Immunogenetics of leishmanial and mycobacterial infections: The Belem Family Study
Immunogenetics of leishmanial and mycobacterial infections: The Belem Family Study
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DOI：
10.1098/rstb.1997.0118
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发表时间：
1997-09-29
影响因子：
6.3
通讯作者：
Shaw, MA
中科院分区：
文献类型：
--
作者：
Blackwell, JM;Black, GF;Shaw, MA
在20世纪70年代和80年代，重组近交系，同源和重组单倍型小鼠品系的分析使我们能够有效地“扫描”小鼠基因组的基因控制利什曼原虫感染的抗性和易感性。基因组的五个主要区域涉及控制由不同利什曼原虫物种引起的感染，因为它们显示与人类基因组区域的保守共线性，立即为人类疾病易感基因提供候选基因区域。利什曼原虫和分枝杆菌病原体的共同巨噬细胞内生态位，以及相似的免疫反应谱和疾病表型，也导致预测相同的基因/候选基因区域可能负责分枝杆菌感染（如麻风病和结核病）的遗传易感性。事实上，其中一种鼠基因（Nramp 1）被鉴定为在控制一系列巨噬细胞内病原体（包括利什曼原虫、沙门氏菌和分枝杆菌感染）中的作用。在最近的研究中，内脏利什曼病和分枝杆菌疾病，结核病和麻风病，多病例的家庭数据，已从巴西东北部收集和分析，以确定这些候选基因/地区在确定疾病易感性的作用。复杂分离分析提供了一个或两个主基因控制结核病易感性的证据。基于家系的连锁分析（分离和连锁分析相结合;同胞对分析），它有能力检测候选基因区域中的标记位点与10-20厘摩以上的推定疾病易感基因之间的连锁，以及传递不平衡测试，它检测超过1厘摩的等位基因关联（约20厘摩）。1兆碱基），已被用于检查四个区域在确定疾病易感性和/或免疫应答表型中的作用。我们的结果表明：（一）主要组织相容性复合体（MHC：小鼠中的H-2，人中的HLA：小鼠染色体17/人6p;候选II类和III类，包括TNF α/β基因）显示与麻风病本身的连锁和等位基因关联，但仅与内脏利什曼病弱关联，并且既不显示与结核病的连锁也不显示与结核病的等位基因关联;（ii）没有证据表明NRAMP 1（小鼠巨噬细胞抗性基因Ity/Lsh/Bcg的定位克隆候选物）之间存在联系（小鼠染色体1/人2 q35），并且在该巴西人群中可以证明对结核病或内脏利什曼病的易感性;（iii）人类染色体17 q区域（候选NOS 2A，SCYA 2 -5）与小鼠11号染色体远端同源，最初被鉴定为携带控制对硕大利什曼原虫的愈合与非愈合反应的Sell基因，与结核病易感性相关;和（iv）控制鼠L.主要感染与人类疾病对三种感染中任何一种的易感性无关，但显示与对分枝杆菌抗原产生免疫应答的能力相关并具有高度显著的等位基因关联。这些研究表明，通过我们对人类感染免疫反应的了解，“小鼠对人”的策略可以识别出人体中重要的候选基因区域。
In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse chromosome 11, originally identified as carrying the Sell gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.