Mangalam Ashutosh K, Rajagopalan Govindarajan, Taneja Veena, David Chella S
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Adv Immunol. 2008;97:65-147. doi: 10.1016/S0065-2776(08)00002-3.
Population studies have shown that among all the genetic factors linked with autoimmune disease development, MHC class II genes on chromosome 6 accounts for majority of familial clustering in the common autoimmune diseases. Despite the highly polymorphic nature of HLA class II genes, majority of autoimmune diseases are linked to a limited set of class II-DR or -DQ alleles. Thus a more detailed study of these HLA-DR and -DQ alleles were needed to understand their role in genetic predisposition and pathogenesis of autoimmune diseases. Although in vitro studies using class-II restricted CD4 T cells and purified class II molecules have helped us in understanding some aspects of HLA class-II association with disease, it is difficult to study the role of class II genes in vivo because of heterogeneity of human population, complexity of MHC, and strong linkage disequilibrium among different class II genes. To overcome this problem, we pioneered the generation of HLA-class II transgenic mice to study role of these molecule in inflammatory disease. These HLA class II transgenic mice were used to develop novel in vivo disease model for common autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus, myasthenia gravis, celiac disease, autoimmune relapsing polychondritis, autoimmune myocarditis, thyroiditis, uveitis, as well as other inflammatory disease such as allergy, tuberculosis and toxic shock syndrome. As the T-cell repertoire in these humanized HLA transgenic mice are shaped by human class II molecules, they show the same HLA restriction as humans, implicate potential triggering mechanism and autoantigens, and identify similar antigenic epitopes seen in human. This review describes the value of these humanized transgenic mice in deciphering role of HLA class II molecules in immunopathogenesis of inflammatory diseases.
人群研究表明，在所有与自身免疫性疾病发生相关的遗传因素中，6号染色体上的MHC II类基因在常见自身免疫性疾病的家族聚集现象中占大多数。尽管HLA II类基因具有高度多态性，但大多数自身免疫性疾病与有限的一组II - DR或 - DQ等位基因相关。因此，需要对这些HLA - DR和 - DQ等位基因进行更详细的研究，以了解它们在自身免疫性疾病的遗传易感性和发病机制中的作用。虽然使用II类限制性CD4 T细胞和纯化的II类分子进行的体外研究有助于我们理解HLA II类与疾病关联的某些方面，但由于人群的异质性、MHC的复杂性以及不同II类基因之间强烈的连锁不平衡，很难在体内研究II类基因的作用。为了克服这个问题，我们率先培育了HLA - II类转基因小鼠，以研究这些分子在炎症性疾病中的作用。这些HLA II类转基因小鼠被用于开发常见自身免疫性疾病的新型体内疾病模型，如类风湿性关节炎、多发性硬化症、胰岛素依赖型糖尿病、重症肌无力、乳糜泻、自身免疫性复发性多软骨炎、自身免疫性心肌炎、甲状腺炎、葡萄膜炎，以及其他炎症性疾病，如过敏、结核病和中毒性休克综合征。由于这些人源化HLA转基因小鼠中的T细胞库由人类II类分子塑造，它们表现出与人类相同的HLA限制性，暗示潜在的触发机制和自身抗原，并识别在人类中可见的相似抗原表位。这篇综述描述了这些人源化转基因小鼠在解读HLA II类分子在炎症性疾病免疫发病机制中的作用方面的价值。
