Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence
Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence
复制标题
胸腺内 Tfh/B 细胞相互作用导致异位 GC 形成和抗 AChR 抗体产生：在触发 MG 发生中的核心作用
DOI：
10.1007/s12035-014-8985-1
复制
发表时间：
2016-01-01
影响因子：
5.1
通讯作者：
Yang, Kun
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoyan;Liu, Shasha;Yang, Kun
重症肌无力（Myasthenia gravis，MG）是一种典型的乙酰胆碱受体（acetylcholine receptor，AChR）抗体介导的自身免疫性疾病。胸腺可能是AChR自身致敏和自身抗体产生的场所，这一观点已被广泛接受。然而，触发胸腺内AChR抗体产生的确切机制仍然未知。滤泡辅助性T细胞是近年来发现的在次级淋巴器官中负责B细胞成熟和抗体产生的细胞，与许多自身免疫性疾病有关。近年来研究发现重症肌无力（MG）患者外周血中辅助性T滤泡细胞（Tfh）增多。它是否出现在MG的胸腺中以及它在胸腺内B细胞中的作用是否有助于自身抗体的产生尚不清楚。因此，本研究旨在更详细地确定是否Tfh/B细胞相互作用存在于MG胸腺，并解决其在异位生发中心（GC）的形成和AChR抗体的生产中的作用。我们观察了MG患者胸腺细胞和外周血单个核细胞（PBMCs）中Tfh细胞及其相关转录因子Bcl-6、关键细胞因子IL-21的表达。同时，我们还发现MG外周血和胸腺中的B细胞和自身抗体滴度增加。共聚焦显微镜结果显示Tfh和B细胞共定位于MG胸腺异位GC内，提示Tfh/B细胞相互作用的存在。体外研究进一步显示Tfh/B细胞相互作用的动态行为，Tfh细胞可能通过其效应细胞因子IL-21诱导自身抗体的分泌。总之，胸腺内Tfh/B细胞相互作用在胸腺异位GCs形成和抗AChR抗体产生中起关键作用，可能是MG发生的触发因素。
Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence.