Analysis of genetic polymorphisms which effects on tuberculosis

影响结核病的基因多态性分析

基本信息

批准号：
12670428
负责人：
NAKASHIMA Hitoshi
金额：
$ 2.3万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

CD4+ helper T (Th) cells can be classified into two different subsets based on their patterns of cytokine production. Th1 cells produce mainly interferon-γ (IFN-γ) and interleukin-2 (IL-2) and promote cell-mediated immunity, whereas Th2 cells secreting IL-4, IL-5, IL-6 and IL-10, are associated with humoral immune responses and induce antibody production. It has been demonstrated that an imbalance between Th1 and Th2 cytokine production is very much concerned with the induction and development of several autoimmune diseases, a correction of this Th1/Th2 balance has in fact led to the prophylaxis and therapy of such diseases in various models of autoimmunity.Tuberculosis is the leading single infectious cause of death worldwide, claiming about 3 million lives annually, and approximately one-third of the world's population is infected with Mycobacterium tuberculosis. Twin, adoption and ethnic studies have indicated that host genetic differences in immune response may affect susceptibilit … More y to mycobacterial infection. Earlier genetic association studies have shown that severe pulmonary tuberculosis was associated with both HLA-DR2 and haptoglobin 2-2. Recently, other studies have revealed polymorphisms in the IL-1 locus, human NRAMP1 gene, vitamin D receptor gene, and HLA-DQ allele also contribute to susceptibility to tuberculosis.To date, genetic deficiencies in five genes involved in the type 1 cytokine cascade (IL-12p40, IFN-gR1, IFN-gR2, IL-12Rb1 and STAT1) have been shown to render hosts susceptible to poorly pathogenic mycobacteria, such as bacillus Calmette Guerin (BCG) and environmental nontuberculous mycobacteria (NTM). These reports highlighted the critical role of IFN-γ-mediated immunity in protection against intracellular pathogens. The absence of such key cytokine or cytokine receptors results in a dramatic clinical phenotype, usually lethal in early childhood, while more subtle polymorphisms which result in only partial impairment of the type-1 cytokine cascade may play a role in susceptibility to tuberculosis among the general population. Here we have searched for polymorphisms in both the β1 and β2 subunits of the IL-12 receptor. We then determined whether IL-12 receptor polymorphisms are associated with susceptibility to tuberculosis by performing a case-control study comparing the frequency of IL12RB1 genotypes in Japanese subjects with tuberculosis and healthy controls. We also confirmed the effect of human IL-12R polymorphisms on IL-12-induced biologic activities, using several functional assays. Less

CD4+辅助辅助剂T（Th）细胞可以根据其细胞因子的产生模式分为两个不同的子集。 Th1细胞主要产生干扰素-γ（IFN-γ）和白介素-2（IL-2）并促进细胞介导的免疫共同体，而分泌IL-4，IL-5，IL-6和IL-10的Th2细胞与体液中的体外免疫伴侣和影响抗体产生有关。已经证明，Th1和Th2细胞因子的产生之间的不平衡非常关注几种自身免疫性疾病的诱导和发展，对这种Th1/Th2平衡的纠正实际上已经导致了预防和治疗这些疾病的治疗，并在各种自身免疫性中造成了多种模型。世界人口中有三分之一感染结核分枝杆菌。双胞胎，采用和种族研究表明，免疫增强响应中的宿主遗传差异可能会影响敏感性……对分枝杆菌感染更大。较早的遗传关联研究表明，严重的肺结核与HLA-DR2和Haptoglobin 2-2均相关。最近，其他研究揭示了IL-1基因座，人NRAMP1基因，维生素D受体基因和HLA-DQ等位基因迄今为止的易感性，五个基因的遗传缺陷，涉及1型1型cytokine cascace（IL-12P40，IFN-GR1，IFN-GR1，IFN-GR1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1，IIL-1）也有助于易感性。易受致病性分枝杆菌的敏感，例如芽孢杆菌（BCG）和环境无结核分枝杆菌（NTM）。这些报告强调了IFN-γ介导的免疫力在防止病原体的保护中的关键作用。这种关键的细胞因子或细胞因子受体的缺乏会导致出色的临床表型，通常在幼儿时期致命，而更细微的多态性仅会导致1型细胞因子级联反应的部分损害可能在整个人群中对结核病的易感性中起作用。在这里，我们在IL-12受体的β1和β2亚基中搜索了多态性。然后，我们确定IL-12受体多态性是否与对结核病的敏感性有关，以比较在结核病和健康对照的日本受试者中IL12RB1基因型的频率。我们还使用多种功能测定法证实了人IL-12R多态性对IL-12诱导的生物学活性的影响。较少的