结核杆菌脂糖对调节性B细胞的诱导及免疫逃逸机制的研究

Mycobacterial Tubercolosis (MTB) is characterized by a high rate of infectivity and long periods of persistence. Much pathogenic mechanism，especially immune evasion by MTB，remains unknown. Mannosylated lipoarabinomannan (ManLAM) is a lipoglycan and major virulence factor in Mycobacterium. In addition to serving as a major cell wall component, it is thought to serve as a modulin with immunoregulatory and anti-inflammatory effects.There has been no reports so far on the interaction between ManLAM and B cells. Regulatory B cells (B10 or Bregs), has recently been shown to down-regulate immune responses that occur during autoimmune diseases or that can be caused by unresolved infections. In recent years, we have been conducting researches on MTB pathogenic mechanism, and in our preliminary experiments, we found that ManLAM induced murine B cells to produce IL-10. In our current work, we plan to confirm the interaction between ManLAM and B10 cells, to investigate the pattern recognition and signaling pathway for IL-10 production in B10 cells in presence of ManLAM, then to illustrate the B10 roles involved in down regulation of immune response contributing to immune evasion by MTB, finally to try to treat the MTB-infected mice by the IL-10-/- B cell adoptive transfer. Our work will provide new information of MTB immune evasion and pathogenesis, and help to develop new therapeutic strategies in clinic.

结核杆菌感染宿主具有高感染性和持久感染的特点，目前人们对结核杆菌感染免疫机制，尤其是免疫逃逸机制不清楚。甘露糖修饰脂阿拉伯甘露聚糖（ManLAM）是结核杆菌胞壁中重要毒力成分,在结核杆菌免疫逃逸中发挥重要作用，目前尚无该脂糖与B细胞相互作用的研究报道；而新发现的调节性B细胞（B10或Breg）广泛参与对免疫细胞的负调控。近年来，我们一直进行结核杆菌感染机制方面研究，在前期对结核杆菌ManLAM的研究中，发现ManLAM可以诱导小鼠B细胞分泌IL-10。本项目拟证实ManLAM诱导B10细胞合成分泌IL-10的分子机制，进而阐明结核杆菌诱导的B10负性调控及相关的免疫逃逸机制，并尝试利用致敏的IL-10-/- B细胞过继免疫输入治疗结核杆菌感染小鼠，以提高宿主的特异性抗结核免疫。本项目的完成将揭示结核杆菌新的免疫逃逸机制，为临床结核病治疗提供新思路和实验数据。

结核杆菌感染宿主具有高感染性和持久感染特点，目前人们对结核杆菌感染免疫机制，尤其是免疫逃逸机制不清楚。甘露糖修饰脂阿拉伯甘露聚糖（ManLAM）是结核杆菌胞壁中重要毒力成分,在结核杆菌免疫逃逸中发挥重要作用。本项目开展了对结核杆菌ManLAM的免疫调控机制研究，发现ManLAM与免疫细胞表面甘露糖受体（MR）以及TLR2受体结合，诱导树突状细胞、巨噬细胞以及B细胞的免疫负调控作用，可诱导这些细胞分泌免疫负调节因子IL-10；而与免疫细胞表面CD44分子结合则发挥免疫刺激的作用，拮抗IL-10的产生，运用自主研发的小分子拮抗ManLAM与MR受体的结合，也能抑制ManLAM诱导IL-10的效应。本项目的完成将揭示结核杆菌新的免疫逃逸机制，为临床结核病治疗提供新思路和实验数据。本项目执行期间，发表文章6篇，其中SCI文章3篇，以第一或共同第一作者发表在Mol. Ther.(2014;22(5):940-51，IF: 7.1，一区,) 和 J Am Chem Soc. (2016;138(36):11680-9，IF: 13，一区)各一篇，获得授权发明专利一项（第二发明人）,培养硕士研究生6名。