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1.
Br J Haematol ; 193(3): 488-496, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33528031

RESUMO

The expression patterns and prognostic significance of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut-off, SAMHD1 was positive in HRS cells of 48/154 (31·2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow-up of 90 months (7-401 months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P = 0·025), disease-specific survival (DSS) (P = 0·013) and overall survival (OS) (P = 0·01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P = 0·005) as well as DSS (P = 0·022) and OS (P = 0·018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Doença de Hodgkin , Linfonodos/enzimologia , Proteína 1 com Domínio SAM e Domínio HD/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bleomicina/administração & dosagem , Linhagem Celular Tumoral , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/enzimologia , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Vimblastina/administração & dosagem
2.
Med Microbiol Immunol ; 208(5): 679-691, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30564919

RESUMO

PURPOSE: To investigate the contribution of SAMHD1 to HIV-1 infection in vivo and its relationship with IFN response, the expression of SAMHD1 and IFN-related pathways was evaluated in HIV-1-infected patients. METHODS: Peripheral blood mononuclear cells (PBMC) from 388 HIV-1-infected patients, both therapy naïve (n = 92) and long-term HAART treated (n = 296), and from 100 gender and age-matched healthy individuals were examined. CD4+ T cells, CD14+ monocytes and gut biopsies were also analyzed in HIV-1-infected subjects on suppressive antiretroviral therapy. Gene expression levels of SAMDH1, ISGs (MxA, MxB, HERC5, IRF7) and IRF3 were evaluated by real-time RT-PCR assays. RESULTS: SAMHD1 levels in HIV-1-positive patients were significantly increased compared to those in healthy donors. SAMHD1 expression was enhanced in treated patients compared to naïve patients (p < 0.0001) and healthy donors (p = 0.0038). Virologically suppressed treated patients exhibited higher SAMHD1 levels than healthy donors (p = 0.0008), viraemic patients (p = 0.0001) and naïve patients (p < 0.0001). SAMHD1 levels were also increased in CD4+ T cells compared to those in CD14+ monocytes and in PBMC compared to those of GALT. Moreover, SAMHD1 was expressed more strongly than ISGs in HIV-1-infected patients and positive correlations were found between SAMHD1, ISGs and IRF3 levels. CONCLUSIONS: SAMHD1 is more strongly expressed than the classical IFN-related genes, increased during antiretroviral therapy and correlated with ISGs and IRF3 in HIV-1-infected patients.


Assuntos
Expressão Gênica , Infecções por HIV/patologia , Fatores Imunológicos/biossíntese , Proteína 1 com Domínio SAM e Domínio HD/biossíntese , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Circulation ; 136(20): 1920-1935, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-28935667

RESUMO

BACKGROUND: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. METHODS: Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry, confirmed by enzyme-linked immunosorbent assay, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next-generation sequencing, functional studies in cultured monocytes and endothelial cells, and hemodynamic and lung studies in a rat. RESULTS: SAM domain and HD domain-containing protein 1 (SAMHD1), an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH versus 12 control lungs. Elevated SAMHD1 was localized to endothelial cells, perivascular dendritic cells, and macrophages, and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH versus control lungs (n=4). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase mRNAs were elevated in PAH versus control lungs (n=10), and proteins were localized to macrophages. HERV-K deoxyuridine triphosphate nucleotidohydrolase induced SAMHD1 and proinflammatory cytokines (eg, interleukin 6, interleukin 1ß, and tumor necrosis factor α) in circulating monocytes, pulmonary arterial endothelial cells, and also activated B cells. Vulnerability of pulmonary arterial endothelial cells (PAEC) to apoptosis was increased by HERV-K deoxyuridine triphosphate nucleotidohydrolase in an interleukin 6-independent manner. Furthermore, 3 weekly injections of HERV-K deoxyuridine triphosphate nucleotidohydrolase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8) and elevated interleukin 6. CONCLUSIONS: Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.


Assuntos
Hipertensão Pulmonar/imunologia , Mediadores da Inflamação/imunologia , Regulação para Cima/fisiologia , Proteínas Virais/biossíntese , Proteínas Virais/imunologia , Adolescente , Adulto , Animais , Complexo Antígeno-Anticorpo/biossíntese , Complexo Antígeno-Anticorpo/imunologia , Células Cultivadas , Criança , Técnicas de Cocultura , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Lactente , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteína 1 com Domínio SAM e Domínio HD/biossíntese , Proteína 1 com Domínio SAM e Domínio HD/imunologia , Adulto Jovem
4.
AIDS ; 30(13): 2053-64, 2016 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-27219130

RESUMO

OBJECTIVE: Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), a newly discovered HIV-1 host restriction factor, has been found to be induced by interferons and to be regulated by microRNA-181a (miR-181a). However, the mechanism of interferons-induced SAMHD1 expression is unclear. DESIGN: We hypothesized that interferons induce SAMHD1 expression through Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways, which is mediated by miR-181a. METHODS: We examined the effect of IFN-α and IFN-γ on SAMHD1 mRNA and protein expression, as well as the levels of phosphorylated SAMHD1 and miR-181a in astrocytes and microglia. To determine whether interferons-induced SAMHD1 expression was mediated by miR-181a, we overexpressed or inhibited miR-181a in these cells and exposed them to interferons. We also detected the effect of SAMHD1 and miR-181a on HIV-1 infection in astrocytes and microglia. RESULTS: Both IFN-α and IFN-γ increased SAMHD1 mRNA and protein expression, and reduced miR-181a levels, particularly in microglia. Phosphorylated SAMHD1was not induced by interferons. Overexpression of miR-181a counteracted induction of SAMHD1 expression by interferons, and inhibition of miR-181a mimicked interferons treatment. Inhibition of JAK-STAT signaling pathways resulted in increased miR-181a levels and decreased SAMHD1 mRNA expression. Knock-down of SAMHD1 or overexpression of miR-181a enhanced HIV-1 infection, whereas inhibition of miR-181a reduced HIV-1 infection. However, inhibition of HIV-1 infection induced by IFN-α was not significantly affected by miR-181a and SAMHD1. CONCLUSION: MiR-181a is an important mediator for interferons-induced SAMHD1 expression in astrocytes and microglia, but not for inhibition of HIV-1 infection induced by IFN-α.


Assuntos
Astrócitos/imunologia , Regulação da Expressão Gênica , Interferons/metabolismo , MicroRNAs/metabolismo , Microglia/imunologia , Proteína 1 com Domínio SAM e Domínio HD/biossíntese , Transdução de Sinais , Células Cultivadas , Perfilação da Expressão Gênica , Humanos
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