AhR在重症肌无力发病机制中的作用

Myasthenia gravis (MG) is a B-cell-mediated, T-cell-dependent autoimmune disease characterized by excessive muscle weakness and fatigue.The disequilibrium of the CD4+ helper T-cell subsets could determine the outcome of the disease and have an important role in the pathogenesis of MG. Studies have shown that the aryl hydrocarbon receptor (AhR) play an important role in the regulation of CD4 + helper T-cells differentiation, but how the AhR to play a role in the MG has not been confirmed. This is for our further discuss MG mechanism study and put forward the new subject. This raises new issues for us to further investigate the mechanism study of MG. In previous work, we have successfully established EAMG（experimental autoimmune myasthenia gravis） experimental animal model and found that the Th subsets pattern changed during the disease process. This further confirms that the AhR involved in EAMG, lays a solid foundation to clarify the relationship between AhR and MG. Taking MG and EAMG as the research object through the immunoloy, molecular, cell biology and pathology methods.The role of AhR in MG/EAMG occurrence and development. Mainly demonstrate the effect of AhR on the differentiation and specific ways of CD4+ helper T-cells.Objective to explore the effect and mechanisms of AhR on B cells.To solve these problems is not only enrich the content of MG pathogenesis, great significance to the clinical target treatment of MG, but also linked the environmental pollution factors and autoimmune diseases together.

重症肌无力（MG）是B细胞介导的T细胞依赖的自身免疫性疾病的研究范例， CD4+T细胞亚型之间的平衡变化决定了疾病的结局，在MG的发病机制中有重要的作用。有研究指出芳香烃受体（AhR）在调节CD4+T细胞分化过程中发挥重要作用，但AhR在MG中如何发挥作用未有人证实，这为我们进一步探讨MG机制研究提出新的课题。我们在前期工作中已成功建立实验性自身免疫性重症肌无力（EAMG）动物模型，并发现疾病的不同进程Th亚群格局发生改变，为进一步研究AhR与MG/EAMG的关系打下坚实的基础。本课题以MG/EAMG为研究对象，通过免疫、分子和细胞生物及病理学为手段明确：AhR在MG/EAMG发生、发展中的作用；阐明AhR对CD4细胞亚型分化的影响及具体途径；探讨AhR对B细胞的作用及具体机制。这些问题的解决不仅丰富MG发病机制的内容，对临床靶点治疗MG意义重大，还将环境污染因素与自身免疫的发生联系起来

重症肌无力（MG）是B细胞介导的T细胞依赖的自身免疫性疾病的研究范例， CD4+T细胞亚型之间的平衡变化决定了疾病的结局，在MG的发病机制中有重要的作用。有研究指出芳香烃受体（AhR）在调节CD4+T细胞分化过程中发挥重要作用，但AhR在MG中如何发挥作用未有人证实，这为我们进一步探讨MG机制研究提出新的课题。在前期的工作中我们成功的建立了实验性重症肌无力模型（EAMG）；检测发病早期和慢性期的Th亚群比例，发现发病早期CFA 组与 EAMG 组的各亚型比例之间没有差异。随着疾病的进展，在发病的慢性期可见，Th亚群的比例改变，促炎的Th1细胞和Th17细胞比例明显增加，抑炎的Th2细胞和 Treg细胞的比例明显降低。在此基础上，我们经过3年的科研工作，如期完成了相关课题内容，得到以下相关实验结果： 1. 随着疾病进展，AhR的表达水平逐渐上升，在EAMG的发生、发展中呈动态变化；2. 体内注射AhR激动剂，检测活化AhR后对EAMG疾病的影响，结果发现体液免疫和病理变化都得到改善，说明激活AhR后对EAMG的发生、发展能起到预防和缓解的作用；3. 体内注射AhR激动剂可影响EAMG的Th亚群比例的改变，促炎的Th17细胞比例下降，抑炎的Treg细胞比例上升；4. AhR通过影响STAT3/STAT5途径调节AChR特异的Th细胞分化。