Molecular Epidemiology of AIDS-Associated Lymphoma

描述(申请人提供)：非霍奇金S B细胞淋巴瘤 (艾滋病-淋巴瘤)在艾滋病毒感染者中的发病率大大增加， 不仅在北美和欧洲，而且在世界范围内。在这项提案中，研究 是为了阐明艾滋病-淋巴瘤的分子流行病学。这个 拟议的研究将利用多中心艾滋病队列的资源 艾滋病自然史研究(MACS)。在以此为基础的先前研究中 获奖，各种免疫系统分子水平的提高与 B细胞活化，包括IL6和IL10、sCD23、sCD27、sCD44和IgE， 都是在临床检测到艾滋病淋巴瘤之前发现的。值得注意的是，有 这种刺激B细胞的表达模式明显不同 在不同亚型的艾滋病-淋巴瘤中发现的分子(Burkitt‘s/SNCCL vs. 其他亚型)，这表明在特征上存在差异 在这些不同亚群发展之前的免疫功能障碍 癌症。除此之外，在最近的工作中，我们看到一个 IL10启动子(-592C/C)的单核苷酸多态性(SNP)，这是 已知会导致IL10表达增加，与 艾滋病的发展--淋巴瘤。这些发现具有重要意义，因为 艾滋病-淋巴瘤的危险因素很少被确定。的具体目标 拟议的研究旨在确定：i)如果增强的B细胞刺激， 免疫球蛋白同型转换活性增强，可检测到c-myc：IG基因 易位和/或可检测到的带有生殖细胞的循环B细胞 中心样表型，先于艾滋病-淋巴瘤的发展，2)如果SNPs在 编码B细胞刺激细胞因子的基因(IL6、IL10、TNFα、LTalpha、 房租)与罹患高血压的风险升高有关 艾滋病-淋巴瘤，以及3)如果受试者的基因被认为是 与发生艾滋病-淋巴瘤的风险降低有关(CCR5 Delta-32 杂合子，SDF-1 3‘非编码区801G/G SNP，或IL10启动子-592 A/A或A/C SNP) 显示B细胞的激活水平较低。完成这些具体任务 AIMS将为我们对分子的理解增加有价值的新信息 艾滋病-淋巴瘤的流行病学，以及免疫功能障碍在 这种癌症的产生和生长。这些信息可能会形成 为未来研究艾滋病-淋巴瘤的发病机制奠定了基础，并可能 导致新的筛查技术能够在早期发现艾滋病-淋巴瘤 肿瘤发展的进程，允许更早和更有效的临床 干预。

DESCRIPTION (Provided by the applicant): Non-Hodgkin' s B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in HIV-infected people, not only in North America and Europe, but worldwide. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-lymphoma. The proposed studies will utilize the resources of the Multicenter AIDS Cohort Study of the Natural History of AIDS (MACS). In prior studies supported by this award, elevated levels of various immune system molecules that are associated with B cell activation, including IL6 and IL10, sCD23, sCD27, sCD44, and IgE, were seen prior to the clinical detection of AIDS-lymphoma. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-lymphoma (Burkitt's/SNCCL vs. other subtypes), suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, in very recent work we saw that a single-nucleotide polymorphism (SNP) in the IL10 promoter (-592 C/C), which is known to result in increased expression of IL10, was associated with the development of AIDS-lymphoma. These findings are of great significance, since few risk factors have been identified for AIDS-lymphoma. The specific aims of the proposed studies are to determine: I ) if enhanced B cell stimulation, elevated immunoglobulin isotype switch activity, detectable c-myc:Ig gene translocations, and/or detectable circulating B cells with a germinal center-like phenotype, precede the development of AIDS- lymphoma, 2) if SNPs in the genes encoding B cell-stimulatory cytokines (IL6, IL10, TNFalpha, LTalpha, RANTES) are associated with an elevated risk for the development of AIDS-lymphoma, and 3) if subjects who have a genotype that has been seen to be associated with a decreased risk for developing AIDS-lymphoma (CCR5 delta-32 heterozygotes, SDF-1 3'UTR 801 G/G SNP, or IL10 promoter -592 A/A or A/C SNP) show lower levels of B cell activation. The accomplishment of these specific aims will add valuable new information to our understanding of the molecular epidemiology of AIDS-lymphoma, as well as the role of immune dysfunction in the generation and growth of this cancer. This information could form the foundation for future studies on the pathogenesis of AIDS-lymphoma, and may lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier and more effective clinical intervention.