Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis
Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis
复制标题
DOI：
10.1016/s0002-9440(10)64574-9
复制
发表时间：
2000-08-01
影响因子：
6
通讯作者：
Teuscher, G
中科院分区：
文献类型：
--
作者：
Butterfield, RJ;Blankenhorn, EP;Teuscher, G
实验性变态反应性脑脊髓炎(EAE)是中枢神经系统(CNS)主要炎症性疾病多发性硬化症(MS)的主要动物模型。尽管遗传学显然在多发性硬化症的易感性中发挥了作用，但识别潜在基因的尝试一直令人失望。MS患者在临床症状的严重性、脱髓鞘的机制和中枢神经系统损害的位置方面存在相当大的差异，这混淆了对遗传数据的解释。基于EAE易感基因座的位置，鼠-人共时定位方法可用于识别MS的候选易感基因座。到目前为止，已经确定了小鼠基因组中控制EAE易感性或临床症状的16个区域。在这项工作中，我们在对EAE敏感的SJL/J和抗EAE的B10.S/DvTe小鼠品系产生的F2杂交群体中检测了EAE组织病理损害的遗传控制。用复合区间作图法定位了10个数量性状基因座(QTL)，其中7个新发现的QTL控制与EAE相关的中枢神经系统病变的分布和严重程度，10号染色体上的QTL控制脑部病变，而第3、7和12号染色体上的QTL控制脊髓病变。此外，第2、9和11号染色体上的性二态QTL控制着雌性的中枢神经系统病变，而第10、11、12、16和19号染色体上的QTL控制着雄性的病变。我们的结果表明，EAE的中枢神经系统损害的严重程度和位置是受基因控制的，控制损害性质和严重程度的遗传成分可以受性别的影响。
Experimental allergic encephalomyelitis (EAE) is the principal genetically determined animal model for multiple sclerosis (MS), the major inflammatory disease of the central nervous system (CNS). Although genetics clearly play a role in susceptibility to MS, attempts to identify the underlying genes have been disappointing. Considerable variation exists between MS patients with regard to the severity of clinical signs, mechanism of demyelination, and location of CNS lesions, confounding the interpretation of genetic data. A mouse-human synteny mapping approach may allow the identification of candidate susceptibility loci for MS based on the location of EAE susceptibility loci. To date, 16 regions of the mouse genome have been identified that control susceptibility or clinical signs of EAE. In this work, we examined the genetic control of histopathological lesions of EAE in an F2 intercross population generated from the EAE susceptible SJL/J and EAE resistant B10.S/DvTe mouse strains. Composite interval mapping was used to identify 10 quantitative trait loci (QTL), including seven newly identified loci controlling the distribution and severity of CNS lesions associated with murine EAE, QTL on chromosome 10 control lesions in the brain, whereas QTL on chromosomes 3, 7, and 12 control lesions in the spinal cord. Furthermore, sexually dimorphic QTL on chromosomes 2, 9, and 11 control CNS lesions in females, whereas QTL on chromosomes 10, 11, 12, 16, and 19 control lesions in males. Our results suggest that the severity and location of CNS lesions in EAE are genetically controlled, and that the genetic component controlling the character and severity of the lesions can be influenced by sex.