Fan Rui, Que Wenjun, Liu Zhuoting, Zheng Wei, Guo Xia, Liu Linqi, Xiao Fei
Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.
Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China; Department of Blood Transfusion, the First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing 400016, China.
Clin Immunol. 2022 Dec;245:109184. doi: 10.1016/j.clim.2022.109184. Epub 2022 Nov 11.
The pathogenesis and progression of myasthenia gravis (MG), an autoimmune disease, involve abnormal function and composition of several immune cell populations. However, details of this dysregulation remain unclear. We performed a cross-section analysis using cytometry time-of-flight on blood samples from 12 generalized MG without glucocorticoid or other immunosuppressant treatment, and 10 sex- and age-matched healthy controls. Combining data from an external validation cohort (MG n = 38, control n = 21), bulk-RNA sequencing and single-cell RNA sequencing, alterations in immune cell populations and differential expression of immune check point were revealed. Several switched memory B cell subsets (CD3- CD19+ CD27+ IgD- CD38+/-) were increased in MG patients. The number of HLA- DQ- CD38+ naïve B cells was higher in MG patients and correlated with the quantitative MG score (QMG). Among NK cells, the number of CD56+ CD16+ NK cells and CD56+ CD16+ CD8+ NK cells were decreased in MG patients and positively correlated with QMG. VISTA+ monocytes were increased in MG patients. Classical T cell subsets showed no significant change; however, the expression of VISTA, LAG3, CTLA4, and CXCR5 was higher in T cells from MG patients. The expression of CD38 was higher in neutrophils from MG patients. The external validation cohort validated the dysregulation of NK cell subtypes, and differences were also observed in subgroups of patients. Bulk-RNA sequencing also revealed increased mRNA expression of VSIR in monocytes of MG patients compared to those from healthy controls, and the antigen presentation and processing pathway was identified as enriched in the functional characterization of VISTA+ monocytes via single-cell RNA sequencing. Our study revealed alterations in several immune cell subsets and identified potential cellular biomarkers for MG diagnosis and disease severity assessment. In addition, the abnormal expression of multiple immune checkpoints in MG provides further rationale for the investigation of immune-checkpoint-related therapy.
重症肌无力（MG）是一种自身免疫性疾病，其发病机制和进展涉及多个免疫细胞群体的功能和组成异常。然而，这种失调的细节仍不清楚。我们对12例未接受糖皮质激素或其他免疫抑制剂治疗的全身型MG患者以及10例性别和年龄匹配的健康对照者的血样进行了飞行时间流式细胞术横断面分析。结合来自外部验证队列（MG患者n = 38，对照n = 21）的数据、批量RNA测序和单细胞RNA测序，揭示了免疫细胞群体的改变和免疫检查点的差异表达。MG患者中几个转换记忆B细胞亚群（CD3- CD19+ CD27+ IgD- CD38+/-）增加。MG患者中HLA- DQ- CD38+初始B细胞的数量更高，且与MG定量评分（QMG）相关。在自然杀伤（NK）细胞中，MG患者中CD56+ CD16+ NK细胞和CD56+ CD16+ CD8+ NK细胞的数量减少，且与QMG呈正相关。MG患者中VISTA+单核细胞增加。经典T细胞亚群无显著变化；然而，MG患者T细胞中VISTA、LAG3、CTLA4和CXCR5的表达更高。MG患者中性粒细胞中CD38的表达更高。外部验证队列验证了NK细胞亚型的失调，并且在患者亚组中也观察到了差异。批量RNA测序还显示，与健康对照者相比，MG患者单核细胞中VSIR的mRNA表达增加，并且通过单细胞RNA测序确定抗原呈递和加工途径在VISTA+单核细胞的功能特征中富集。我们的研究揭示了几个免疫细胞亚群的改变，并确定了用于MG诊断和疾病严重程度评估的潜在细胞生物标志物。此外，MG中多个免疫检查点的异常表达为免疫检查点相关治疗的研究提供了进一步的理论依据。
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