The immunogenetics of Behçet's disease: A comprehensive review.
The immunogenetics of Behçet's disease: A comprehensive review.
复制标题
DOI：
10.1016/j.jaut.2015.08.013
复制
发表时间：
2015-11
影响因子：
12.8
通讯作者：
Remmers EF
中科院分区：
文献类型：
--
作者：
Takeuchi M;Kastner DL;Remmers EF
白塞病是一种慢性多系统炎性疾病，主要特征为复发性口腔溃疡、眼部受累、生殖器溃疡和皮肤病变，表现为缓解和加重。据认为，环境和遗传因素都有助于其发生和发展。虽然白塞病的病因尚不清楚，但最近的免疫遗传学发现为其发病机制提供了线索。除了40多年前发现的HLA-B*51的正相关性之外，最近的研究报告了主要组织相容性复合体I类区域的其他独立关联。HLA-B *15、-B*27、-B*57和-A*26是白塞病的独立危险因素，而HLA-B *49和- A*03是对白塞病有保护作用的独立I类等位基因。全基因组关联研究已经确定了在IL 23 R-IL 12 RB 2、IL 10、STAT 4、CCR 1-CCR 3、KLRC 4、ERAP 1、TNFAIP 3和FUT 2基因座中具有全基因组显著性（P < 5 × 10−8）的关联。此外，靶向的下一代测序揭示了IL 23 R、TLR 4、NOD 2和MEFV的罕见非同义变体参与白塞氏病的发病机制。与疾病易感基因座的风险等位基因相关的基因功能或mRNA表达的显著差异表明疾病相关基因座中的哪些基因影响疾病发病机制。这些基因包括先天性和适应性免疫，并证实了主要极化辅助性T细胞（Th）1与Th 2细胞的重要性，以及Th 17细胞的参与。此外，在HLA-B*51和内质网相关蛋白酶ERAP 1的风险编码单倍型之间观察到的上位性提供了一个线索，即基于HLA I类肽呈递的机制有助于这种复杂的疾病。
Behçet’s disease is a chronic multisystem inflammatory disorder characterized mainly by recurrent oral ulcers, ocular involvement, genital ulcers, and skin lesions, presenting with remissions and exacerbations. It is thought that both environmental and genetic factors contribute to its onset and development. Although the etiology of Behçet’s disease remains unclear, recent immunogenetic findings are providing clues to its pathogenesis. In addition to the positive association of HLA-B*51, which was identified more than four decades ago, and which has since been confirmed in multiple populations, recent studies report additional independent associations in the major histocompatibility complex class I region. HLA-B*15, -B*27, -B*57, and -A*26 are independent risk factors for Behçet’s disease, while HLA-B*49 and – A*03 are independent class I alleles that are protective for Behçet’s disease. Genome-wide association studies have identified associations with genome-wide significance (P < 5 × 10−8) in the IL23R–IL12RB2, IL10, STAT4, CCR1-CCR3, KLRC4, ERAP1, TNFAIP3, and FUT2 loci. In addition, targeted next-generation sequencing has revealed the involvement of rare nonsynonymous variants of IL23R, TLR4, NOD2, and MEFV in Behçet’s disease pathogenesis. Significant differences in gene function or mRNA expression associated with the risk alleles of the disease susceptibility loci suggest which genes in a disease-associated locus influence disease pathogenesis. These genes encompass both innate and adaptive immunity and confirm the importance of the predominant polarization towards helper T cell (Th) 1 versus Th2 cells, and the involvement of Th17 cells. In addition, epistasis observed between HLA-B*51 and the risk coding haplotype of the endoplasmic reticulum-associated protease, ERAP1, provides a clue that an HLA class I-peptide presentation-based mechanism contributes to this complex disease.