TOXICOLOGY OF METAL INDUCED IMMUNOPATHOLOGY

描述：(改编自调查人员的摘要)。长期的 这个项目的目标是确定一种机制(S) 铅等环境因素与遗传因素相互作用影响 自身免疫性疾病的发病，如系统性红斑狼疮 (SLE)。已知系统性红斑狼疮的易感性受复杂的多基因控制 被认为受到环境因素的影响，能够 调节有遗传倾向的个体的免疫系统。这个 这项提案的目标是追求这样一种假设，即环境 毒物导致系统性红斑狼疮的触发和加重。焦点 将通过利用铅对系统性红斑狼疮易感性的影响 新西兰混合(NZM)系小鼠的一种新模型。这些重组人 近交系是从经典的nzb x的亲本菌株衍生而来的。 NZW F1杂交女性SLE模型；易感基因混合， 通过重组和分离从祖先基因组继承而来， 与肾炎、中枢神经系统狼疮等的表型差异有关 自身免疫表型。因此，NZM菌株提供了一种新的方法 观察环境对引发或加重系统性红斑狼疮的影响 在一组密切相关的易患狼疮的H-2相同菌株中。这部小说 优势是一些NZM菌株具有部分或低外显性 自身免疫可能比极端情况下的老鼠提供更多的信息 易感性或抵抗力。具体目标是：(1)确定 铅暴露对时间进程、严重程度、形态发生和 自身免疫复合体介导的肾炎和中枢神经系统的免疫病理学 具有高、部分和低外显率的选定NZM菌株的病理学。 (2)确定铅对小鼠B细胞自身免疫表现的影响 包括抗dsDNA和抗染色质菌株特定模式 自身抗体谱，库姆斯阳性(抗红细胞自身抗体)， 抗磷脂和B细胞亢进。(3)评估T细胞的激活 以及细胞因子谱(IL-2和IFNG与IL-4和IL-5)和附件 细胞因子水平(IL-1、IL-6和TNFa)和4评估参与 疾病调节中的荷尔蒙模式。拟议的研究将提供 铅对系统性红斑狼疮易感性影响的基本情况 在识别SLE时，具有可变数量的阈值易感基因 基因，以及对环境在多大程度上 影响自身免疫和自身免疫性疾病的因素。

DESCRIPTION: (Adapted from the investigator's abstract). The long-term goal of this project is to determine the mechanism(s) by which an environmental agent such as lead (Pb) interplays with genetics to influence the onset of an autoimmune disease such as Systemic Lupus Erythematosus (SLE). Susceptibility to SLE is known to be under complex polygenic control and is thought to be influenced by environmental agents capable of modulating the immune system of individuals with a genetic liability. The goal of this proposal is to pursue the hypothesis that environmental toxicants contribute to the triggering and exacerbation of SLE. The focus will be on the effects of Pb on susceptibility to SLE by taking advantage of a new model in New Zealand Mixed (NZM) strains of mice. These recombinant inbred strains were derived from the parental strains of the classic NZB x NZW Fl hybrid female SLE model; the mixtures of susceptibility genes, inherited from the ancestral genomes by recombination and segregation, contribute to phenotypic differences of nephritis, CNS lupus, and other autoimmune phenotypes. The NZM strains, therefore, offer a new way of looking at the effects of the environment on triggering or exacerbating SLE in a closely related set of lupus-prone, H-2 identical strains. The novel advantage is that some NZM strains with partial or low penetrance of autoimmunity may be more informative than mice at the extremes of susceptibility or resistance. The Specific Aims are: (1) determine the effects of Pb exposure on the time course, severity, morphogenesis, and immunopathology of autoimmune immune-complex-mediated nephritis and CNS pathology in selected NZM strains with high, partial, and low penetrance. (2) ascertain effects of Pb on manifestations of B-cell autoimmunity to include strain-specific patterns of anti-dsDNA and anti-chromatin autoantibody profiles, Coombs' positivity (anti-erythrocyte autoantibodies), anti-phospholipid, and B-cell hyperactivity. (3) assess T-cell activation and cytokine profiles (IL-2 and IFNg vs IL-4 and IL-5) and accessory cytokine levels (IL-1, IL-6 and TNFa) and 4 evaluate the involvement of hormonal patterns in disease modulation. The proposed research will provide basic information on the effects of Pb on SLE susceptibility in individuals with variable numbers of threshold liability genes, in identifying SLE genes, and a general understanding of the extent to which environmental factors may influence autoimmunity and autoimmune disease.