IL-7RA调控IL-7R/TSLPR信号传导通道对MS易感性的影响

Multiple sclerosis (MS) is the most common chronic neurologic disease of young adults, affecting more than 2 million people worldwide. Extensive studies of population genetics have shown a major heritable component to the disease. Human leukocyte antigen gene (HLA)has the strongest association with multiple sclerosis (MS) susceptibility in both Caucasians and Asians, while several genome-wide survey identified non-HLA genes that are also related to MS susceptibility from 2007. Among these, the interleukin-7 receptor alpha gene (IL-RA)has been widely studied. We have investigated the association of IL-RA polymorphisms with MS susceptibility in Japanese and first report this association in Asians(2010, Neurology). We also found that rs6897932, this polymorphisms is a much stronger risk factor for MS in Asians than in Caucasians. Therefore, it is very important to illustrate the mechinism that IL-7RA affects MS susceptibility. Transcription of the gene produces two dominant isoforms, with or without exon 6, which code for membrane-bound or soluble IL-7Rα, respectively. The decreased expression of membrane-bound IL-7Rα cause decreased IL-7R/TSLPR signaling. IL-7 and thymic stromal lymphopoietin (TSLP) are critical for Treg/Th1/ Th2/ Th17 proliferation, maturation and differentiation. Most resting lymphocytes express the IL-7 receptor, which is composed of the IL-7R a-chain and the common cytokine g-chain. Basal responsivness of naı¨ve subsets to IL-7 is important for their sustained survival and facilitates homeostatic cycling and differentiation of recent thymic emigrant (RTE). Expression levels of membrane-bound IL-7Ra (CD127) on conventional CD4+T cells correlate with frequencies of recent thymic emigrant (RTE)- CD4+T cells in healthy individuals and HIV-infected patients as well as in patients with MS. Proportions of RTE-Treg are critical for the function of total Treg. The secretion of TSLP by Hassall’s corpuscles has been demonstrated to condition CD11c+myeloid dendritic cells (MDCs) to induce the differentiation of thymocytes into Treg. In multiple sclerosis (MS), requencies of RTE-Treg are reduced and the disparity between RTE-Treg and long-lived memory Treg coincides with the MS-associated Treg defect. Altered signaling through their receptors (IL-7R), TSLP receptor (TSLPR), sharing the IL-7Ra-chain (IL-7R a), might contribute to impaired Treg development and altered Th1/ Th2/ Th17 homeostasis.Therefore, in the present study, we try to prove the hypothesis above. we assessed IL-7R a-expression on conventional T cells; frequencies, phenotypes and suppressive activities of Treg, plasma levels of IL-7 and soluble IL-7Rα; frequencies of Th1/Th2/Th17 and screened for MS-associated IL-7RA gene polymorphism rs6897932. We suggest that altered IL-7R/TSLPR signaling contributes to impaired Treg neogenesis in MS, which is compensated by expanded memory-Treg and altered Th1/ Th2/ Th17 homeostasis, finally results in dysimmunity

多发性硬化(MS)发病机制迄今尚不明确。IL-7RA是继HLA之后又一个MS易感基因。本研究者在日本完成了首次亚洲MS人群的IL-7RA基因筛查，证实MS易感性与rs6897932多态性位点密切相关，且对亚洲人群易感性的影响远大于欧美人群，甚至超过HLA基因。其原因可能与该位点改变可溶性IL-7R比例，触发IL-7R/TSLPR受体通道功能变化，引起一系列由初始CD4+T淋巴细胞为开端的功能性T淋巴细胞的分化与成熟发生改变，打破Th1/Th2/Th17/Treg稳态平衡，导致MS。本研究采用病例对照研究，通过测定病例与对照组可溶性IL-7Rα在体内的表达水平、CD4+T细胞分化的各功能性T淋巴细胞功能活性等免疫学方法，分析Th1/Th2/Th17/Treg平衡理论的合理性，并结合基因筛查结果，力图揭示IL-7RA基因多态性影响MS易感性的免疫途径，为深入阐明亚洲人群MS发病机制提供崭新方向