Mature Antigen-Experienced T Helper Cells Synthesize and Secrete the B Cell Chemoattractant CXCL13 in the Inflammatory Environment of the Rheumatoid Joint
Mature Antigen-Experienced T Helper Cells Synthesize and Secrete the B Cell Chemoattractant CXCL13 in the Inflammatory Environment of the Rheumatoid Joint
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DOI：
10.1002/art.23966
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发表时间：
2008-11-01
影响因子：
--
通讯作者：
Pitzalis, Costantino
中科院分区：
文献类型：
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作者：
Manzo, Antonio;Vitolo, Barbara;Pitzalis, Costantino
Objective.滑膜B细胞在类风湿性关节炎（RA）中起关键作用，参与自身抗体合成、T细胞活化和细胞因子产生。CXCL 13是一种B细胞化学引诱物，在滑膜B细胞组织中起作用; CXCL 13在炎症中的调节决定因素的特征很差。本研究旨在探讨RA患者滑膜T细胞在CXCL 13异位表达中的功能参与。采用免疫组化、原位杂交、定量聚合酶链反应、流式细胞术和酶联免疫吸附试验，通过原位-离体分析和类风湿性滑膜组织和原代细胞的体外功能测定，研究CXCL 13的产生和调控。在RA滑液T细胞中检测到CXCL 13信使RNA和蛋白表达以及CXCL 13自发分泌，但在外周血T细胞中未检测到（或仅偶尔检测到）。组织表达分析证实了CXCL 13在T淋巴细胞浸润B细胞滤泡和小的血管周围聚集体中的细胞质定位。在滑液中的多色表征表明CXCL 13在抗原经历的T辅助细胞中表达，其通常以终末分化和缺乏滤泡辅助T细胞标志物CXCR 5和BCL 6蛋白为特征。体外功能检测显示T细胞受体-CD 28结合对原代细胞产生和分泌CXCL 13有增强作用。我们的研究结果定义了一个新的功能特性的滑膜T细胞，证明他们积极参与本地生产的B细胞趋化因子，并支持直接贡献的适应性免疫系统和抗原依赖性信号的机制中的B细胞定位在RA。
Objective. Synovial B cells play a critical role in rheumatoid arthritis (RA), being involved in autoantibody synthesis, T cell activation, and cytokine production. CXCL13 is a B cell chemoattractant that is instrumental in synovial B cell organization; the regulatory determinants of CXCL13 in inflammation are poorly characterized. This study was undertaken to investigate the functional involvement of synovial T cells in the ectopic expression of CXCL13 in RA.Methods. CXCL13 production and regulation were addressed using immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, multicolor flow cytometry, and enzyme-linked immunosorbent assay, by in situ-ex vivo analysis and in vitro functional assays with rheumatoid synovial tissue and primary cells.Results. CXCL13 messenger RNA and protein expression and spontaneous CXCL13 secretion were detected in RA synovial fluid T cells but were not detected (or were detected only occasionally) in peripheral blood T cells. Analysis of tissue expression confirmed cytoplasm localization of CXCL13 in T lymphocytes infiltrating B cell follicles and small perivascular aggregates. Multicolor characterizations in synovial fluid demonstrated CXCL13 expression in antigen-experienced T helper cells, frequently characterized by terminal differentiation and the lack of the follicular helper T cell markers CXCR5 and BCL6 protein. In vitro functional assays revealed the enhancing effect of T cell receptor-CD28 engagement on CXCL13 production and secretion in primary cells.Conclusion. Our findings define a new functional property of synovial T cells, demonstrating their active involvement in the local production of B cell chemoattractants, and support a direct contribution of the adaptive immune system and antigen-dependent signals in the mechanisms of B cell localization in RA.