RESUMO
Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed-Sternberg (RS) cells originating from germinal centre B-cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP-1) expression. LMP-1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP-1 may rescue proapoptotic B-cells through downregulation of B-cell receptor (BCR) components, mimicking and inducing multiple distinct B-cell signalling pathways to promote proliferation and survival, such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kappa b (NF-кB), and cellular MYC (c-MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP-1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.
Assuntos
Herpesvirus Humano 4 , Doença de Hodgkin , Proteínas da Matriz Viral , Doença de Hodgkin/virologia , Doença de Hodgkin/patologia , Doença de Hodgkin/metabolismo , Humanos , Proteínas da Matriz Viral/metabolismo , Proteínas da Matriz Viral/genética , Herpesvirus Humano 4/genética , Transdução de Sinais , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Instabilidade Genômica , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologia , Células de Reed-Sternberg/virologiaRESUMO
Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin's cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.
Assuntos
Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin/virologia , Interações Hospedeiro-Patógeno , Biomarcadores Tumorais , Transformação Celular Viral , DNA Viral/genética , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/epidemiologia , Humanos , Evasão da Resposta Imune , Hospedeiro Imunocomprometido , Masculino , Células de Reed-Sternberg/virologia , Risco , Fatores de Risco , Proteínas Virais/fisiologia , Latência ViralRESUMO
Previous studies have investigated the prognostic relevance of MMP9 in classical Hodgkin lymphoma (cHL), with negative results. However, we have found that MMP9 immunoistochemical expression by Hodgkin-Reed-Sternberg cells is associated with reduced overall survival in a subset of young adult Brazilian patients diagnosed with cHL. Additionally, we have observed that MMP9 expression by neoplastic cells in cHL is associated with EBV positivity. These results may support a rational basis for additional studies on the role of this metalloproteinase as a target for therapy in classical Hodgkin lymphoma.
Assuntos
Doença de Hodgkin/enzimologia , Doença de Hodgkin/patologia , Metaloproteinase 9 da Matriz/metabolismo , Células de Reed-Sternberg/enzimologia , Células de Reed-Sternberg/patologia , Adolescente , Adulto , Feminino , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Células de Reed-Sternberg/virologia , Análise de Sobrevida , Adulto JovemRESUMO
El linfoma de Hodgkin (LH) es una neoplasia del sistema linfático. La incidencia mundial anual del LH es de 3-10/100,000 habitantes. El mecanismo mediante el cual se lleva a cabo la transformación celular no es completamente claro; sin embargo, algunas evidencias parecen indicar que ciertos virus oncogénicos como el virus Epstein Barr (VEB), pueden tener alto impacto en la patogénesis de la linfoproliferación. También algunos factores genéticos y ambientales pueden estar involucrados, pues se ha encontrado una alta incidencia de casos de LH entre individuos de una misma familia que comparten características genéticas y conviven en un mismo ambiente. En México se han realizado estudios encaminados a conocer la prevalencia del VEB en pacientes con LH y se ha encontrado la presencia de este virus hasta en el 64,2%. El VEB ha sido detectado en las Células Reed Sternberg (CRS) y en Células de Hodgkin (CH) en el 50% de los casos de LH clásico. No se ha dado hasta ahora una explicación satisfactoria, pero se ha propuesto que la variabilidad geográfica y la variabilidad inmunológica desempeñan un papel determinante en la positividad del VEB en LH. A pesar de los avances que hasta ahora se tienen, no existen suficientes evidencias que permitan establecer una clara asociación entre los factores del huésped, el medio ambiente y el agente patógeno en el riesgo de la linfoproliferación que conduce al desarrollo de LH. La presente revisión tiene como objetivo analizar algunos de los factores de riesgo que influyen durante la interacción huésped, agente patógeno y medio ambiente en la etiología del LH.
Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkins cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.
Assuntos
Feminino , Humanos , Masculino , Infecções por Vírus Epstein-Barr/virologia , Interações Hospedeiro-Patógeno , /fisiologia , Doença de Hodgkin/virologia , Biomarcadores Tumorais , Transformação Celular Viral , DNA Viral/genética , Infecções por Vírus Epstein-Barr/imunologia , Regulação Viral da Expressão Gênica , /genética , /imunologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/epidemiologia , Evasão da Resposta Imune , Hospedeiro Imunocomprometido , Risco , Fatores de Risco , Células de Reed-Sternberg/virologia , Latência Viral , Proteínas Virais/fisiologiaRESUMO
The tumor microenvironment of classical Hodgkin lymphoma (cHL) is clearly responsible for the maintenance of the malignant Hodgkin-Reed-Sternberg (HRS) cells, and Epstein-Barr virus (EBV) has been shown to play a role in this immune evasion. EBV can increase the migration of CD4(+)CD25(+)FOXP3(+) lymphocytes, named regulatory T cells (Tregs). In this study, we assessed the distribution and biological significance of Tregs in patients with cHL. Tissue microarrays were constructed using diagnostic biopsies available in 130 cHL patients and stained with CD4, CD8, CD25, and FOXP3 antibodies. For the present study, only cHL patients whose histology could be confirmed and EBV association established were studied. From the 130 cHL patients selected for this study, 56 were classified as EBV-related and 74 EBV non-related cHL. There were no association between clinical characteristics and the expression of Tregs. However, higher levels of Tregs correlated with EBV presence on HRS cells (p = 0.02), although it did not influence event-free survival (EFS) and overall survival (p = 0.98 and p = 0.59, respectively). This study demonstrates that Tregs expression correlates with EBV presence in HRS cells and has no impact on survival of patients with cHL. Further studies investigating the mechanisms in which EBV recruits Tregs to the tumor microenvironment will contribute not only to our understanding on the pathogenesis of cHL but also to the development of new therapeutic strategies.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Doença de Hodgkin/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Criança , Intervalo Livre de Doença , Feminino , Herpesvirus Humano 4 , Doença de Hodgkin/mortalidade , Doença de Hodgkin/virologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Células de Reed-Sternberg/virologia , Análise Serial de Tecidos , Adulto JovemRESUMO
Intracranial and intraspinal involvement is a rare complication of Hodgkin's disease. We report a case of a patient with diagnosis of AIDS and Hodgkin's lymphoma who developed brain and spinal involvement at the time of the relapse of the neoplasm disease. Mixed cellularity histology was the subtype of Hodgkin's disease in our patient; we identified the Epstein-Barr virus genome in the Reed-Sternberg cells by immunohistochemistry and in situ hybridization.
Assuntos
Adulto , Humanos , Masculino , Síndrome da Imunodeficiência Adquirida/complicações , Neoplasias do Sistema Nervoso Central/complicações , Infecções por Vírus Epstein-Barr/complicações , Doença de Hodgkin/complicações , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Evolução Fatal , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Imuno-Histoquímica , Hibridização In Situ , Imageamento por Ressonância Magnética , Células de Reed-Sternberg/virologia , Tomografia Computadorizada por Raios XRESUMO
Intracranial and intraspinal involvement is a rare complication of Hodgkin's disease. We report a case of a patient with diagnosis of AIDS and Hodgkin's lymphoma who developed brain and spinal involvement at the time of the relapse of the neoplasm disease. Mixed cellularity histology was the subtype of Hodgkin's disease in our patient; we identified the Epstein-Barr virus genome in the Reed-Sternberg cells by immunohistochemistry and in situ hybridization.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Neoplasias do Sistema Nervoso Central/complicações , Infecções por Vírus Epstein-Barr/complicações , Doença de Hodgkin/complicações , Adulto , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Evolução Fatal , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Imuno-Histoquímica , Hibridização In Situ , Imageamento por Ressonância Magnética , Masculino , Células de Reed-Sternberg/virologia , Tomografia Computadorizada por Raios XRESUMO
We studied 40 cases of Hodgkin's disease (HD) from Costa Rica for evidence of Epstein-Barr virus (EBV) in the Reed-Sternberg and Hodgkin (RS-H) cells. We also compared the epidemiologic features of these patients with previous reports of HD in industrialized and developing nations. Because Costa Ricans enjoy a relatively higher standard of living than the residents of other developing Central American nations yet live in the same general geographic region and are genetically similar, we believed that this comparison might shed additional light on the hypothesis that the prevalence of EBV in HD and the epidemiologic factors of HD are influenced by socioeconomic factors. In 16 (40%) of 40 cases, immunohistochemical studies demonstrated that the RS-H cells were positive for EBV latent membrane protein (LMP), including 1 case of lymphocytic depletion analyzed, 12 (86%) of 14 cases of mixed cellularity, and 3 (15%) of 20 cases of nodular sclerosis. All five cases of lymphocytic predominance were negative. In the 16 EBV LMP-positive cases, polymerase chain reaction studies revealed that the virus was type A in 12 cases and type B in 4 cases. Nodular sclerosis was the most common type of HD, accounting for 20 cases (50%), followed by mixed cellularity, with 14 cases (35%). The relatively low prevalence of EBV in the RS-H cells of HD and the high incidence of nodular sclerosis in Costa Rica are similar to industrialized nations and are unlike HD in neighboring Central American countries. These findings further support the hypothesis that the prevalence of EBV in HD and the epidemiologic features of HD are most closely linked with socioeconomic conditions, and geographic location or ethnic heritage are of relatively less importance.