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

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是美国第六大常见癌症。尽管在明显的免疫抑制的情况下发生NHL的风险大大升高，但绝大多数NHL，特别是B细胞NHL，发生在似乎具有免疫活性的个体中。对于免疫活性人群中新发的B细胞NHL的病因学知之甚少。Epstein-Barr病毒（EBV），一种亲B细胞的γ-疱疹病毒，在免疫抑制的个体中明显地与NHL的病因学有关，这种肿瘤通常具有可检测的克隆EBV DNA或基因产物。然而，只有少数（约5%）的NHL中看到的假定免疫功能正常的个人是EBV基因组阳性，其中大部分是非B细胞NHL，所以在这种个人的NHL的病因EBV的作用是不太清楚。本研究的总体目标是确定促进慢性B细胞刺激和/或导致控制不良的EB病毒（EBV）感染的免疫系统环境是否会导致B细胞NHL风险增加。慢性B细胞刺激可增加B细胞DNA修饰活性的发生，从而增加产生引发这些癌症的分子错误（致癌基因的易位或突变）的可能性。另一种可能促进这种遗传错误的机制是EBV感染的免疫调节控制的丧失，因为EBV可以通过感染和转化B细胞以及通过上调诱导体细胞超突变和随后的癌基因突变的分子的表达来促进淋巴瘤发生。本研究的具体目的是：1）确定可能的B细胞活化的指标，包括升高的B细胞刺激性细胞因子和/或与B细胞活化相关的分子的血清水平，是否与B细胞NHL的后续发展相关（弥漫性大B细胞淋巴瘤[DLBCL]和滤泡性淋巴瘤）明显免疫活性个体; 2）确定在B细胞NHL（DLBCL和滤泡性淋巴瘤）的发展之前是否观察到与EBV的再活化一致的针对EBV的抗体的改变模式，和3）定义这些生物标志物的变化与DLBCL和滤泡性淋巴瘤的发展之间的时间关系。这些目标将在巢式病例对照研究（约600例偶发B细胞NHL病例和600例匹配对照）中使用国防部血清储存库中存档的系列诊断前血清标本进行阐述。因此，这项研究将提供一个窗口，宿主和病毒因素在关键时期的B细胞NHL发病机制的反复评估连续标本诊断前。我们的方法是评估系列标本中一系列免疫和EBV相关的生物标志物，作为检测导致疾病的“生物足迹”的一种手段。这些研究应该提供有价值的洞察力的作用，免疫功能障碍和/或免疫调节控制的EBV感染的B细胞NHL的发展。

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.