Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis
Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis
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DOI：
10.1007/s00109-005-0684-y
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Stewart, GJ
中科院分区：
文献类型：
--
作者：
Booth, DR;Arthur, AT;Stewart, GJ
多发性硬化症（MS）是中枢神经系统的一种神秘疾病，其导致具有脱髓鞘和轴突损伤的病理标志的硬化斑块，其可以由来自外周循环的细胞直接或间接地协调。大多数MS患者在疾病的早期阶段（RRMS）遵循复发-缓解过程，但大多数最终进入继发进展期（SPMS）。大约10%的患者从发病起就遵循初级进展过程（PPMS）。我们测量了患有和不患有慢性进行性MS（CPMS）、PPMS和SPMS的人的全血中的基因表达，以发现在活动性疾病中可能在外周血中差异表达的基因，从而鉴定具有病理意义的基因和途径;我们研究了与MS相关的基因组区域中编码的失调基因启动子的遗传差异。在对照组中，大多数失调基因的集合几乎没有重叠。核糖体蛋白基因的表达通常与细胞增殖和活化相关，与SPMS相比，在PPMS中的大多数下调基因中显著过度表达（P <10（-4，.2 χ（2））。T细胞增殖基因IL7R（CD127）在PPMS中也表达不足，但与对照相比在SPMS中上调。一种白细胞介素7受体（IL7R）启动子单核苷酸多态性（SNP）-504C在PPMS三重性中传递不足（P = 0.05，TDT），并且该等位基因的携带者在来自两个独立患者队列的PPMS病例中代表性不足（合并P = 0.006，FE）. 4种已知的IL 7R启动子单倍型在健康对照中的表达水平相似，但在CPMS中的表达水平不同（P <0.01，t检验）。这些数据支持PPMS与SPMS具有显著发病差异的假设，并且IL 7R可能是PPMS中有用的治疗靶点。
Multiple sclerosis ( MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing - remitting course in the early stages of the disease ( RRMS) but most ultimately enter a secondary progressive phase ( SPMS). About 10% of patients follow a primary progressive course from the onset ( PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS ( CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over- represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4),.2 chi(2)). The T cell proliferation gene IL7R ( CD127) was also underexpressed in PPMS, but was up- regulated in SPMS compared to the controls. One interleukin 7 receptor ( IL7R) promoter single nucleotide polymorphism ( SNP), - 504 C, was undertransmitted in PPMS trios ( P= 0.05, TDT), and carriers of this allele were under- represented in PPMS cases from two independent patient cohorts ( combined P= 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.