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。尽管在明显免疫抑制的情况下，发生NHL的风险大大增加，但绝大多数NHL，特别是B细胞NHL，发生在似乎具有免疫能力的个体中。相对而言，我们对免疫功能正常人群中B细胞NHL的病因知之甚少。eb病毒（EBV）是一种嗜B细胞的γ -疱疹病毒，它与免疫抑制个体的NHL病因学有明显关系，这类肿瘤通常具有可检测到的EBV克隆DNA或基因产物。然而，在假定具有免疫能力的个体中，只有少数（约5%）的NHL是EBV基因组阳性的，并且其中大多数是非b细胞NHL，因此EBV在这些个体中NHL病因学中的作用尚不清楚。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的风险增加。慢性B细胞刺激可增加B细胞dna修饰活性的发生，从而增加分子错误（致癌基因易位或突变）产生的可能性，从而引发这些癌症。另一种可能促进这种遗传错误的机制是EBV感染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，以及通过诱导体细胞超突变和随后的癌基因突变的分子表达上调来促进淋巴瘤的发生。本研究的具体目的是：1)确定是否可能的B细胞活化指标，包括血清中B细胞刺激细胞因子和/或与B细胞活化相关的分子水平升高，与明显免疫功能正常个体的B细胞NHL（弥漫性大B细胞淋巴瘤[DLBCL]和滤泡性淋巴瘤）的后续发展有关；2)确定EBV抗体模式的改变是否与EBV再激活一致，在B细胞NHL （DLBCL和滤泡性淋巴瘤）发生之前出现，3)确定这些生物标志物的变化与DLBCL和滤泡性淋巴瘤发生之间的时间关系。这些目标将在一项巢式病例对照研究（约600例B细胞NHL病例和600例匹配对照）中得到解决，该研究使用了国防部血清库中存档的一系列诊断前血清标本。因此，本研究将通过在诊断前对序列标本的重复评估，为了解B细胞NHL发病关键时期的宿主和病毒因素提供一个窗口。我们的方法是在一系列标本中评估一系列免疫和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。这些研究应该为eb病毒感染的免疫功能障碍和/或免疫调节控制缺失在B细胞NHL发展中的作用提供有价值的见解。

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.