Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.713
Filtrar
1.
Am J Surg Pathol ; 45(5): 694-700, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739792

RESUMO

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder may resemble nonspecific inflammation. We report 3 cases of immunosuppressed adult patients with small lymphocytic EBV ulcers in the skin and oral mucosa, characterized by a lack of atypical lymphocytic infiltration. All 3 cases were diagnosed in routine practice. For comparisons, cases of conventional Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) were reviewed which were extracted from our pathology archives (n=11). The present patients were 2 females and 1 male, aged above 70 years. The primary disease was rheumatoid arthritis (n=2) and dermatitis herpetiformis (n=1). The main source of immunosuppression was prednisolone (n=2) and methotrexate (n=1). The ulcers were located in the oral cavity, buttock, and/or external genitalia. Histology evaluation revealed nonspecific lymphocytic infiltration. Epstein-Barr virus-encoded small RNA (EBER)-positive cells were small and coexpressed CD20. The number of EBER-positive cells ranged from 52 to 132/HPF, which was within the range of that observed in the reviewed conventional EBVMCUs (range, 48 to 1328; median, 121). All 3 cases regressed spontaneously or by the reduction of immunosuppressants. Although the present cases lacked cytologic atypia, those clinical course and loads of EBER-positive cells (>50/HPF) suggested EBV involvement. Current cases of EBVMCU with small lymphocytic infiltration underscore the need for EBER in situ hybridization when an etiology of ulcer with predominant lymphocytes in an immunosuppressed patient is unclear.


Assuntos
Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/patogenicidade , Linfócitos/patologia , Mucosa Bucal/patologia , Infecções Oportunistas/patologia , Úlceras Orais/patologia , Úlcera Cutânea/patologia , Idoso , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/imunologia , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Linfócitos/imunologia , Linfócitos/virologia , Masculino , Mucosa Bucal/imunologia , Mucosa Bucal/virologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Úlceras Orais/imunologia , Úlceras Orais/virologia , Fatores de Risco , Úlcera Cutânea/imunologia , Úlcera Cutânea/virologia , Carga Viral
2.
Ann Hematol ; 100(4): 865-878, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33547921

RESUMO

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of haematopoietic stem cell transplantation (HSCT), occurring in a setting of immune suppression and dysregulation. The disease is in most cases driven by the reactivation of the Epstein-Barr virus (EBV), which induces B cell proliferation through different pathomechanisms. Beyond EBV, many factors, variably dependent on HSCT-related immunosuppression, contribute to the disease development. PTLDs share several features with primary lymphomas, though clinical manifestations may be different, frequently depending on extranodal involvement. According to the WHO classification, histologic examination is required for diagnosis, allowing also to distinguish among PTLD subtypes. However, in cases of severe and abrupt presentation, a diagnosis based on a combination of imaging studies and EBV-load determination is accepted. Therapies include prophylactic and pre-emptive interventions, aimed at eradicating EBV proliferation before symptoms onset, and targeted treatments. Among them, rituximab has emerged as first-line option, possibly combined with a reduction of immunosuppression, while EBV-specific cytotoxic T lymphocytes are effective and safe alternatives. Though prognosis remains poor, survival has markedly improved following the adoption of the aforementioned treatments. The validation of innovative, combined approaches is the future challenge.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Adulto , Idoso , Linfócitos B/patologia , Linfócitos B/virologia , Criança , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 4/fisiologia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologia , MicroRNAs/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Fatores de Risco , Rituximab/uso terapêutico , Linfócitos T Citotóxicos/transplante , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Ativação Viral
3.
4.
Nat Commun ; 12(1): 117, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402692

RESUMO

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Recidiva Local de Neoplasia/genética , Receptores de Somatostatina/genética , Proteínas da Matriz Viral/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/virologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/virologia , Octreotida/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/metabolismo , Transdução de Sinais , Análise de Sobrevida , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
EMBO J ; 40(2): e105699, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347626

RESUMO

Pathogen type 3 secretion systems (T3SS) manipulate host cell pathways by directly delivering effector proteins into host cells. In Vibrio parahaemolyticus, the leading cause of bacterial seafood-borne diarrheal disease, we showed that a T3SS effector, VgpA, localizes to the host cell nucleolus where it binds Epstein-Barr virus nuclear antigen 1-binding protein 2 (EBP2). An amino acid substitution in VgpA (VgpAL10A ) did not alter its translocation to the nucleus but abolished the effector's capacity to interact with EBP2. VgpA-EBP2 interaction led to the re-localization of c-Myc to the nucleolus and increased cellular rRNA expression and proliferation of cultured cells. The VgpA-EBP2 interaction elevated EBP2's affinity for c-Myc and prolonged the oncoprotein's half-life. Studies in infant rabbits demonstrated that VgpA is translocated into intestinal epithelial cells, where it interacts with EBP2 and leads to nucleolar re-localization of c-Myc. Moreover, the in vivo VgpA-EBP2 interaction during infection led to proliferation of intestinal cells and heightened V. parahaemolyticus' colonization and virulence. These observations suggest that direct effector stimulation of a c-Myc controlled host cell growth program can contribute to pathogenesis.


Assuntos
Proteínas de Bactérias/metabolismo , Nucléolo Celular/metabolismo , Proliferação de Células/fisiologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sistemas de Secreção Tipo III/metabolismo , Vibrio parahaemolyticus/metabolismo , Virulência/fisiologia , Animais , Células CACO-2 , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Regulação Bacteriana da Expressão Gênica/fisiologia , Herpesvirus Humano 4/patogenicidade , Humanos , RNA Ribossômico/metabolismo , Proteínas de Ligação a RNA/metabolismo , Coelhos , Vibrioses/metabolismo
6.
PLoS Pathog ; 16(12): e1009023, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382850

RESUMO

Extracellular vesicles (EV) mediate intercellular communication events and alterations in normal vesicle content contribute to function and disease initiation or progression. The ability to package a variety of cargo and transmit molecular information between cells renders EVs important mediators of cell-to-cell crosstalk. Latent membrane protein 1 (LMP1) is a chief viral oncoprotein expressed in most Epstein-Barr virus (EBV)-associated cancers and is released from cells at high levels in EVs. LMP1 containing EVs have been demonstrated to promote cell growth, migration, differentiation, and regulate immune cell function. Despite these significant changes in recipient cells induced by LMP1 modified EVs, the mechanism how this viral oncogene modulates the recipient cells towards these phenotypes is not well understood. We hypothesize that LMP1 alters EV content and following uptake of the LMP1-modified EVs by the recipient cells results in the activation of cell signaling pathways and increased gene expression which modulates the biological properties of recipient cell towards a new phenotype. Our results show that LMP1 expression alters the EV protein and microRNA content packaged into EVs. The LMP1-modified EVs also enhance recipient cell adhesion, proliferation, migration, invasion concomitant with the activation of ERK, AKT, and NF-κB signaling pathways. The LMP1 containing EVs induced transcriptome reprogramming in the recipient cells by altering gene expression of different targets including cadherins, matrix metalloproteinases 9 (MMP9), MMP2 and integrin-α5 which contribute to extracellular matrix (ECM) remodeling. Altogether, our data demonstrate the mechanism in which LMP1-modified EVs reshape the tumor microenvironment by increasing gene expression of ECM interaction proteins.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas da Matriz Viral/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Infecções por Vírus Epstein-Barr/fisiopatologia , Vesículas Extracelulares/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/virologia , Invasividade Neoplásica/genética , Transdução de Sinais , Microambiente Tumoral , Proteínas da Matriz Viral/fisiologia
7.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321820

RESUMO

Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein-Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.


Assuntos
Herpesvirus Humano 4/genética , Neoplasias Gástricas/metabolismo , Animais , Transformação Celular Viral , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia
8.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
9.
Proc Natl Acad Sci U S A ; 117(25): 14421-14432, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32522871

RESUMO

Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.


Assuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/patogenicidade , Linfoma de Células B/patologia , Plasmócitos/patologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Fibroblastos , Herpesvirus Humano 4/metabolismo , Humanos , Linfoma de Células B/virologia , Camundongos , Camundongos Knockout , Plasmócitos/virologia , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo
10.
Medicine (Baltimore) ; 99(26): e20822, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590768

RESUMO

INTRODUCTION: Extranodal natural killer/T-cell lymphoma (ENKTL) - nasal type is an aggressive form of malignant non-Hodgkin lymphoma with a very poor prognosis. Especially primary pulmonary ENKTL is a relatively rare form of non-Hodgkin lymphoma. Until now, the prevalence of primary pulmonary ENKTL is unknown. Since 2001, only 18 cases of primary pulmonary ENKTL have been published, in addition to the 2 cases reported here. PATIENT CONCERNS: We describe 2 cases of primary pulmonary ENKTL. Both patients were male non-smokers, aged 61 and 49 years. Their main clinical symptoms included cold-like symptoms and intermittent fever (39.3°C and 38.8°C) for some days (40 days and 3 weeks). Both patients had no relevant personal or family medical history. DIAGNOSIS: The patients were initially misdiagnosed with community-acquired pneumonia. Primary pulmonary ENKTL was confirmed by immunohistochemical staining of computed tomography-guided transthoracic needle biopsy specimens. Both cases were positive for CD56, CD3, and in situ hybridization for Epstein-Barr virus-encoded small RNA, but negative for CD20. INTERVENTIONS: Initially, both patients were treated inadequately with intravenous moxifloxacin administration (unknown dosage and 400 mg q.d) in their local hospitals. Once diagnosed with primary pulmonary ENKTL in our hospital, they received 3 cycles of chemotherapy with combined regimens of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE), and in the second patient, bone marrow transplantation was performed following the third chemotherapy cycle. OUTCOMES: Clinical follow-up after the chemotherapy showed that the condition of the first patient progressively deteriorated. He died 2 months following the initial diagnosis. However, the presence of the hemophagocytic lymphohistocytosis gradually improved in the second patient during chemotherapy. Ultimately, the second patient died of acute transplant rejection 6 months after the initial diagnosis. CONCLUSION: The diagnosis of ENKTL should be considered when patients present with fever and expansile consolidation of the lung not responding to antibiotics. The diagnosis depends on histopathology and immunophenotyping. Percutaneous transthoracic needle biopsy is a safe and effective biopsy method. Chemotherapy may improve the prognosis, but this should be confirmed by prospective multicenter studies.


Assuntos
Linfoma Extranodal de Células T-NK/diagnóstico , Biópsia por Agulha/métodos , Complexo CD3/análise , Complexo CD3/sangue , Antígeno CD56/análise , Antígeno CD56/sangue , Diagnóstico Tardio , Herpesvirus Humano 4/patogenicidade , Humanos , Linfoma Extranodal de Células T-NK/sangue , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos
11.
PLoS Pathog ; 16(6): e1008590, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542010

RESUMO

EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV's ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral non-coding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1-infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV to form tumors in CBH mice and suggest that P3HR1 virus can be used to model EBV positive lymphomas with both Wp-restricted and type II latency in vivo.


Assuntos
Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr/genética , Deleção de Genes , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Proteínas Virais/genética , Latência Viral , Animais , Linhagem Celular , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Camundongos , Proteínas Virais/metabolismo
12.
Ann Hematol ; 99(10): 2243-2253, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32307569

RESUMO

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.


Assuntos
Coinfecção/virologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/patogenicidade , Transtornos Linfoproliferativos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Diagnóstico Diferencial , Progressão da Doença , Feminino , Centro Germinativo/patologia , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/terapia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Imunocompetência , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma não Hodgkin/virologia , Linfoma de Efusão Primária/diagnóstico , Linfoma de Efusão Primária/virologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
13.
Cancer Immunol Immunother ; 69(9): 1751-1766, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32335702

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma with an aggressive clinical course. To investigate the potential of immune-checkpoint therapy, we retrospectively studied the tumor microenvironment (TME) using high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 "other" CNSL lymphomas with the presence of the Epstein-Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition and the functional spectrum of cytotoxic T cells were similar. But cytotoxic T cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T cells and geographic-type necrosis each predicted inferior outcome in PCNSL. Both M1-like (CD68 + CD163low) and M2-like (CD68 + CD163high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated with a better survival. PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0.4% of all CD8+ T cells. TIM-3, a marker for T cell exhaustion, was significantly more expressed in CD8posPD-1pos T cells compared to CD8posPD-1neg T cells, and a similar increased expression was observed in M2-like pro-tumoral phagocytes. In conclusion, the clinical impact of TME composition supports the use of immune-checkpoint therapies in PCNSL. Based on observed differences in immune-checkpoint expression, combinations that boost cytotoxic T cell activation (by blocking TIM-3 or TGFBR1) prior to the administration of PD-L1 inhibition could be of interest.


Assuntos
Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Linfoma/imunologia , Linfoma/terapia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Sistema Nervoso Central/virologia , Criança , Feminino , Herpesvirus Humano 4/patogenicidade , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfoma/virologia , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/imunologia , Estudos Retrospectivos , Linfócitos T Citotóxicos/imunologia , Adulto Jovem
14.
Sci Rep ; 10(1): 6115, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273550

RESUMO

Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.


Assuntos
Monoaminoxidase/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epigênese Genética , Células Epiteliais/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , Interleucina-6/metabolismo , Monoaminoxidase/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
15.
J Glob Health ; 10(1): 010405, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32257153

RESUMO

Background: Epstein Barr Virus (EBV) infects 90%-95% of all adults globally and causes ~ 1% of all cancers. Differing proportions of Burkitt's lymphoma (BL), gastric carcinoma (GC), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) are associated with EBV. We sought to systematically review the global epidemiological evidence for risk factors that (in addition to EBV) contribute to the development of the EBV-associated forms of these cancers, assess the quality of the evidence, and compare and contrast the cancers. Methods: MEDLINE, Embase and Web of Science were searched for studies of risk factors for EBV-associated BL, GC, HL and NPC without language or temporal restrictions. Studies were excluded if there was no cancer-free comparator group or where analyses of risk factors were inadequately documented. After screening and reference list searching, data were extracted into standardised spreadsheets and quality assessed. Due to heterogeneity, a narrative synthesis was undertaken. Results: 9916 hits were retrieved. 271 papers were retained: two BL, 24 HL, one GC and 244 NPC. The majority of studies were from China, North America and Western Europe. Risk factors were categorised as dietary, environmental/non-dietary, human genetic, and infection and clinical. Anti-EBV antibody load was associated with EBV-associated GC and BL. Although the evidence could be inconsistent, HLA-A alleles, smoking, infectious mononucleosis and potentially other infections were risk factors for EBV-associated HL. Rancid dairy products; anti-EBV antibody and EBV DNA load; history of chronic ear, nose and/or throat conditions; herbal medicine use; family history; and human genetics were risk factors for NPC. Fresh fruit and vegetable and tea consumption may be protective against NPC. Conclusions: Many epidemiological studies of risk factors in addition to EBV for the EBV-associated forms of BL, GC, HL and NPC have been undertaken, but there is a dearth of evidence for GC and BL. Available evidence is of variable quality. The aetiology of EBV-associated cancers likely results from a complex intersection of genetic, clinical, environmental and dietary factors, which is difficult to assess with observational studies. Large, carefully designed, studies need to be strategically undertaken to harmonise and clarify the evidence. Registration: PROSPERO CRD42017059806.


Assuntos
Carcinoma/virologia , Herpesvirus Humano 4/patogenicidade , Neoplasias/virologia , Linfoma de Burkitt/virologia , Doença de Hodgkin/virologia , Humanos , Neoplasias Nasofaríngeas/virologia , Fatores de Risco , Neoplasias Gástricas/virologia
16.
PLoS Pathog ; 16(4): e1008477, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251475

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies.


Assuntos
Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Tacrolimo/farmacologia , Animais , Linfócitos B/metabolismo , DNA Viral , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/virologia , Feminino , Perfilação da Expressão Gênica/métodos , Antígeno HLA-A2 , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Transplante de Órgãos/efeitos adversos , Transcriptoma/genética , Carga Viral
17.
Int J Mol Sci ; 21(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178406

RESUMO

Chronic periodontitis is spreading worldwide and mutually interacts with systemic diseases like diabetes mellitus. Although periodontopathic bacteria are inevitable pathogens in their onset and progression, many cases are not ascribable to the virulence of these bacteria because the effect of plaque control is limited. In contrast, Epstein-Barr virus (EBV) in the periodontium has been correlated with chronic periodontitis and has recently been considered as a promising pathogenic candidate for this disease. However, several important questions have yet to be addressed. For instance, although EBV latently infects more than 90% of individuals over the world, why do patients with chronic periodontitis exclusively harbor progeny EBV in the oral cavity? In addition, how does latently infected or reactivated EBV in the periodontium relate to the onset or progression of chronic periodontitis? Finally, is periodontitis incurable because EBV is the pathogen for chronic periodontitis? In this review, we attempt to answer these questions by reporting the current understanding of molecular relations and mechanisms between periodontopathic bacteria and EBV reactivation in the context of how this relationship may pertain to the etiology of chronic periodontitis.


Assuntos
Periodontite Crônica/virologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/patogenicidade , Animais , Humanos , Bolsa Periodontal/virologia , Periodonto/virologia
18.
APMIS ; 128(2): 129-135, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32133709

RESUMO

Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma. The prevalence of BL is ten-fold higher in areas with stable transmission of Plasmodium falciparum malaria, where it is the most common childhood cancer, and is referred to as endemic BL (eBL). In addition to its association with exposure to P. falciparum infection, eBL is strongly associated with Epstein-Barr virus (EBV) infection (>90%). This is in contrast to BL as it occurs outside P. falciparum-endemic areas (sporadic BL), where only a minority of the tumours are EBV-positive. Although the striking geographical overlap in the distribution of eBL and P. falciparum was noted shortly after the first detailed description of eBL in 1958, the molecular details of the interaction between malaria and eBL remain unresolved. It is furthermore unexplained why exposure to P. falciparum appears to be essentially a prerequisite to the development of eBL, whereas other types of malaria parasites that infect humans have no impact. In this brief review, we summarize how malaria exposure may precipitate the malignant transformation of a B-cell clone that leads to eBL, and propose an explanation for why P. falciparum uniquely has this capacity.


Assuntos
Linfoma de Burkitt/etiologia , Linfoma de Burkitt/parasitologia , Malária Falciparum/complicações , Parasitos/patogenicidade , Plasmodium falciparum/patogenicidade , Animais , Criança , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/patogenicidade , Humanos , Malária Falciparum/parasitologia
20.
PLoS Pathog ; 16(2): e1008365, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32059024

RESUMO

Humans are infected with two distinct strains (Type 1 (T1) and Type 2 (T2)) of Epstein-Barr virus (EBV) that differ substantially in their EBNA2 and EBNA 3A/B/C latency genes and the ability to transform B cells in vitro. While most T1 EBV strains contain the "prototype" form of the BZLF1 immediate-early promoter ("Zp-P"), all T2 strains contain the "Zp-V3" variant, which contains an NFAT binding motif and is activated much more strongly by B-cell receptor signalling. Whether B cells infected with T2 EBV are more lytic than cells infected with T1 EBV is unknown. Here we show that B cells infected with T2 EBV strains (AG876 and BL5) have much more lytic protein expression compared to B cells infected with T1 EBV strains (M81, Akata, and Mutu) in both a cord blood-humanized (CBH) mouse model and EBV-transformed lymphoblastoid cell lines (LCLs). Although T2 LCLs grow more slowly than T1 LCLs, both EBV types induce B-cell lymphomas in CBH mice. T1 EBV strains (M81 and Akata) containing Zp-V3 are less lytic than T2 EBV strains, suggesting that Zp-V3 is not sufficient to confer a lytic phenotype. Instead, we find that T2 LCLs express much higher levels of activated NFATc1 and NFATc2, and that cyclosporine (an NFAT inhibitor) and knockdown of NFATc2 attenuate constitutive lytic infection in T2 LCLs. Both NFATc1 and NFATc2 induce lytic EBV gene expression when combined with activated CAMKIV (which is activated by calcium signaling and activates MEF2D) in Burkitt Akata cells. Together, these results suggest that B cells infected with T2 EBV are more lytic due to increased activity of the cellular NFATc1/c2 transcription factors in addition to the universal presence of the Zp-V3 form of BZLF1 promoter.


Assuntos
Linfócitos B/metabolismo , Fatores de Transcrição NFATC/genética , Animais , Linfócitos B/virologia , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr , Expressão Gênica/genética , Regulação Viral da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Virais/metabolismo , Ativação Viral , Latência Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...