Teuscher Cory, Bunn Janice Y, Fillmore Parley D, Butterfield Russell J, Zachary James F, Blankenhorn Elizabeth P
Immunobiology Program, C317 Given Medical Building, University of Vermont, Burlington, VT 05405, USA.
Am J Pathol. 2004 Nov;165(5):1593-602. doi: 10.1016/S0002-9440(10)63416-5.
Multiple sclerosis (MS), the principal inflammatory demyelinating disease of the central nervous system (CNS), is believed to have an immunopathological etiology arising from gene-environment interactions. In this study, we examined the effect of sex, age, and season at immunization on the susceptibility of (B10.S x SJL/J) F(2) intercross mice to experimental allergic encephalomyelitis (EAE), the foremost animal model of MS. Results of logistic regression analyses suggest that female mice were more likely to exhibit CNS lesions than male mice [odds ratio (OR) = 2.28 for brain lesions; OR = 2.37 for spinal cord (SC) lesions]. Although statistically significant associations were seen between brain and SC lesions and age at the time of injection or month of injection when examined separately; these associations disappeared when controlling for sex in multiple logistic regression analyses. These results suggest that the sex of the mouse is more important in influencing the development of brain and SC lesions than was either age or month of immunization. When examining clinical disease as the endpoint, the OR for the age at immunization is 1.04, indicating that the odds of being affected increase by 4% for each increasing week of age. When controlled for age, the OR for injection in the summer months (July through September) is 1.90, suggesting that the odds of being clinically affected are 90% greater for F(2) intercross animals injected in the summercompared to those injected in the winter to spring months (February through May). In contrast to CNS lesions, the age and season at immunization significantly and independently influenced susceptibility to clinical EAE and did so equally in both males and females. Linkage analysis to eae5, the H2-linked locus controlling susceptibility to clinical disease, was performed using 6- to 12- and >12-week-old cohorts as well as summer and winter/spring cohorts of F(2) mice. Significant linkage of clinical EAE to eae5 was observed with the 6- to 12-week-old and summer populations. In contrast, linkage of clinical EAE to eae5 was not detected with the >12-week-old and winter/spring populations. These results indicate that age and seasonal effects are capable of overriding eae5-dependent genetic control of susceptibility to clinical EAE and have significant implications for the genetics of MS.
多发性硬化症（MS）是中枢神经系统（CNS）主要的炎性脱髓鞘疾病，被认为具有由基因 - 环境相互作用引起的免疫病理病因。在本研究中，我们研究了性别、年龄以及免疫时的季节对（B10.S×SJL/J）F₂杂交小鼠对实验性自身免疫性脑脊髓炎（EAE）易感性的影响，EAE是MS最重要的动物模型。逻辑回归分析结果表明，雌性小鼠比雄性小鼠更易出现中枢神经系统病变[脑病变的优势比（OR）=2.28；脊髓（SC）病变的OR =2.37]。虽然单独检查时，脑和脊髓病变与注射时的年龄或注射月份之间存在统计学上的显著关联；但在多因素逻辑回归分析中控制性别后，这些关联消失了。这些结果表明，小鼠的性别在影响脑和脊髓病变的发展方面比免疫时的年龄或月份更重要。当以临床疾病作为终点进行检查时，免疫时年龄的OR为1.04，表明年龄每增加一周，受影响的几率增加4%。在控制年龄后，夏季（7月至9月）注射的OR为1.90，这表明与冬季至春季（2月至5月）注射的F₂杂交动物相比，夏季注射的动物出现临床症状的几率高90%。与中枢神经系统病变不同，免疫时的年龄和季节显著且独立地影响对临床EAE的易感性，并且在雄性和雌性中作用相同。使用6至12周龄和大于12周龄的队列以及F₂小鼠的夏季和冬季/春季队列，对控制临床疾病易感性的H2连锁基因座eae5进行连锁分析。在6至12周龄和夏季群体中观察到临床EAE与eae5之间存在显著连锁。相反，在大于12周龄和冬季/春季群体中未检测到临床EAE与eae5之间的连锁。这些结果表明，年龄和季节效应能够超越eae5依赖的对临床EAE易感性的遗传控制，并且对MS的遗传学具有重要意义。
