Abstract:
: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 PLP(91-110) 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 IL-17. Further, we have observed that myelin-specific antibodies play an important role in PLP(91-110) 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.
journal_name
J Autoimmunjournal_title
Journal of autoimmunityauthors
Luckey D,Bastakoty D,Mangalam AKdoi
10.1016/j.jaut.2011.05.001subject
Has Abstractpub_date
2011-09-01 00:00:00pages
122-8issue
2eissn
0896-8411issn
1095-9157pii
S0896-8411(11)00043-6journal_volume
37pub_type
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pub_type: 社论,历史文章
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of autoimmunity
pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1016/0896-8411(91)90030-g
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1016/j.jaut.2009.12.007
更新日期:2010-08-01 00:00:00
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1006/jaut.1999.0297
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pub_type: 杂志文章,评审
doi:10.1016/j.jaut.2012.01.014
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
doi:10.1006/jaut.2000.0479
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journal_title:Journal of autoimmunity
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1016/0896-8411(90)90148-l
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pub_type: 杂志文章,评审
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