RESUMO
BACKGROUND & AIMS: The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown. METHODS: Innate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. RESULTS: The 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity. CONCLUSION: Antigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepatite D Crônica/imunologia , Vírus Delta da Hepatite/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/imunologia , Imunidade Adaptativa , Adulto , Idoso , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Degranulação Celular , Linhagem Celular Tumoral , Citocinas/sangue , Progressão da Doença , Feminino , Hepatite D Crônica/sangue , Hepatite D Crônica/diagnóstico , Hepatite D Crônica/virologia , Vírus Delta da Hepatite/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Memória Imunológica , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Fígado/metabolismo , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/virologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Fenótipo , Adulto JovemRESUMO
Resveratrol, a plantderived stilbene compound, has exhibited anticancerous properties, including breast cancer. Stilbenes have a molecular structure highly similar to estrogen and have the ability to bind estrogen receptors and regulate activity. Numerous studies have demonstrated the effectiveness of resveratrol in estrogen receptorpositive (ERpositive) subtypes of breast cancer, yet the effects in ERnegative subtypes, including triplenegative breast cancer (TNBC), have been limited. In the present study, resveratrol and 28 analogues were tested on a panel of ERpositive and TNBC cell lines to determine effects on cell viability. Several compounds exhibited significant impacts on cell viability and suggested changes in cell morphology, with high potency of select compounds compared to resveratrol observed in a dosedependent manner. Due to the lack of estrogen receptors in TNBC and the estrogenic nature of stilbenes, regulation of breast cancerassociated cellular pathways was assessed for five analogues shown to significantly inhibit cell viability. Top regulated pathways included apoptosis (confirmed by caspase assay) and DNA damage repair. Overall, our results indicated several resveratrol analogues to be active in ERnegative phenotypes, acting through an ER receptorindependent manner, supporting further investigation into their mechanism of action and use as potential chemotherapeutics in higherrisk breast cancer cases.