Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.
Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.
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DOI：
10.1371/journal.pgen.1000369
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Knight JC
中科院分区：
文献类型：
--
作者：
Ramagopalan SV;Maugeri NJ;Handunnetthi L;Lincoln MR;Orton SM;Dyment DA;Deluca GC;Herrera BM;Chao MJ;Sadovnick AD;Ebers GC;Knight JC
多发性硬化症（MS）是一种复杂的性状，其中MHC II类区域的等位基因变异对遗传风险产生最强的影响。MS的流行病学数据提供了强有力的证据，表明环境因素在人群水平上影响这种疾病的不寻常的地理分布。越来越多的证据表明，阳光或维生素D是病因学中的一个关键环境因素。我们假设，这种环境的候选人可能与遗传因素相互作用，并寻求在MHC II类区域的响应调节元件。序列分析定位一个单一的MHC维生素D反应元件（VDRE）的HLA-DRB 1的启动子区。对来自HLA-DRB 1纯合子的超过1,000条染色体中的该启动子的测序显示，该推定的VDRE在HLA-DRB 1 *15单倍型上绝对保守。与此相反，有显着的变化之间的非MS相关单倍型。电泳迁移率变动分析显示，维生素D受体特异性募集到HLA-DRB 1 *15启动子中的VDRE，通过使用HLA-DRB 1 *15纯合子的淋巴母细胞的染色质免疫沉淀实验证实。使用荧光素酶报告基因测定的瞬时转染显示了该VDRE的功能作用。用HLA-DRB 1 *15基因启动子瞬时转染的B细胞在用1，25-二羟维生素D3刺激时表现出增加的表达（P = 0.002），该表达在缺失VDRE或在非MS相关HLA-DRB 1单倍型中发现的同源“VDRE”序列时均丧失。 流式细胞术分析显示，在添加维生素D后，仅在携带HLA-DRB 1 *15的淋巴母细胞样细胞中HLA-DRB 1的细胞表面表达特异性增加。这项研究进一步暗示维生素D作为一个强有力的环境候选人在MS显示直接的功能相互作用的主要基因座决定遗传易感性。这些发现支持了该病的主要流行病学和遗传特征之间的联系，对疾病机制和预防的研究具有重要的实际意义。多发性硬化症（MS）是一种复杂的神经系统疾病，具有很强的遗传成分。6号染色体上的主要组织相容性复合体（MHC）对疾病风险产生最强的遗传效应。MHC中HLA-DRB 1位点处或附近的区域影响MS的风险。HLA-DRB 1具有超过400种不同的等位基因。北方欧洲的主要单倍型，以DRB 1 *1501的存在为标志，使MS的风险增加3倍。环境在MS中也起着关键作用。最显著的例证是该疾病在与种族相匹配的人群中的地理分布。这导致了这样的建议，即阳光，特别是维生素D，是影响MS风险的环境因素。支持这一点的间接证据来自研究，表明维生素D参与免疫和神经系统功能。目前的研究试图揭示维生素D和HLA-DRB 1之间的任何关系。研究发现，维生素D与HLA-DRB 1 *1501特异性相互作用，影响其表达。因此，这项研究提供了更直接的支持，已经强大的流行病学证据表明，阳光和维生素D在确定MS的风险，并意味着在关键时期补充维生素D可能是预防疾病的关键。
Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention. Multiple Sclerosis (MS) is a complex neurological disease with a strong genetic component. The Major Histocompatibility Complex (MHC) on chromosome 6 exerts the strongest genetic effect on disease risk. A region at or near the HLA-DRB1 locus in the MHC influences the risk of MS. HLA-DRB1 has over 400 different alleles. The dominant haplotype of Northern Europe, marked by the presence of DRB1*1501, increases risk of MS by 3-fold. The environment also plays a key role in MS. The most striking illustration of this is the geographical distribution of the disease in populations matched for ethnicity. This has led to the proposal that sunshine, and in particular, vitamin D, is an environmental factor influencing the risk of MS. Circumstantial evidence supporting this comes from studies showing the involvement of vitamin D in immune and nervous system function. The current investigation sought to uncover any relationship between vitamin D and HLA-DRB1. It was found that vitamin D specifically interacts with HLA-DRB1*1501 to influence its expression. This study therefore provides more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention.
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影响因子：
30.8
作者：
Knight, JC;Keating, BJ;Kwiatkowski, DP
通讯作者：
Kwiatkowski, DP
影响因子：
4.5
作者：
Ramagopalan, Sreeram V.;Morris, Andrew P.;Ebers, George C.
通讯作者：
Ebers, George C.
影响因子：
14.5
作者：
HAMMOND, SR;MCLEOD, JG;MCCALL, MG
通讯作者：
MCCALL, MG
影响因子：
5
作者：
Kruger, A;Quack, P;Höhler, T
通讯作者：
Höhler, T
DOI：
10.1111/j.1600-0447.1960.tb08674.x
发表时间：
1960-01-01
期刊：
ACTA PSYCHIATR ET NEUROL SCAND SUPPL
影响因子：
--
作者：
ACHESON, E. D.;BACHRACH, C. A.;WRIGHT, F. M.
通讯作者：
WRIGHT, F. M.