Wilder R L, Griffiths M M, Cannon G W, Caspi R, Remmers E F
Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bldg. 10, Room 9N240, Bethesda, Maryland 20892, USA.
Ann N Y Acad Sci. 2000;917:784-96. doi: 10.1111/j.1749-6632.2000.tb05444.x.
DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP)-induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.
DA和LEW近交系大鼠对多种实验性自身免疫性疾病异常敏感。这些疾病包括类风湿性关节炎模型，如胶原诱导的关节炎（CIA）和佐剂诱导的关节炎（AIA）；多发性硬化症模型，如髓鞘碱性蛋白（MBP）诱导的实验性自身免疫性脑脊髓炎（MBP-EAE）；以及自身免疫性葡萄膜炎模型，如视网膜S抗原（SAG）和光感受器间类视黄醇结合蛋白（IRBP）诱导的实验性自身免疫性葡萄膜炎（分别为SAG-EAU和IRBP-EAU）。DA和LEW大鼠对各种滥用药物也容易上瘾，如可卡因。此外，它们表现出多种行为和生化特征，这些特征似乎与它们对成瘾的易感性有关。相比之下，F344和BN大鼠表现出截然不同的表型。它们对CIA、AIA、MBP-EAE、SAG-EAU和IRBP-EAU相对有抵抗力，并且对成瘾也相对有抵抗力。有趣的是，与F344和BN大鼠相比，DA和LEW大鼠下丘脑-垂体-肾上腺（HPA）轴功能均存在异常。例如，DA和LEW大鼠皮质类固醇的昼夜分泌非常异常；也就是说，它们的皮质酮水平昼夜变化极小。由于皮质类固醇可能对免疫功能和自身免疫性疾病易感性有重大影响，也可能影响对滥用药物的敏感性，我们已开始剖析这些不同表型差异的遗传控制，最初重点关注自身免疫性疾病表达的调控。使用涉及DA×F344（CIA和AIA）、DA×BN（CIA）以及LEW×F344[IRBP-EAU和链球菌细胞壁关节炎（SCWA）]的F2杂交的全基因组扫描技术，我们迄今已确定了14个调节这些杂交中疾病表达的基因组区域[数量性状基因座（QTL）]。涉及这些基因座的QTL同源基因大鼠的培育和分析正在进行中，这将使我们能够研究自身免疫性疾病易感性、药物成瘾以及HPA轴和应激反应功能之间的关系。然而，这些初步数据表明，自身免疫性疾病性状的遗传控制非常复杂。
