HLA-DQB1*0602 Determines Disease Susceptibility in a New "Humanized" Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice
HLA-DQB1*0602 Determines Disease Susceptibility in a New "Humanized" Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice
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DOI：
10.4049/jimmunol.0900784
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Ben-Nun, Avraham
中科院分区：
文献类型：
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作者：
Kaushansky, Nathali;Altmann, Daniel A.;Ben-Nun, Avraham
多发性硬化症（MS）是一种主要针对中枢神经系统髓鞘的慢性神经系统自身免疫性疾病，其易感性长期以来一直与HLA II类基因相关。尽管已经鉴定了其他几种HLA和非HLA疾病易感等位基因，但RLA-DR 15单倍型的等位基因（DRB 1 *1501、DRB 5 *0101和DQB 1 *0602）仍然是最强的易感因素。许多研究表明，HLA-DRB 1 *1501等位基因决定MS相关的易感性。然而，由于HLA 11类区域内的强烈连锁不平衡，很难明确地确定DRB 1 *1501和DQB 1 *0602产物的相对作用。在这项研究中，我们使用HLA II类转基因小鼠照亮DRB 1 *1501和DQB 1 *0602等位基因或其组合的相对贡献，对一种新的“人源化”MS样疾病的髓鞘相关少突碱性蛋白（MOBP）诱导的易感性。尽管许多免疫学研究主要集中在HLA-DRB 1 *1501产物在MS中的作用上，但我们表明HLA-DRB 1 *1501转基因对MOBP疾病诱导是难治的，而HLA-DQB 1 *0602转基因通过对MOBP 15 -36和MOBP 55 -77致脑炎表位反应的T细胞是易感的。尽管两种转基因小鼠均与这些表位反应，但MOBP 15 -36-和MOBP 55 -77-反应性T细胞在HLA-DRB 1 *1501转基因小鼠中为Th 2型，在HLA-DQB 1 *0602转基因小鼠中为致病性Th 1/Th 17细胞。MS的这种新的人源化模型进一步暗示了针对MS发病机制中的MOBP的自身免疫，提供了致病性HLA-DQ相关的抗髓鞘自身免疫的第一个证据，并且是第一个提供HLA-DQB 1 *0602与MS相关的基本原理的。这些发现对DQB 1 * 0602等位基因作为MS的遗传风险因素的候选资格具有重要意义。The Journal of Immunology，2009，一百八十三：3531-3541.
The susceptibility to multiple sclerosis (MS), a chronic neurological autoimmune disease that primarily targets CNS myelin, has long been associated with HLA class-II genes. Although several other HLA and non-HLA disease predisposing alleles have been identified, alleles of the RLA-DR15 haplotype (DRB1*1501, DRB5*0101, and DQB1*0602) remain the strongest susceptibility factor. Many studies have suggested that the HLA-DRB1*1501 allele determines MS-associated susceptibility. However, due to strong linkage disequilibrium within the HLA class 11 region, it has been difficult to unequivocally determine the relative roles of the DRBI*1501 and DQB1*0602 products. In this study we use HLA class-II transgenic mice to illuminate the relative contributions of the DRB1*1501 and DQB1*0602 alleles or their combination to susceptibility toward a new "humanized" MS-like disease induced by myelin-associated oligodendrocytic basic protein (MOBP). Although many immunological studies have focused overwhelmingly on the role of the HLA-DRB1*1501 product in MS, we show that HLA-DRB1*1501 transgenics are refractory to MOBP disease induction, whereas the HLA-DQB1*0602 transgenics are susceptible via T cells reactive against MOBP15-36 and MOBP55-77 encephalitogenic epitopes. Although both transgenics react against these epitopes, the MOBP15-36- and MOBP55-77-reactive T cells are of Th2-type in HLA-DRB1*1501 transgenics and are pathogenic Th1/Th17 cells in the HLA-DQB1*0602 transgenic mice. This new humanized model of MS further implicates autoimmunity against MOBP in MS pathogenesis, provides the first evidence of pathogenic HLA-DQ-associated anti-myelin autoimmunity, and is the first to offer a rationale for HLA-DQB1*0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for MS. The Journal of Immunology, 2009, 183: 3531-3541.