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1.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638901

RESUMO

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings.


Assuntos
Fibroblastos/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Linfoma/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Células Jurkat , Linfoma/tratamento farmacológico , Linfoma/virologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/virologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439817

RESUMO

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are viruses globally distributed that have been associated with the development and prognosis of many pathologies, including hematological diseases. This study aimed to characterize the epidemiological profile of EBV infection and the infection-correlated hepatic manifestations in patients with hematological diseases of the northern Brazilian state of Amazonas. A total of 228 patients were serologically tested for the presence of anti-EBV and anti-CMV IgG antibodies through an enzyme-linked immunosorbent assay. The coinfection with CMV, sociodemographic and laboratory records of all patients were also assessed. The overall prevalence observed among the study population for EBV infection and EBV/CMV coinfection was 85.09% (95% CI: 0.80-0.90) and 78.51% (95% CI: 0.73-0.84), respectively. The age group 31-40 years old were more susceptible to EBV/CMV coinfection (95% CI: 1.59-93.41, p = 0.011), while young people aged 1-10 years old were less affected for both EBV infection (CI 95%; 0.66-0.91, p = 0.001) and EBV/CMV coinfection (95% CI: 0.52-0.81, p < 0.0001). High serum levels of the liver biomarker ferritin were associated with EBV infection (95% CI: 1.03-1.54, p = 0.031) and EBV/CMV coinfection (95% CI: 1.02-1.70, p = 0.038). Our findings indicated that the elevated prevalence of EBV infection is not associated with the hematological diseases or transfusion rates, but with the socioeconomic status of the study population. Also, this study suggests that the EBV infection and its coinfection with CMV are related to the increase of serum ferritin levels.


Assuntos
Anemia/epidemiologia , Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/epidemiologia , Infecções por Vírus Epstein-Barr/epidemiologia , Ferritinas/sangue , Leucemia/epidemiologia , Linfoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/imunologia , Anemia/patologia , Anemia/virologia , Biomarcadores/sangue , Transfusão de Sangue/estatística & dados numéricos , Brasil/epidemiologia , Criança , Pré-Escolar , Coinfecção , Citomegalovirus/crescimento & desenvolvimento , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Leucemia/imunologia , Leucemia/patologia , Leucemia/virologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Linfoma/imunologia , Linfoma/patologia , Linfoma/virologia , Masculino , Pessoa de Meia-Idade , Prevalência , Classe Social
4.
PLoS Pathog ; 17(6): e1009618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34106998

RESUMO

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).


Assuntos
Linfócitos B/patologia , Linfócitos B/virologia , Neoplasias do Sistema Nervoso Central/virologia , Epigênese Genética , Infecções por Vírus Epstein-Barr/patologia , Animais , Linfócitos B/metabolismo , Transformação Celular Viral/fisiologia , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4 , Linfoma/metabolismo , Linfoma/patologia , Linfoma/virologia , Camundongos , Osteopontina/metabolismo
6.
Curr Oncol ; 28(2): 1249-1255, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809772

RESUMO

The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) coronavirus has generated a pandemic, in which there are population groups at higher risk and who are potentially fatal victims of the disease. Cancer patients have been considered a group with special susceptibility, particularly patients with lung tumour involvement and haematological neoplasms. The Spanish Lymphoma Oncology Group (GOTEL) carried out a multicenter study of SARS-CoV-2 seroprevalence in patients with lymphoma. Results: A total of 150 patients were included between 22 May and 11 June 2020. The mean age was 65 years (range 17-89), 70 women (46.5%) and 80 men (53, 5%). At the time of diagnosis of lymphoma, 13 cases were stage I (9%), 27 (18%) stage II, 37 (24.5%) stage III, and 73 (48.5%) stage IV, while 6.6% had a primary extranodal origin. A total of 10 cases with positive serology for SARS-CoV-2 were identified, which is a prevalence of 6% in this population. None of the patients required intensive care unit management and all fully recovered from the infection. Conclusion: IgG antibody seroprevalence in lymphoma patients appears similar to that of the general population and does not show greater aggressiveness.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/epidemiologia , Linfoma/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulina G/sangue , Linfoma/sangue , Linfoma/tratamento farmacológico , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Espanha/epidemiologia , Adulto Jovem
7.
Arch Virol ; 166(7): 1893-1901, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33900468

RESUMO

Koala retrovirus (KoRV), a major pathogen of koalas, exists in both endogenous (KoRV-A) and exogenous forms (KoRV-B to J). However, the impact of infection with multiple subtypes is not well understood. Accordingly, in this study, we surveyed a representative sample from a Japanese zoo population to determine the infection status for three KoRV subtypes (KoRV-A, B, and C) and to investigate the proviral and RNA load profiles in animals with single- and multiple-subtype infections, using peripheral blood mononuclear cells (PBMCs) and plasma. Six koalas were evaluated in the study; all were infected with KoRV-A, and two koalas were coinfected with non-A subtypes (KoRV-B and/or KoRV-C). The highest KoRV total RNA and viral loads in PBMCs and plasma were found in a koala infected with multiple subtypes (KoRV-A, -B and -C). The other koala infected with multiple subtypes (KoRV-A and B) showed the highest proviral PBMC load but the lowest RNA copy number in PBMC and plasma. PBMCs from this animal were cultured for further investigation, and KoRV RNA was detected in the cells and culture supernatant after 7 and/or 14 days. The koalas harboring multiple subtypes had a higher white blood cell count than those harboring only KoRV-A and were judged to be leukemic, and they subsequently died due to lymphoma. Accordingly, we conclude that coinfection with multiple KoRV subtypes may be linked to more-severe disease. In a sequence alignment, the detected KoRV-A env gene showed 100% sequence identity to the reference gene, whereas the KoRV-B and -C env genes varied from their reference sequences.


Assuntos
Phascolarctidae/virologia , Retroviridae/genética , Animais , Células Cultivadas , Evolução Molecular , Leucócitos Mononucleares/virologia , Linfoma/virologia , RNA Viral/genética , Infecções por Retroviridae , Carga Viral/genética
8.
Front Immunol ; 12: 640918, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833760

RESUMO

Epstein Barr virus (EBV) is one of the most successful pathogens in humans with more than 95% of the human adult population persistently infected. EBV infects only humans and threatens these with its potent growth transforming ability that readily allows for immortalization of human B cells in culture. Accordingly, it is also found in around 1-2% of human tumors, primarily lymphomas and epithelial cell carcinomas. Fortunately, however, our immune system has learned to control this most transforming human tumor virus in most EBV carriers, and it requires modification of EBV associated lymphomagenesis and its immune control by either co-infections, such as malaria, Kaposi sarcoma associated herpesvirus (KSHV) and human immunodeficiency virus (HIV), or genetic predispositions for EBV positive tumors to emerge. Some of these can be modelled in humanized mice that, therefore, provide a valuable platform to test curative immunotherapies and prophylactic vaccines against these EBV associated pathologies.


Assuntos
Transformação Celular Viral/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/imunologia , Linfoma/virologia , Animais , Carcinogênese/imunologia , Transformação Celular Viral/genética , Coinfecção/genética , Coinfecção/imunologia , Coinfecção/virologia , Modelos Animais de Doenças , Herpesvirus Humano 4 , Humanos , Linfoma/genética , Linfoma/imunologia , Camundongos , Vírus Oncogênicos/genética , Vírus Oncogênicos/imunologia
9.
FASEB J ; 35(4): e21505, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33723887

RESUMO

Epstein-Barr virus (EBV) causes malignant carcinomas including B cell lymphomas accompanied by the systemic inflammation. Previously, we observed that phosphatidylserine (PS)-exposing subset of extracellular vesicles (EVs) secreted from an EBV strain Akata-transformed lymphoma (Akata EVs) convert surrounding phagocytes into tumor-associated macrophages (TAMs) via induction of inflammatory response, which is in part mediated by EBV-derived micro RNAs. However, it is still unclear about EV-carried other potential inflammatory factors associated with TAM formation in EBV lymphomas. To this end, we sought to explore proteomic and phospholipidomic profiles of PS-exposing EVs derived from EBV-transformed lymphomas. Mass spectrometric analysis revealed that several immunomodulatory proteins including integrin αLß2 and fibroblast growth factor 2 (FGF2) were highly expressed in PS-exposing Akata EVs compared with another EBV strain B95-8-transformed lymphoma-derived counterparts which significantly lack TAM-inducing ability. Pharmacological inhibition of either integrin αLß2 or FGF2 hampered cytokine induction in monocytic cultured cells elicited by PS-exposing Akata EVs, suggesting the involvement of these proteins in EV-mediated TAM induction in EBV lymphomas. In addition, phospholipids containing precursors of immunomodulatory lipid mediators were also enriched in PS-exposing Akata EVs compared with B95-8 counterparts. Phospholipidomic analysis of fractionated Akata EVs by density gradient centrifugation further demonstrated that PS-exposing Akata EVs might be identical to certain Akata EVs in low density fractions containing exosomes. Therefore, we concluded that a variety of immunomodulatory cargo molecules in a certain EV subtype are presumably conducive to the development of EBV lymphomas.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Vesículas Extracelulares/metabolismo , Linfoma/virologia , Microambiente Tumoral/fisiologia , Proliferação de Células/fisiologia , Infecções por Vírus Epstein-Barr/virologia , Exossomos/metabolismo , Exossomos/virologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 4/fisiologia , Humanos , Linfoma/metabolismo
10.
PLoS Pathog ; 17(3): e1009419, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33720992

RESUMO

Epstein-Barr virus (EBV) infection is associated with the development of specific types of lymphoma and some epithelial cancers. EBV infection of resting B-lymphocytes in vitro drives them to proliferate as lymphoblastoid cell lines (LCLs) and serves as a model for studying EBV lymphomagenesis. EBV nuclear antigen 3C (EBNA3C) is one of the genes required for LCL growth and previous work has suggested that suppression of the CDKN2A encoded tumor suppressor p16INK4A and possibly p14ARF is central to EBNA3C's role in this growth transformation. To directly assess whether loss of p16 and/or p14 was sufficient to explain EBNA3C growth effects, we used CRISPR/Cas9 to disrupt specific CDKN2A exons in EBV transformed LCLs. Disruption of p16 specific exon 1α and the p16/p14 shared exon 2 were each sufficient to restore growth in the absence of EBNA3C. Using EBNA3C conditional LCLs knocked out for either exon 1α or 2, we identified EBNA3C induced and repressed genes. By trans-complementing with EBNA3C mutants, we determined specific genes that require EBNA3C interaction with RBPJ or CtBP for their regulation. Unexpectedly, interaction with the CtBP repressor was required not only for repression, but also for EBNA3C induction of many host genes. Contrary to previously proposed models, we found that EBNA3C does not recruit CtBP to the promoters of these genes. Instead, our results suggest that CtBP is bound to these promoters in the absence of EBNA3C and that EBNA3C interaction with CtBP interferes with the repressive function of CtBP, leading to EBNA3C mediated upregulation.


Assuntos
Oxirredutases do Álcool/metabolismo , Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Linfoma/virologia , Linfócitos B/patologia , Linfócitos B/virologia , Linhagem Celular , Humanos , Regulação para Cima
11.
Mol Biol Rep ; 48(2): 1801-1817, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33523370

RESUMO

Previous literature supports the variations in microRNAs expression levels among lymphoma patients due to EBV infection. These alterations can be observed in both EBV-encoded-microRNAs and EBV-induced cellular microRNAs. Moreover, changes in the microRNA profile could be significant in disease progression. This study aimed to assess published literature to obtain a microRNA profile for both EBV-encoded microRNAs and EBV-induced cellular microRNAs among lymphoma patients. We searched common available electronic databases by using relevant keywords. The result demonstrated that EBV infection could alter the microRNA expression levels among lymphoma patients. In Burkitt lymphoma, hsa-miR197 and miR510 were most frequently assessed human micro RNAs. Also, miR-BART6-3P and miR-BART17-5P were the most frequent viral micro RNAs in Burkitt lymphoma. Other human important micro RNAs were hsa-miR155 (in Diffuse large B cell lymphoma (DLBCL)), hsa-miR145 (in Nasal natural killer T cell lymphoma (NNKTCL)), miR-96, miR-128a, miR-128b, miR-129, and miR-205 (in Classic Hodgkin lymphoma (CHL)), miR-21, miR-142-3P, miR-126, miR-451 and miR-494-3P (in Nasal natural killer cell lymphoma (NNKCL)). Also, viral assessed micro RNAs were miR-BART1-5P (in DLBCL and NNKTCL), miR-BART-5 (in CHL), and EBV-miR-BART20-5P (in NNKCL). In conclusion, it could be suggested that EBV-encoded-microRNAs and EBV-induced cellular-microRNAs can be utilized as helpful factors for different types of lymphoma diagnoses or prognostic factors. Moreover, the mentioned microRNAs can also be promising therapeutic targets and can be used to modulate the oncogenes.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma/diagnóstico , Linfoma/metabolismo , MicroRNAs/metabolismo , RNA Viral/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Humanos , Linfoma/genética , Linfoma/virologia , MicroRNAs/genética , Prognóstico , RNA Viral/genética
13.
Sci Rep ; 11(1): 637, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33437016

RESUMO

Marek's disease virus (MDV) encodes a basic-leucine zipper (BZIP) protein, Meq, which is considered the major MDV oncoprotein. It has been reported that the oncogenicity of Meq is associated with its interaction with C-terminal binding protein 1 (CtBP), which is also an interaction partner of Epstein-Barr virus encoded EBNA3A and EBNA3C oncoproteins. Since both EBNA3C and CtBP interact with histone deacetylase 1 (HDAC1) and HDAC2, we examined whether Meq shares this interaction with chicken HDAC1 (chHDAC1) and chHDAC2. Using confocal microscopy analysis, we show that Meq co-localizes with chHDAC1 and chHDAC2 in the nuclei of MDV lymphoblastoid tumor cells. In addition, immunoprecipitation assays demonstrate that Meq interacts with chHDAC1 and chHDAC2 in transfected cells and MDV lymphoblastoid tumor cells. Using deletion mutants, interaction domains were mapped to the N-terminal dimerization domain of chHDAC1 and chHDAC2, and the BZIP domain of Meq. Our results further demonstrate that this interaction mediates the degradation of chHDAC1 and chHDAC2 via the proteasome dependent pathway. In addition, our results show that Meq also induces the reduction of global ubiquitinated proteins through a proteasome dependent pathway. In conclusion, our results provide evidence that Meq interacts with chHDAC1 and chHDAC2, and induces their proteasome dependent degradation.


Assuntos
Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Linfoma/patologia , Proteínas Oncogênicas Virais/metabolismo , Doenças das Aves Domésticas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Galinhas , Herpesvirus Galináceo 2/isolamento & purificação , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/virologia , Linfoma/metabolismo , Linfoma/virologia , Doença de Marek/complicações , Doença de Marek/metabolismo , Doença de Marek/patologia , Doença de Marek/virologia , Proteínas Oncogênicas Virais/genética , Doenças das Aves Domésticas/metabolismo , Doenças das Aves Domésticas/virologia , Proteólise
14.
J Infect Chemother ; 27(2): 387-389, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33328135

RESUMO

The duration of viral shedding of SARS-CoV-2 is usually less than 10 days. We experienced a COVID-19 case with prolonged viral shedding for 2 months. His cell mediated immunity has been depressed (CD4+T cell <100/µl) due to advanced malignant lymphoma and chemotherapy which had been completed 4 months prior to the onset of symptoms of COVID-19. We administered several treatments against COVID-19, however the results of Polymerase Chain Reaction (PCR) from nasopharyngeal specimens remained positive to SARS-CoV-2 for 2 months. Moreover, virus isolation assays performed on Day 59 also remained positive. He was finally discharged on Day 69 with two consecutive negative PCR results for SARS-CoV-2. Immunocompromised status may prolong viral shedding and it is therefore important for the clinician to take into account this when assessing such patients.


Assuntos
COVID-19/imunologia , Hospedeiro Imunocomprometido , Linfoma/complicações , SARS-CoV-2/isolamento & purificação , Eliminação de Partículas Virais , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/terapia , COVID-19/virologia , Humanos , Linfoma/virologia , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo , Resultado do Tratamento
15.
Blood ; 137(11): 1468-1477, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33202420

RESUMO

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.


Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Linfoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Tolerância Imunológica , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Transcriptoma , Microambiente Tumoral
18.
J Neurovirol ; 26(6): 961-963, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32910430

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease affecting the central nervous system as a result of reactivation of the John Cunningham (JC) polyomavirus and occurs almost exclusively in immunosuppressed individuals. The disease course of PML is variable but usually progressive and often fatal. Treatment is predominantly focused on immune restoration, although this is difficult to do outside of human immunodeficiency virus-associated PML. A recent case series demonstrated a potential role for programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, to contain and/or clear JC virus. Herein, we discuss the first reported Australian case of a 61-year-old female with PML secondary to chemoimmunotherapy demonstrating complete clearance of JC virus as well as clinical and radiological stabilisation following pembrolizumab treatment.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Hipertensão/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Linfoma/tratamento farmacológico , Agamaglobulinemia/diagnóstico por imagem , Agamaglobulinemia/imunologia , Agamaglobulinemia/virologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/virologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/imunologia , Hipertensão/virologia , Vírus JC/efeitos dos fármacos , Vírus JC/crescimento & desenvolvimento , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Ativação Linfocitária/efeitos dos fármacos , Linfoma/diagnóstico por imagem , Linfoma/imunologia , Linfoma/virologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
19.
Pathology ; 52(6): 676-685, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32768248

RESUMO

It is well-known that Epstein-Barr virus (EBV) is the promoter of cell tumourigenesis. We found that EBV is also a promoter of lymphoma cell dissemination, because we found the typical morphopathological phenomenon of cell adhesion, which confirmed that the adhesion of tumour cells was higher than that of normal cells. We also observed that tumour cells disrupted the dynamic pathological changes of vascular endothelial cells, and this made it clear that the rate of tumour cell metastasis was directly proportional to the degree of EBV infection. Furthermore, when we discovered exosomes, it was considered that this was associated with cancer stem cells, suggesting the formation of a microenvironment before tumour cell metastasis. In addition, competitive inhibition was found in cell adhesion, indicating the breakthrough point of preventing tumour cell metastasis, which has clinical reference value for tumour immunotherapy.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Linfoma/virologia , Animais , Carcinogênese , Adesão Celular , Linhagem Celular Tumoral , Células Endoteliais/patologia , Infecções por Vírus Epstein-Barr/patologia , Exossomos/patologia , Humanos , Imuno-Histoquímica , Linfócitos/patologia , Linfoma/patologia , Camundongos , Camundongos SCID , Metástase Neoplásica , Microambiente Tumoral
20.
PLoS Pathog ; 16(7): e1008701, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32735617

RESUMO

Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 does not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis.


Assuntos
Infecções por Herpesviridae/metabolismo , Interleucina-16/metabolismo , Infecções Tumorais por Vírus/metabolismo , Ativação Viral/fisiologia , Latência Viral/fisiologia , Animais , Linfócitos B/virologia , Infecções por Herpesviridae/imunologia , Interleucina-16/imunologia , Linfoma/virologia , Camundongos , Rhadinovirus/imunologia , Rhadinovirus/metabolismo
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