avaliar o quadro neurológico dos pacientes.The objective of this study was to compare Osame's scale of motor incapacity and the expanded scale of the state of incapacity of Kurtzke with the spastic paraplegia rating scale for the clinical evaluation of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS: Patients with the diagnosis of infection by HTLV-I/HTLV-II and with the clinical suspicion of HAM/TSP were included in the study. RESULTS: There were 45 patients who were evaluated. When analyzing the results of the scales, the researchers found the following averages of 21.08 points for the spastic paraplegia rating scale, 4.35 points for Osame's scale, and 4.77 points for Kurtzke's scale. The relation between the scale of paraplegia with Osame's was very significant with p < 0.0001, and regarding Kurtzke's scale, there was a similar result of p < 0.0001. When comparing Osame's, Kurtze's, and the spastic paraplegia rating scale with the time of disease, the researchers found a significant result of p = 0.0004 for the scale of spastic paraplegia, p = 0.0018 for Osame's scale, and p < 0.0001 for Kurtzke's scale. CONCLUSION: The spastic paraplegia rating scale has a good relation with Osame's and Kurtzke's scales showing a p index that is very significant that indicates that, although the scale was not initially made to be applied to patients with HAM/TSP because of the infection by HLTV, it showed to be as efficient as Osame's and Kurtzke's scales in evaluating the patients' neurological conditions