CCL21 Overexpressed on Lymphatic Vessels Drives Thymic Hyperplasia in Myasthenia
CCL21 Overexpressed on Lymphatic Vessels Drives Thymic Hyperplasia in Myasthenia
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DOI：
10.1002/ana.21628
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发表时间：
2009-10-01
影响因子：
11.2
通讯作者：
Le Panse, Rozen
中科院分区：
文献类型：
--
作者：
Berrih-Aknin, Sonia;Ruhlmann, Nathalie;Le Panse, Rozen
目的：重症肌无力（MG）是一种由抗乙酰胆碱受体（AChR）自身抗体介导的神经肌肉疾病，与胸腺增生有关，其特征在于含有致病性抗体产生B细胞的异位生发中心。我们的胸腺转录组研究表明，免疫细胞的招募者CCL21的表达增加。方法：采用酶联免疫吸附试验（ELISA）和荧光激活细胞分选技术（FCM）检测CCL21及其受体CCR7在MG中的表达。用transwell法检测T、B细胞对CCL 21的趋化作用。胸腺细胞过度表达CCL21的性质进行了研究免疫化学和激光捕获显微切割结合实时PCR.Results：我们表明，CCL21是过度表达特异性增生MG胸腺，而血细胞中的CCR 7水平没有变化。我们表明，虽然CCL 21吸引人类T和B细胞，它的作用更强烈的幼稚B细胞。CCL21过表达在皮质激素治疗的MG患者中正常化，表明靶向这种趋化因子可能代表一种新的选择性治疗，减少异常的外周淋巴细胞募集。此外，我们将CCL21的蛋白质和信使RNA过表达定位于特定的内皮血管。这些血管的性质的调查表明不同的血管生成过程中MG胸腺：高内皮微静脉血管生成和淋巴管生成。出乎意料的是，CCL21的过度表达起源于传入淋巴管endothelial vessels.Interpretation：我们假设，胸腺过度表达CCL21对专门的淋巴管导致异常的外周淋巴细胞募集，使幼稚B细胞与MG胸腺的炎症环境特征接触，在那里它们可以对AChR敏感。
Objective: Myasthenia gravis (MG), a neuromuscular disease mediated by anti-acetylcholine receptor (AChR) autoantibodies, is associated with thymic hyperplasia characterized by ectopic germinal centers that contain pathogenic antibody-producing B cells. Our thymic transcriptome study demonstrated increased expression of CCL21, a recruiter of immune cells. Accordingly, we are investigating its implication in MG pathogenesis.Methods: The expression of CCL21 and its CCR7 receptor was analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting, respectively. Chemotaxis of T and B cells to CCL21 was measured by transwell assay. The nature of the thymic cells overexpressing CCL21 was investigated by immunochemistry and laser-capture microdissection combined with real-time PCR.Results: We demonstrate that CCL21 is overexpressed specifically in hyperplastic MG thymuses, whereas there is no variation in CCR7 levels on blood cells. We show that although CCL21 attracts both human T and B cells, it acts more strongly on naive B cells. CCL21 overexpression is normalized in corticoid-treated MG patients, suggesting that targeting this chemokine could represent a new selective treatment, decreasing the abnormal peripheral lymphocyte recruitment. Moreover, we locate protein and messenger RNA overexpression of CCL21 to specific endothelial vessels. Investigation of the nature of these vessels demonstrated different angiogenic processes in MG thymuses: high endothelial venule angiogenesis and lymphangiogenesis. Unexpectedly, CCL21 overexpression originates from afferent lymphatic endothelial vessels.Interpretation: We postulate that thymic overexpression of CCL21 on specialized lymphatic vessels results in abnormal peripheral lymphocyte recruitment, bringing naive B cells in contact with the inflammatory environment characteristic of MG thymuses, where they can be sensitized against AChR.