Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis
Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis
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DOI：
10.1093/rheumatology/key428
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发表时间：
2019-06-01
期刊：
影响因子：
5.5
通讯作者：
Tak, Paul P.
中科院分区：
文献类型：
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作者：
Ramwadhdoebe, Tamara H.;van Baarsen, Lisa G. M.;Tak, Paul P.
目标.利妥昔单抗治疗RA患者的确切潜在机制尚不清楚，并且缺乏关于B细胞耗竭对次级淋巴器官中免疫细胞影响的知识。我们分析了类风湿关节炎患者淋巴组织对利妥昔单抗的反应。14例RA患者接受2 × 1000 mg利妥昔单抗静脉注射，并在首次输注前和输注后4周进行淋巴结（LN）活检。采用流式细胞术、免疫组化和定量PCR检测组织学变化。5例健康人LN活检标本作为对照。与HC相比，RA患者LN活检显示CD 21（+）CD 23（+）IgD（高）IgM（可变）滤泡B细胞和CD 3（+）CD 25（+）CD 69（+）早期活化的组织驻留T细胞的频率增加。治疗后，LN B细胞不完全耗竭。CD 27（-）IgD（+）初始B细胞和CD 27（+）IgD（+）未转换记忆B细胞（包括CD 27（+）IgD（+）IgM（+）亚群和滤泡B细胞）显著减少。引人注目的是，利妥昔单抗治疗后，CD 27（+）IgD（-）转换的记忆B细胞在LN活检中持续存在。在T细胞区室中，观察到利妥昔单抗治疗后早期活化的组织驻留T细胞的频率显著降低，但晚期活化的T细胞持续存在。RA患者LN活检组织中诱导B细胞增殖的细胞因子IL-21的表达高于HC，且表达不受利妥昔单抗治疗的影响。利妥昔单抗不能治愈RA，这可能是由于淋巴组织中转换记忆B细胞的持续存在，这表明需要另外靶向促进B细胞存活和分化的因子。
Objectives. The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking. We analysed lymphoid tissue responses to rituximab in RA patients.Methods. Fourteen RA patients received 2 x 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion. Tissues were examined by flow cytometry, immunohistochemistry and quantitative PCR. LN biopsies from five healthy individuals (HC) served as controls.Results. LN biopsies of RA patients showed increased frequencies of CD21(+)CD23(+)IgD(high)IgM(variable) follicular B cells and CD3(+)CD25(+)CD69(+) early activated, tissue resident T cells when compared with HCs. After treatment, there was incomplete depletion of LN B cells. There was a significant decrease in CD27(-)IgD(+) naive B cells, and CD27(+)IgD(+)unswitched memory B cells including the CD27(+)IgD(+)IgM(+) subset and follicular B cells. Strikingly, CD27(+)IgD(-) switched memory B cells persisted in LN biopsies after rituximab treatment. In the T cell compartment, a significant decrease was observed in the frequency of early activated, tissue resident T cells after rituximab treatment, but late activated T cells persisted. B cell proliferation inducing cytokine IL-21 was higher expressed in LN biopsies of RA patients compared with HC and expression was not affected by rituximab treatment.Conclusion. Rituximab does not cure RA, possibly due to persistence of switched memory B cells in lymphoid tissues suggesting that factors promoting B cell survival and differentiation need to be additionally targeted.