Prediagnostic Markers of Immune Activation and Viral Infection and Risk of NHL

免疫激活和病毒感染的诊断前标志物以及 NHL 风险

• 批准号: 7656801
• 负责人: OTONIEL MARTINEZ-MAZA
• 金额: $ 39.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656801
• 关键词: AIDS-Related Non-Hodgkin' s Lymphoma; Address; Adult; Antibodies; Appearance; Archives; B-Cell Activation; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological Markers; Cells; Chronic; DNA-Directed DNA Polymerase; Department of Defense; Development; Diagnosis; Diffuse; Disease; Environment; Epstein-Barr Virus Infections; Etiology; Event; Follicular Lymphoma; Generations; Genetic; Genome; Goals; Hodgkin Disease; Human Herpesvirus 4; Human Resources; IL6 gene; IgE; Immune System Diseases; Immune system; Immunity; Immunocompetent; Immunoglobulin Somatic Hypermutation; Immunologic Markers; Immunosuppression; Individual; Infection; Interleukin-10; Investigation; Lead; Lesion; Lymphomagenesis; Malignant Neoplasms; Minority; Molecular; Mutation; Neopterin; Nested Case-Control Study; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Pathogenesis; Pattern; Persons; Population; Positioning Attribute; Probability; Prospective Studies; Proteins; Recording of previous events; Research; Resources; Risk; Role; Sampling; Serum; Specimen; United States; Up-Regulation; Vaccination; Viral; Virus; Virus Diseases; activation-induced cytidine deaminase; critical period; cytokine; experience; gammaherpesvirus; immunosuppressed; insight; large cell Diffuse non-Hodgkin' s lymphoma; multidisciplinary; neoplastic cell; novel; repository; tumor; viral DNA

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the United States. Although the risk of developing NHL is greatly elevated in the setting of overt immunosuppression, the great majority of NHL, and in particular B cell NHL, occur in individuals who appear to be immunocompetent. Relatively little is known about the etiology of the B cell NHL that arise de novo in immunocompetent populations. Epstein-Barr virus (EBV), a B cell-tropic gamma-herpesvirus, is clearly implicated in the etiology of NHL in immunosuppressed individuals, with such tumors often having detectable clonal EBV DNA or gene products. However, only a minority (approximately 5%) of the NHL seen in presumably immunocompetent individuals are EBV genome-positive, and most of these are non-B cell NHL, so the role of EBV in the etiology of NHL in such individuals is less clear. The overall goal of this study is to determine whether an immune system environment that promotes chronic B cell stimulation, and/or results in poorly-controlled Epstein-Barr virus (EBV) infection, will lead to an increased risk of B cell NHL. Chronic B cell stimulation can increase the occurrence of B cell DNA-modifying activities, thereby increasing the probability for the generation of molecular errors (translocations or mutations of oncogenes) that initiate these cancers. Another mechanism that could promote such genetic errors is loss of immunoregulatory control of EBV infection, as EBV can promote lymphomagenesis by the infection and transformation of B cells, as well as via the up-regulation of the expression of molecules that induce somatic hypermutation and subsequent oncogene mutation. The specific aims of this study are: 1) determine if indicators of likely B-cell activation, including elevated serum levels of B cell-stimulatory cytokines and/or of molecules that are associated with B cell activation, are associated with the subsequent development of B cell NHL (diffuse large B cell lymphoma [DLBCL] and follicular lymphoma) in apparently immunocompetent individuals; 2) determine whether altered patterns of antibodies to EBV, consistent with reactivation of EBV, are seen preceding the development of B cell NHL (DLBCL and follicular lymphoma), and 3) define the temporal relationship between changes in these biomarkers and the development of DLBCL and follicular lymphoma. These aims will be addressed in a nested case-control study (approximately 600 incident B cell NHL cases and 600 matched controls) using serial pre-diagnosis serum specimens archived in the Department of Defense Serum Repository. Therefore, this investigation will provide a window on host and viral factors during the critical period of B cell NHL pathogenesis by repeated assessment of sequential specimens prior to diagnosis. Our approach is to assess a range of immunity- and EBV-related biomarkers in serial specimens, as a means of detecting "bio- footprints" leading to disease. These studies should provide valuable insight on the role of immune dysfunction and/or loss of immunoregulatory control of EBV infection on the development of B cell NHL.

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是美国第六大最常见的癌症。尽管在公开免疫抑制的情况下，发展NHL的风险大大升高，但在似乎具有免疫能力的个体中，大多数NHL，尤其是B细胞NHL的风险都大大升高。关于免疫能力人群中从头开始的B细胞NHL的病因相对鲜为人知。 EPSTEIN-BARR病毒（EBV）是B细胞 - 循环γ-HERPESVIRUS，在免疫抑制个体中明显与NHL的病因有关，这种肿瘤通常具有可检测的克隆EBV DNA或基因产物。但是，在可能是免疫能力的个体中，只有少数NHL（约5％）是EBV基因组阳性，其中大多数是非B细胞NHL，因此EBV在此类个体的病因中的作用不太清楚。这项研究的总体目标是确定促进慢性B细胞刺激的免疫系统环境和/或导致控制不良的爱泼斯坦 - 巴尔病毒（EBV）感染会导致B细胞NHL的风险增加。慢性B细胞刺激可以增加B细胞DNA修饰活性的发生，从而增加启动这些癌症的分子误差（易位或突变）的产生的可能性。可能促进这种遗传错误的另一种机制是对EBV感染的免疫调节控制的丧失，因为EBV可以通过B细胞的感染和转化来促进淋巴细胞的发生，以及通过诱导体细胞超成熟和随后的Oncogene突变的分子表达的上调。这项研究的具体目的是：1）确定可能B细胞激活的指标（包括与B细胞激活相关的B细胞刺激性细胞因子和/或分子的血清水平升高）与B细胞NHL的随后发展有关2）确定在B细胞NHL的发展（DLBCL和Follicular淋巴瘤）的发展之前，是否发现了与EBV重新激活的抗体的改变模式，以及3）定义这些生物标志物中的变化与DLBCL和DLBCL和Follicular淋巴瘤的变化之间的时间关系。这些目标将在使用串行诊断前血清标本存档的嵌套病例对照研究（大约600个事件B细胞NHL病例和600个匹配的对照）中解决。因此，这项研究将在B细胞NHL发病机理的关键时期通过在诊断之前重复评估顺序标本来提供有关宿主和病毒因子的窗口。我们的方法是评估串行标本中的一系列免疫力和与EBV相关的生物标志物，以检测导致疾病的“生物足迹”。这些研究应提供有关免疫功能障碍和/或对EBV感染对B细胞NHL发展的免疫调节控制的作用的宝贵见解。