Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice.
Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice.
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DOI：
10.1016/j.jaut.2011.05.001
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发表时间：
2011-09
影响因子：
12.8
通讯作者：
Mangalam AK
中科院分区：
文献类型：
--
作者：
Luckey D;Bastakoty D;Mangalam AK
多发性硬化症（MS）是一种中枢神经系统的炎性脱髓鞘自身免疫性疾病，具有遗传和环境易感性。在所有与MS易感性相关的遗传因素中，HLA-II类单倍型如DR 2/DQ 6、DR 3/DQ 2和DR 4/DQ 8显示出最强的关联。虽然HLA-DR等位基因在MS中的直接作用已被证实，但由于强烈的连锁不平衡，HLA-DQ等位基因在疾病发病机制中的作用一直难以理解。群体研究表明，DQ等位基因可能在MS的进展中发挥调节作用。为了更好地理解HLA-DR和-DQ基因对MS的易感性和抗性的机制，我们利用表达缺乏内源性小鼠II类基因的HLA II类基因的单转基因小鼠和双转基因小鼠。HLA II类转基因小鼠帮助我们在各种HLA-DR和-DQ分子的背景下识别PLP的免疫显性表位。我们已经证明，HLA-DR 3转基因小鼠对PLP 91 -110诱导的实验性自身免疫性脑脊髓炎（EAE）易感，而DQ 6（DQB 1 *0601）和DQ 8（DQB 1 *0302）转基因小鼠具有抗性。令人惊讶的是，DQ 6/DR 3双转基因小鼠具有抗性，而DQ 8/DR 3小鼠显示出比DR 3小鼠更高的疾病发病率和严重程度。DQ 6对DQ 6/DR 3小鼠的保护作用由IFNγ介导，而DQ 8分子的疾病加重作用由IL 17介导。此外，我们观察到髓鞘特异性抗体在HLA-DR 3DQ 8转基因小鼠中PLP 91 -110诱导的EAE中起重要作用。基于这些观察，我们假设HLA-DR和-DQ基因之间的上位相互作用在MS的易感性中起重要作用，我们的HLA转基因小鼠模型提供了一种新的工具来研究连锁不平衡在MS中的作用。
Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS has both, a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA-class II haplotypes such as DR2/DQ6, DR3/DQ2, and DR4/DQ8 show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP91-110 induced experimental autoimmune encephalomyelitis (EAE), while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL17. Further, we have observed that myelin-specific antibodies play an important role in PLP91-110 induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS.
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DOI：
10.1084/jem.183.6.2635
发表时间：
1996-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ito K;Bian HJ;Molina M;Han J;Magram J;Saar E;Belunis C;Bolin DR;Arceo R;Campbell R;Falcioni F;Vidović D;Hammer J;Nagy ZA
通讯作者：
Nagy ZA
影响因子：
3.3
作者：
LININGTON, C;ENGELHARDT, B;LASSMAN, H
通讯作者：
LASSMAN, H
影响因子：
9.8
作者：
Barcellos, LF;Oksenberg, JR;Hauser, SL
通讯作者：
Hauser, SL
影响因子：
4.4
作者：
Cross, AH;Stark, JL
通讯作者：
Stark, JL
影响因子：
4.4
作者：
Du, C;Sriram, S
通讯作者：
Sriram, S