Butterfield R J, Blankenhorn E P, Roper R J, Zachary J F, Doerge R W, Teuscher C
Department of Veterinary Pathobiology, The University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Am J Pathol. 2000 Aug;157(2):637-45. doi: 10.1016/S0002-9440(10)64574-9.
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.
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症（MS）的主要遗传决定动物模型，MS是中枢神经系统（CNS）的主要炎症性疾病。虽然遗传学显然在MS易感性中起作用，但识别潜在基因的尝试一直令人失望。MS患者在临床体征严重程度、脱髓鞘机制和CNS病变位置方面存在相当大的差异，这使得对遗传数据的解释变得复杂。小鼠-人类同线性图谱绘制方法可能有助于根据EAE易感基因座的位置识别MS的候选易感基因座。迄今为止，已在小鼠基因组中确定了16个区域，这些区域控制EAE的易感性或临床体征。在这项研究中，我们在由EAE易感的SJL/J和EAE抗性的B10.S/DvTe小鼠品系产生的F2杂交群体中研究了EAE组织病理学病变的遗传控制。采用复合区间作图法鉴定了10个数量性状基因座（QTL），包括7个新鉴定的控制与小鼠EAE相关的CNS病变分布和严重程度的基因座。第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号染色体上的性别二态性QTL控制雌性的CNS病变，而第10、11、12、16和19号染色体上的QTL控制雄性的病变。我们的结果表明，EAE中CNS病变的严重程度和位置受遗传控制，并且控制病变特征和严重程度的遗传成分可受性别影响。
