Molecular Epidemiology of AIDS-Associated Lymphoma

描述（由申请方提供）：非霍奇金B细胞淋巴瘤 （艾滋病淋巴瘤）在艾滋病毒感染者中的发生率大大提高， 不仅在北美和欧洲，而且在全世界。在这份报告中，研究 阐明艾滋病淋巴瘤的分子流行病学。的 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）在先前的研究中， 奖励，各种免疫系统分子的水平升高， B细胞活化，包括IL 6和IL 10、sCD 23、sCD 27、sCD 44和IgE， 在艾滋病淋巴瘤的临床检测之前看到。值得注意的是， 这种B细胞刺激因子的表达模式存在明显差异， 在不同亚型的艾滋病淋巴瘤中观察到的分子（Burkitt's/SNCCL vs. 其他亚型），这表明，有不同的特点， 免疫功能障碍，先于这些不同子集的发展， 癌的除此之外，在最近的工作中，我们看到， IL 10启动子（-592 C/C）中的单核苷酸多态性（SNP）， 已知导致IL 10表达增加，与 艾滋病淋巴瘤的发展。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。的具体目标 所提出的研究是为了确定：I）如果增强的B细胞刺激， 免疫球蛋白同种型转换活性升高，可检测到c-myc：IG基因 易位，和/或可检测到的循环B细胞与germ 中心样表型，先于艾滋病淋巴瘤的发展，2）如果SNP在 编码B细胞刺激性细胞因子（IL 6，IL 10，TNF α，LT α， RANTES）与以下疾病的发生风险升高相关： 艾滋病-淋巴瘤，以及3）如果受试者具有被认为是 与发展为艾滋病淋巴瘤（CCR 5 δ-32）的风险降低相关 杂合子，SDF-1 3 'UTR 801 G/G SNP，或IL 10启动子-592 A/A或A/C SNP） 显示较低水平的B细胞活化。这些具体的成就 aims将为我们对分子生物学的理解提供有价值的新信息。 艾滋病淋巴瘤的流行病学，以及免疫功能障碍在艾滋病中的作用。 这种癌症的产生和发展。这些信息可以构成 为今后研究艾滋病淋巴瘤的发病机制奠定了基础， 导致新的筛查技术，能够在早期发现艾滋病淋巴瘤， 肿瘤的发展过程，允许更早，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.