The immunogenetics of multiple sclerosis: A comprehensive review.
The immunogenetics of multiple sclerosis: A comprehensive review.
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DOI：
10.1016/j.jaut.2015.06.010
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发表时间：
2015-11
影响因子：
12.8
通讯作者：
Oksenberg JR
中科院分区：
文献类型：
--
作者：
Hollenbach JA;Oksenberg JR
多发性硬化症（MS）是一种中枢神经系统的慢性炎症性疾病，是年轻人非创伤性神经功能障碍的常见原因。个体发展MS的可能性受到她或他的种族背景和疾病家族史的强烈影响，这表明遗传易感性是风险的关键决定因素。超过100个位点与易感性密切相关，而主要信号基因组范围映射到人类白细胞抗原（HLA）基因簇的II类区域，并解释高达10.5%的遗传变异潜在风险。HLA-DRB 1 *15：01的作用最强，平均优势比为3.08。然而，复杂的等位基因层次谱系，顺/反单倍型效应，和独立的保护信号在I类区域的基因座已经被描述为以及。尽管对MS中的HLA区域进行了显著的分子解剖，但仍需要进一步的研究来产生统一的模型来解释MHC在疾病发病机制中的作用。由于发现了杀伤细胞免疫球蛋白样受体（KIR）和HLA等位基因与感染性、自身免疫性疾病、移植结果和妊娠的组合关联，多位点免疫基因组学研究现在蓬勃发展。KIR分子及其HLA配体是免疫系统的核心，对人类健康至关重要，由复杂的遗传系统编码，具有非常高的序列和结构变异水平以及复杂的表达模式。然而，迄今为止的研究在MS中的KIR已经很少，并限于非常低的分辨率基因分型。现代测序方法学的应用，结合最先进的生物信息学和分析方法，将使我们能够充分了解MS中HLA和KIR变异的影响。
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS.