Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis
Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis
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DOI：
10.1136/annrheumdis-2019-215195
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发表时间：
2019-11-01
影响因子：
27.4
通讯作者：
Sumida, Takayuki
中科院分区：
文献类型：
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作者：
Kurata, Izumi;Matsumoto, Isao;Sumida, Takayuki
目的类风湿关节炎(RA)患者外周血中滤泡辅助性T细胞(TFH)比例增加，但TFH细胞对抗体分泌的影响尚不清楚。我们用小鼠模型研究了类风湿因子(TFH)细胞对自身抗体生成的调节作用。用质谱仪检测关节炎病程中自身抗体的致关节炎和唾液酸化的变化。研究了TFH介导的下裂作用的调节，并在体外和体内确定了负责的细胞表面分子。结果RA患者外周血中的Tfh细胞，尤其是产生白细胞介素17的Tfh(Tfh17)细胞在关节炎发病时升高，并促进自身抗体的产生。发作期的自身抗体比消退期的自身抗体表现出更强的炎症特性，质谱分析显示它们在唾液酸化方面的差异。在体外共培养中，Tfh细胞通过OX40表达增强，OX40在Tfh和Tfh17细胞中高表达。阻断OX40通过减少Tfh17细胞和恢复自身抗体唾液酸化来阻止关节炎的发展。类风湿关节炎患者外周血中大量表达OX40的Tfh17细胞，其比例与唾液酸化相关酶α2，6-唾液酸转移酶1的表达呈负相关。结论Tfh细胞上表达的OX40可调节自身抗体唾液酸化，在自身免疫性关节炎的发生发展中起重要作用。
Objective An increased proportion of circulating follicular helper T (Tfh) cells was reported in rheumatoid arthritis (RA), but it remains uncertain how Tfh cells affect antibody hyposialylation. We investigated the regulation of autoantibody hyposialylation by Tfh cells in RA using murine model.Methods Behaviours of Tfh cells and their function on B cell promotion were analysed. Change of arthritogenicity and sialylation of autoantibodies during the course of arthritis was examined by mass spectrometry. Tfh-mediated regulation of hyposialylation was investigated, and the responsible cell surface molecule was specified both in vitro and in vivo. The relation between circulating Tfh cells and hyposialylation was analysed in patients with RA.Results An increase in Tfh, particularly interleukin-17 producing Tfh (Tfh17) cells, at the onset of arthritis and their enhancement of autoantibody production were found. Autoantibodies at the onset phase demonstrated stronger inflammatory properties than those at the resolution phase, and mass spectrometric analysis revealed their difference in sialylation. In vitro coculture showed enhanced hyposialylation by the Tfh cells via OX40, which was highly expressed in the Tfh and Tfh17 cells. Blockade of OX40 prevented the development of arthritis with reduction in Tfh17 cells and recovery of autoantibody sialylation. Analysis of patients with RA showed abundance of OX40-overexpressing Tfh17 cells, and their proportion correlated negatively with the expression of alpha 2,6-sialyltransferase 1, an enzyme responsible for sialylation.Conclusions OX40 expressed on Tfh cells can regulate autoantibody sialylation and play a crucial role in the development of autoimmune arthritis.