Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion Sanitaria, Madrid, Spain.
J Neuroinflammation. 2018 Oct 26;15(1):296. doi: 10.1186/s12974-018-1336-9.
Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration.
Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls.
EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules.
These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS.
最近在实验性自身免疫性脑脊髓炎（多发性硬化症的动物模型）的研究中，组蛋白甲基转移酶增强子的锌指 2 多梳抑制复合物 2 亚基（EZH2）参与细胞黏附和迁移等重要过程。
在这里，我们旨在通过研究 EZH2 在多发性硬化症中的作用来扩展这些初步观察结果。通过实时 PCR 测量 121 例多发性硬化症患者（62 例未治疗和 59 例治疗）和 24 例健康对照者外周血单个核细胞（PBMC）中 EZH2 的 mRNA 表达水平。
与对照组相比，未经治疗的患者 PBMC 中的 EZH2 表达水平降低，治疗显著上调了 EZH2 的表达。与对照组相比，MS 患者的 miR-124 表达增加。血液免疫表型显示，EZH2 表达主要局限于 CD4+和 CD8+T 细胞，未经治疗的 MS 患者外周血中循环 EZH2+CD4+和 CD8+T 细胞减少。表达 EZH2 的 CD8+T 细胞表现出主要的中央记忆表型，而 EZH2+CD4+T 细胞具有效应记忆特性，这两种 T 细胞亚群都产生 TNF-α。与血液相比，EZH2+T 细胞在脑脊液中更为丰富，并且在 MS 患者的慢性活动性病变中也发现了 EZH2+T 细胞。在 PBMC 中进行 EZH2 抑制和微阵列分析与关键 T 细胞黏附分子的显著下调有关。
这些发现表明 EZH2 在 MS 患者 T 细胞迁移中起作用。表达 EZH2 的 CD4+和 CD8+T 细胞表达 TNF-α的观察结果需要进一步研究，以更深入地探讨 EZH2+阳性细胞在多发性硬化症中的致病潜力。
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