Heavy Metal-Induced Autoimmunity

重金属引起的自身免疫

• 批准号: 6744149
• 负责人: DWIGHT H KONO
• 金额: $ 37.04万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744149
• 关键词: autoimmune disorder; disease /disorder model; environmental toxicology; genetic susceptibility; immunogenetics; laboratory mouse; linkage mapping; mercury poisoning

DESCRIPTION (Applicant's Abstract): Although evidence indicates that environmental factors play a major role in precipitating systemic in genetically susceptible individuals, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae including lymphoproliferation, hypergammaglobulinemia and overt systemic autoimmunity. Predisposition to such metal-induced immunopathology has been shown, in mice and other experimental animals, to be influenced by both MHC and non-MHC genes, as well susceptibility to spontaneous lupus. Among the various mouse strains examined thus far, the DBA/2 appears to be the only background that is not susceptible to mercury-induced autoimmunity (HgIA) despite expressing a susceptible H-2 haplotype (H-2d). To define the genetic basis for this trait, two genome-wide scans were conducted in F2 intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are susceptible to HgIA. A single major quantitative trait locus (QTL) on chromosome 1, designated Hmr1, was the only region identified in common in both crosses. The aims of this proposal are to define the role of Hmr1 in heavy metal-induced and spontaneous autoimmunity using reciprocal interval-specific congenic strains and to dissect the Hmr1 interval by more precisely mapping linked traits. Mapping studies will determine whether Hmr1 represents one or more genetic alterations, examine the relationship of Hmr1 to a previously defined NZB QTL on chromosome I (Lbw7) and reduce the interval containing Hmr1 to less than one centimorgan (cM). Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury induced autoimmunity should provide important insights on the pathogenesis of autoimmunity and may reveal novel targets for intervention.

描述（申请人的摘要）：尽管证据表明 环境因素在促进全身性的主要作用 遗传易感的个体，对这些机制知之甚少 涉及。某些重金属，例如汞，是有效的环境 产生多种免疫病理后遗症的免疫刺激剂，包括 淋巴细胞增生，高γ-球蛋白血症和明显的全身自身免疫性。 在小鼠中已经表明了这种金属诱导的免疫病理学的易感性 和其他实验动物，受MHC和非MHC基因的影响， 以及对自发狼疮的敏感性。在各种小鼠菌株中 迄今为止检查的DBA/2似乎是唯一的背景 易受汞引起的自身免疫（HGIA） 易感H-2单倍型（H-2D）。为了定义该特征的遗传基础， 在DBA/2菌株的F2间交叉中进行了两次全基因组扫描 使用SJL或NZB菌株，两者都容易受到HGIA的影响。一个 染色体1上的单个主要定量性状基因座（QTL），指定为HMR1， 是两个十字架中唯一共有的区域。这个目的 提案是定义HMR1在重金属引起的和自发中的作用 使用互惠间隔特定的先天性菌株使用自身免疫性并剖析 HMR1间隔通过更精确映射的链接性状。映射研究将 确定HMR1是否代表一种或多种遗传改变，检查 HMR1与先前定义的NZB QTL在染色体I（LBW7）和 将包含HMR1的间隔减少到少于1厘米（CM）。 识别和表征敏感性/抗性基因和 与汞诱导自身免疫性的免疫发育相关的机制 应该提供有关自身免疫发病机理的重要见解，并且可能 揭示干预的新颖目标。