Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China.
Shanghai Medical College, Fudan University, Shanghai, China.
Front Immunol. 2022 Aug 1;13:931821. doi: 10.3389/fimmu.2022.931821. eCollection 2022.
Myasthenia gravis (MG) is a T cell-driven, autoantibody-mediated disorder affecting transmission in neuromuscular junctions. The associations between the peripheral T cells and MG have been extensively studied. However, they are mainly of observational nature, thus limiting our understanding of the effect of inflammatory biomarkers on MG risk. With large data sets now available, we used Mendelian randomization (MR) analysis to investigate whether the biomarkers on T cells are causally associated with MG and further validate the relationships.
We performed a two-sample MR analysis using genetic data from one genome-wide association study (GWAS) for 210 extensive T-cell traits in 3,757 general population individuals and the largest GWAS for MG currently available (1,873 patients versus 36,370 age/gender-matched controls) from US and Italy. Then the biomarkers of interest were validated separately in two GWASs for MG in FIN biobank (232 patients versus 217,056 controls) and UK biobank (152 patients versus 386,631 controls).
In the first analysis, three T-cell traits were identified to be causally protective for MG risk: 1) CD8 on terminally differentiated CD8 T cells (OR [95% CI] = 0.71 [0.59, 0.86], P = 5.62e-04, adjusted P =2.81e-02); 2) CD4 regulatory T proportion in T cells (OR [95% CI] = 0.44 [0.26, 0.72], P = 1.30e-03, adjusted P =2.81e-02); 3) HVEM expression on total T cells (OR [95% CI] = 0.67 [0.52, 0.86], P = 1.61e-03, adjusted P =2.81e-02) and other eight T-cell subtypes (e.g., naïve CD4+ T cells). In particular, HVEM is a novel immune checkpoint on T cells that has never been linked to MG before. The SNPs on the TNFRSF14 further support a more direct link between the HVEM and MG. The validation analysis replicated these results in both FIN and UK biobanks. Both datasets showed a concordant protective trend supporting the findings, albeit not significant.
This study highlighted the role of HVEM on T cells as a novel molecular-modified factor for MG risk and validated the causality between T cells and MG. These findings may advance our understanding of MG's immunopathology and facilitate the future development of predictive disease-relevant biomarkers.
重症肌无力（MG）是一种 T 细胞驱动、自身抗体介导的疾病，影响神经肌肉接头的传递。外周 T 细胞与 MG 之间的关联已得到广泛研究。然而，这些研究主要是观察性的，因此限制了我们对炎症生物标志物对 MG 风险影响的理解。随着现在有了大量的数据，我们使用孟德尔随机化（MR）分析来研究 T 细胞上的生物标志物是否与 MG 有因果关系，并进一步验证这些关系。
我们使用来自一个全基因组关联研究（GWAS）的 3757 名普通人群中 210 种广泛的 T 细胞特征的遗传数据，以及来自美国和意大利的目前最大的 MG GWAS（1873 名患者与 36370 名年龄/性别匹配的对照）进行了两样本 MR 分析。然后，我们分别在 FIN 生物银行（232 名患者与 217056 名对照）和英国生物银行（152 名患者与 386631 名对照）的两个 MG GWAS 中对感兴趣的生物标志物进行了验证。
在第一项分析中，有三个 T 细胞特征被确定为对 MG 风险具有保护作用：1）终末分化 CD8 T 细胞上的 CD8（OR[95%CI] = 0.71[0.59, 0.86]，P=5.62e-04，调整后 P=2.81e-02）；2）T 细胞中 CD4 调节性 T 比例（OR[95%CI] = 0.44[0.26, 0.72]，P=1.30e-03，调整后 P=2.81e-02）；3）总 T 细胞上的 HVEM 表达（OR[95%CI] = 0.67[0.52, 0.86]，P=1.61e-03，调整后 P=2.81e-02）和其他八种 T 细胞亚型（例如，幼稚 CD4+T 细胞）。特别是，HVEM 是 T 细胞上的一种新型免疫检查点，以前从未与 MG 相关联。TNFRSF14 上的 SNPs 进一步支持了 HVEM 与 MG 之间的更直接联系。验证分析在 FIN 和英国生物银行中复制了这些结果。两个数据集都显示出一致的保护趋势，支持这些发现，尽管没有统计学意义。
本研究强调了 HVEM 在 T 细胞上作为 MG 风险的新型分子修饰因子的作用，并验证了 T 细胞与 MG 之间的因果关系。这些发现可能有助于我们更好地理解 MG 的免疫病理学，并为未来预测与疾病相关的生物标志物的开发提供便利。
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