北京大学学报(医学版) ›› 2019, Vol. 51 ›› Issue (3): 445-450. doi: 10.19723/j.issn.1671-167X.2019.03.011

• 论著 • 上一篇    下一篇

成红细胞样Ter细胞在胶原诱导性关节炎发病中的作用

王平1,宋婧1,方翔宇1,李鑫1,刘栩1,贾园1,栗占国1,2,胡凡磊1△()   

  1. 1. 北京大学人民医院风湿免疫科,风湿病机制及免疫诊断北京市重点实验室, 北京 100044
    2. 北京大学药学院天然药物及仿生药物国家重点实验室, 北京 100191
  • 收稿日期:2019-03-18 出版日期:2019-06-18 发布日期:2019-06-26
  • 作者简介:胡凡磊,北京大学人民医院风湿免疫科副研究员、博士生导师。中国免疫学会临床免疫分会青年委员、副秘书长,国家自然科学基金和北京自然科学基金评审专家,Frontiers in Immunology、Experimental and Therapeutic Medicine编委,Annals of the Rheumatic Diseases、Clinical and Experimental Immunology、Rheumatology等15余本英文杂志审稿人。北京市科技新星,亚太风湿病联盟(Asia Pacific League of Associations for Rheumatology, APLAR)优秀青年学者,中国免疫学会青年学者,北京免疫学会青年学者,白求恩基金管理委员会风湿免疫优秀人才,北京大学人民医院学术新星。
    长期从事自身免疫病,尤其是类风湿关节炎发病机制以及免疫诊治的研究,具体包括:(1)B细胞;(2)免疫调节性细胞;(3)新型天然免疫分子;(4)感染;(5)小分子药物。研究方向为以临床问题为出发点的基础及转化研究,取得系列性创新性成果。近5年发表SCI论文30余篇,其中第一/通信作者16篇,影响因子>12分2篇,单篇最高影响因子12.811。承担国家自然科学基金面上项目和青年项目、北京市科技新星计划项目等共9项,共同承担国家自然科学基金重大研究计划1项。申请/获得国家发明专利3项,并获多项科研奖励,包括中华医学科技奖二等奖、北京医学科技奖二等奖等。
  • 基金资助:
    国家自然科学基金(81671604、81302554、31530020、81801617)、北京市科技新星计划(Z181100006218044)和北京大学临床医学+X青年专项(PKU2019LCXQ018)-中央高校基本科研业务费

Role of erythroblast-like Ter cells in the pathogenesis of collagen-induced arthritis

Ping WANG1,Jing SONG1,Xiang-yu FANG1,Xin LI1,Xu LIU1,Yuan JIA1,Zhan-guo LI1,2,Fan-lei HU1△()   

  1. 1. Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis, Beijing 100044, China;
    2. State Key Laboratory of Natural and Biomime-tic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China
  • Received:2019-03-18 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China (81671604, 81302554, 31530020,81801617), the Beijing Nova Program (Z181100006218044) and the Fundamental Research Funds for the Central Universities: Peking University Clinical Medicine Plus X-Young Scholars Project (PKU2019LCXQ018)

摘要: 目的 通过检测Ter细胞在不同发病阶段胶原诱导性关节炎(collagen-induced arthritis,CIA)小鼠脾脏中的数量变化及高峰期CIA小鼠脾脏Ter细胞与关节评分和T、B细胞亚群比例的相关性,探讨Ter细胞在CIA发生和发展中的作用,从而进一步深入理解类风湿关节炎的发病机制。方法 6~8周的DBA/1小鼠进行CIA模型的诱导,二次免疫后开始对CIA小鼠进行关节评分。根据发病时间和关节评分将CIA分为发病早期、高峰期、晚期三个阶段。发病高峰期小鼠根据最终关节评分再分为高评分组(>8分)和低评分组(≤8分),流式细胞术检测na?ve小鼠和各个阶段CIA小鼠脾脏中Ter细胞比例及发病高峰期CIA小鼠脾脏T、B 细胞亚群比例,并进行关联分析。结果 发病高峰期CIA小鼠脾脏Ter细胞比例较na?ve小鼠明显升高(8.522%±2.645% vs. 1.937%±0.725%,P<0.01), 高评分组小鼠脾脏Ter细胞比例明显低于低评分组(6.217%±0.841% vs. 10.827%±0.917%,P<0.01)。高评分组小鼠脾脏Th1细胞比例明显高于低评分组(1.337%±0.110% vs. 0.727%±0.223%,P<0.05),高评分组小鼠脾脏Th17细胞比例高于低评分组(0.750%±0.171% vs. 0.477%±0.051%,P=0.099),高评分组小鼠脾脏生发中心B(germinal center B,GC-B)细胞比例明显高于低评分组(1.243%±0.057% vs. 1.097%±0.015%,P<0.05)。相关性分析结果显示,发病高峰期CIA小鼠脾脏Ter细胞比例与CD4 +T、Th1、Th17、GC-B细胞比例均呈强负相关,与B10细胞比例呈强正相关,相关性均有统计学意义,提示这群细胞在CIA中可能具有保护作用。动态变化研究显示,随着疾病进展,发病晚期CIA小鼠脾脏Ter细胞比例较高峰期明显降低(0.917%±0.588% vs. 8.522%±2.645%,P<0.001), 进一步提示这群细胞在关节炎中的保护作用。 结论 Ter细胞在发病高峰期CIA小鼠脾脏中明显增加,与小鼠关节评分及致病性免疫细胞比例呈负相关,与保护性免疫细胞比例呈正相关,发病晚期CIA小鼠Ter细胞比例明显降低,提示Ter细胞可能作为一种保护性细胞参与类风湿关节炎的发生和发展,但其具体作用及机制仍需后续进一步的体内及体外实验验证。

关键词: 关节炎, 实验性, Ter细胞, 炎症, 胶原

Abstract: Objective: To explore the role of Ter cells in the development of the collagen-induced arthritis (CIA), we detected their quantity changes in the spleen of different stages of CIA mice and analyzed the correlation between Ter cells and the joint scores, and we also analyzed the correlation between Ter cells and the frequencies of T and B cell subsets, so as to further understand the pathogenesis of rheumatoid arthritis.Methods: The six to eight weeks DBA/1 mice were used to prepare CIA model. After the second immunization, we began to evaluate the joint score. According to the time of CIA onset and the joint score, the CIA mice were divided into three stages: early, peak and late stages. According to the final joint score, the CIA mice at the peak stage were subdivided into the high score group (score>8) and the low score group (score≤8). The frequencies of Ter cells in the spleen of the na?ve mice and the CIA mice at various stages and the frequencies of T and B cell subsets in the spleen of the CIA mice at the peak stage were detected by flow cytometry, then we carried on the correlation analysis. Results: The frequencies of Ter cells in the spleen of the CIA mice was significantly higher than those of the na?ve mice (8.522%±2.645% vs. 1.937%±0.725%, P<0.01), the frequencies of Ter cells in the spleen of the high score group mice was significantly lower than those of the low score group (6.217%±0.841% vs. 10.827%±0.917%, P<0.01). The frequencies of Th1 cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.337%±0.110% vs. 0.727%±0.223%, P<0.05). The frequencies of Th17 cells in the spleen of the high score group mice was higher than those of the low score group mice (0.750%±0.171% vs. 0.477%±0.051%, P=0.099). The frequencies of germinal center B cells in the spleen of the high score group mice was significantly higher than those of the low score group mice (1.243%±0.057% vs. 1.097%±0.015%, P<0.05). Correlation analysis results showed that the frequencies of Ter cells in the spleen of the CIA mice at the peak stage was strongly negatively correlated with the frequencies of CD4 + T, Th1, Th17, and germinal center B cells, and was strongly positively correlated with the frequencies of B10 cells, indicating that these cells might have a protective effect in CIA. Studies on dynamic changes showed that the frequencies of Ter cells in the spleen of the CIA mice at the late stage was significantly lower than those at the peak stage (0.917%±0.588% vs. 8.522%±2.645%, P<0.001), suggesting the protective effect of these cells in arthritis. Conclusion: Ter cells were significantly increased in the spleen of the CIA mice at peak stage, and were negatively correlated with joint scores and pathogenic immune cells, and positively correlated with protective immune cells. Ter cells were significantly decreased in the spleen of the CIA mice at the late stage. What we mentioned above suggests that Ter cells might be involved in the progression of rheumatoid arthritis as an immunomodulatory cell,but further in vivo and in vitro experiments are needed to verify its specific effects and mechanism.

Key words: Arthritis, experimental, Ter cells, Inflammation, Collagen

中图分类号: 

  • R593.22

图1

Ter细胞在不同品系小鼠脾脏中的分布"

图2

Ter细胞在发病高峰期CIA小鼠中明显增加(n=6)"

图3

CIA发病高峰期Ter细胞比例与关节评分及T、B细胞亚群的相关性分析"

图4

CIA不同发病阶段Ter细胞的动态变化(n=6)"

[1] Smolen JS, Aletaha D, Barton A , et al. Rheumatoid arthritis[J]. Nat Rev Dis Primers, 2018,4:18001.
doi: 10.1038/nrdp.2018.1
[2] McInnes IB, Schett G . The pathogenesis of rheumatoid arthritis[J]. N Engl J Med, 2011,365(23):2205-2219.
doi: 10.1056/NEJMra1004965
[3] Gol-Ara M, Jadidi-Niaragh F, Sadria R , et al. The role of diffe-rent subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis[J]. Arthritis, 2012,2012:805875.
[4] Kerkman PF , Rombouts Y, van der Voort EI, et al. Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis[J]. Ann Rheum Dis, 2013,72(7):1259-1263.
doi: 10.1136/annrheumdis-2012-202893
[5] Xu LL, Liu X, Liu HJ , et al. Impairment of granzyme B-pro-ducing regulatory B cells correlates with exacerbated rheumatoid arthritis[J]. Front Immunol, 2017,8:768.
doi: 10.3389/fimmu.2017.00768
[6] Guo CQ, Hu FL, Yi HF , et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis[J]. Ann Rheum Dis, 2016,75(1):278-285.
doi: 10.1136/annrheumdis-2014-205508
[7] Han YM, Liu QY, Hou J , et al. Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression[J]. Cell, 2018,173(3):634-648.
doi: 10.1016/j.cell.2018.02.061
[8] Bessis N, Decker P, Assier E , et al. Arthritis models: usefulness and interpretation[J]. Semin Immunopathol, 2017,39(4):469-486.
doi: 10.1007/s00281-017-0622-4
[9] Gizinski AM, Fox DA . T cell subsets and their role in the pathogenesis of rheumatic disease[J]. Curr Opin Rheumatol, 2014,26(2):204-210.
doi: 10.1097/BOR.0000000000000036
[10] Dahdah A, Habir K, Nandakumar KS , et al. Germinal center B cells are essential for collagen-induced arthritis[J]. Arthritis Rheumatol, 2018,70(2):193-203.
doi: 10.1002/art.40354
[11] Daien CI, Gailhac S, Mura T , et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and inversely correlated with disease activity[J]. Arthritis Rheumatol, 2014,66(8):2037-2046.
doi: 10.1002/art.v66.8
[12] Song ZQ, Yang F, Du H , et al. Role of artemin in non-small cell lung cancer[J]. Thorac Cancer, 2018,9(5):555-562.
doi: 10.1111/tca.2018.9.issue-5
[13] Wang J, Wang H, Cai J , et al. Artemin regulates CXCR4 expression to induce migration and invasion in pancreatic cancer cells through activation of NF-κB signaling[J]. Exp Cell Res, 2018,365(1):12-23.
doi: 10.1016/j.yexcr.2018.02.008
[14] Gao L, Bo HJ, Wang Y , et al. Neurotrophic factor artemin promotes invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro[J]. Pancreas, 2015,44(1):134-143.
doi: 10.1097/MPA.0000000000000223
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