Steady state generation of mucosal IgA+ plasmablasts is not abrogated by B cell depletion therapy with rituximab
Steady state generation of mucosal IgA+ plasmablasts is not abrogated by B cell depletion therapy with rituximab
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DOI：
10.1136/ard.2010.149005.19
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发表时间：
2010-12
影响因子：
27.4
通讯作者：
H. Mei;D. Frölich;Claudia Giesecke;C. Loddenkemper;K. Reiter;S. Schmidt;E. Feist;C. Daridon;H. Tony;Andreas Radbruch;T. Dörner
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文献类型：
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作者：
H. Mei;D. Frölich;Claudia Giesecke;C. Loddenkemper;K. Reiter;S. Schmidt;E. Feist;C. Daridon;H. Tony;Andreas Radbruch;T. Dörner
利妥昔单抗（抗-CD 20）的B细胞耗竭疗法已被确立用于治疗RA。虽然利妥昔单抗有效地清除循环B细胞，但其对组织B细胞，特别是肠道相关淋巴组织中的B细胞的影响仍不清楚，并被讨论为个体无反应性的潜在原因。在此，我们研究了rituxumab治疗对RA患者循环和组织驻留伊加浆母细胞的影响，这些浆母细胞与粘膜B细胞活化相关。类风湿性关节炎患者给予2 × 1g利妥昔单抗，并在利妥昔单抗输注前和输注后2-9个月通过流式细胞术分析外周血循环B细胞和浆母细胞。在第二个疗程期间，还对一些患者进行了额外分析。使用Ki-67表达分析细胞增殖，并使用体外transwell系统评估浆母细胞向CXCL 12和CCL 28的迁移。外周血CD 20+幼稚和记忆B细胞数量减少至治疗前初始数量的>0.02%，而浆母细胞/浆细胞在血液中持续检测到0.26 - 119%。这些循环浆母细胞/浆细胞在B细胞耗竭期之前和整个耗竭期表达粘膜表型，即伊加、β 7整联蛋白和CCR 10。新近活化的浆母细胞表现为HLA-DR的高表达、体外向CXCL 12和CCL 28的迁移以及Ki-67的表达。一致地，伊加+浆母细胞和浆细胞也在利妥昔单抗治疗的患者的固有层活检中鉴定。循环浆母细胞的数量与DAS 28值无显著相关性。值得注意的是，在B细胞耗竭期间产生的外周血伊加+浆母细胞产生的抗体经常与细菌抗原结合。我们的研究结果表明，在利妥昔单抗清除B细胞期间，粘膜浆母细胞的持续生成，指向某些功能性B细胞的抗性，驻留在粘膜中并允许伊加+浆母细胞的分化。我们的数据表明利妥昔单抗靶向粘膜B细胞和抗体产生的能力有限。
B cell depletion therapy with rituximab (anti-CD20) has been established for treating RA. While rituximab efficiently removes circulating B cells, its effects on tissue-based B cells, especially on those in gut-associated lymphoid tissues, remained unclear and are discussed as potential reasons for individual unresponsiveness. Here we studied the ffect of rituxuimab treatment on circulating and tissue-resident IgA plasmablasts as correlates of mucosal B cell activation in patients with RA. Patients with rheumatoid arthritis were given 2x1g rituximab and peripheral blood was analyzed for circulating B cells and plasmablasts by flow cytometry before and at 2-9 months after rituximab infusion. Some patients were also analyzed additionally analyzed during a second treatment course. Cell proliferation was analyzed using Ki-67 expression and plasmablast migration was assessed towards CXCL12 and CCL28 using an in vitro transwell system. Peripheral blood CD20+ naïve and memory B cell numbers were reduced to >0.02% of their intial numbers before therapy, while plasmablasts/plasma cells were persistently detectable in the blood at ∼26-119%. These circulating plasmablasts/plasma cells expressed a mucosal phenoytpe, i.e. IgA, beta7 integrin and CCR10 before and throughout the B cell depletion phase. Recently activated plasmablasts were revelead by high epxression of HLA-DR, in vitro migration towards CXCL12 and CCL28 and Ki-67 expression. Consistently, IgA+ plasmablasts and plasma cells were also identified in lamina propria biopsies of rituxuimab treated patients. Numbers of circulating plasmablasts did not significantly correlate with DAS28 values. Notably, antibody produced by peripheral blood IgA+ plasmablasts generated during B cell depletion frequently bound to bacterial antigens. Our results suggest the persistent generation of mucosal plasmablasts during B cell depletion with rituximab, pointing towards the resistance of some functional B cells, residing in the mucosa and permitting the differentiation of IgA+ plasmablasts. Our data suggest that rituximab has a limited capacity to target mucosal B cells and antibody production.