Mattapallil Mary J, Sahin Azize, Silver Phyllis B, Sun Shu-Hui, Chan Chi-Chao, Remmers Elaine F, Hejtmancik J Fielding, Caspi Rachel R
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
J Immunol. 2008 May 15;180(10):6751-9. doi: 10.4049/jimmunol.180.10.6751.
Uveitis is a complex multifactorial autoimmune disease of the eye characterized by inflammation of the uvea and retina, degeneration of the retina, and blindness in genetically predisposed patients. Using the rat model of experimental autoimmune uveitis (EAU), we previously identified three quantitative trait loci (QTL) associated with EAU on rat chromosomes 4, 12, and 10 (Eau1, Eau2, and Eau3). The primary goal of the current study is to delineate additional non-MHC chromosomal regions that control susceptibility to EAU, and to identify any QTLs that overlap with the QTLs of other autoimmune diseases. Using a set of informative microsatellite markers and F(2) generations of resistant and susceptible MHC class II-matched rat strains (F344 and LEW), we have identified several new significant or suggestive QTLs on rat chromosomes 2, 3, 7, 10, and 19 that control susceptibility to EAU. A protective allele was identified in the susceptible LEW strain in the Eau5 locus at D7Wox18, and epistatic interactions between QTLs were found to influence the severity of disease. The newly identified regions (Eau4 through Eau9) colocalize with the genetic determinants of other autoimmune disease models, and to disease-regulating syntenic regions identified in autoimmune patients on human chromosomes 4q21-31, 5q31-33, 16q22-24, 17p11-q12, 20q11-13, and 22q12-13. Our results suggest that uveitis shares some of the pathogenic mechanisms associated with other autoimmune diseases, and lends support to the "common gene, common pathway" hypothesis for autoimmune disorders.
葡萄膜炎是一种复杂的多因素自身免疫性眼病，其特征为葡萄膜和视网膜炎症、视网膜变性，以及在具有遗传易感性的患者中导致失明。利用实验性自身免疫性葡萄膜炎（EAU）大鼠模型，我们之前在大鼠4号、12号和10号染色体上鉴定出了3个与EAU相关的数量性状基因座（QTL）（Eau1、Eau2和Eau3）。本研究的主要目标是描绘出其他控制EAU易感性的非MHC染色体区域，并识别出与其他自身免疫性疾病的QTL重叠的任何QTL。使用一组信息丰富的微卫星标记以及抗性和易感性MHC II类匹配大鼠品系（F344和LEW）的F(2)代，我们在大鼠2号、3号、7号、10号和19号染色体上鉴定出了几个控制EAU易感性的新的显著或提示性QTL。在D7Wox18的Eau5基因座的易感LEW品系中鉴定出了一个保护性等位基因，并且发现QTL之间的上位相互作用会影响疾病的严重程度。新鉴定出的区域（Eau4至Eau9）与其他自身免疫性疾病模型的遗传决定因素共定位，并且与在人类4号染色体4q21 - 31、5号染色体5q31 - 33、16号染色体16q22 - 24、17号染色体17p11 - q12、20号染色体20q11 - 13和22号染色体22q12 - 13上的自身免疫性患者中鉴定出的疾病调节同线区域共定位。我们的结果表明，葡萄膜炎与其他自身免疫性疾病共享一些致病机制，并支持自身免疫性疾病的“共同基因，共同途径”假说。
