Université Paris-Saclay, CEA, INSERM UMR 1184, Le Kremlin Bicêtre, France.
Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, Pediatric Neurology Department, Le Kremlin Bicêtre, France.
Front Immunol. 2021 Jun 16;12:679770. doi: 10.3389/fimmu.2021.679770. eCollection 2021.
Myelin oligodendrocytes glycoprotein (MOG) antibody-associated disease (MOGAD) represent 25% of pediatric acquired demyelinating syndrome (ADS); 40% of them may relapse, mimicking multiple sclerosis (MS), a recurrent and neurodegenerative ADS, which is MOG-Abs negative.
To identify MOG antigenic immunological response differences between MOGAD, MS and control patients, and between relapsing non-relapsing subgroups of MOGAD.
Three groups of patients were selected: MOGAD (n=12 among which 5 relapsing (MOGR) and 7 non-relapsing (MOGNR)), MS (n=10) and control patients (n=7). Peripheral blood mononuclear cells (PBMC) collected at the time of the first demyelinating event were cultured for 48 h with recombinant human (rh)-MOG protein (10 μg/ml) for a specific stimulation or without stimulation as a negative control. The T cells immunophenotypes were analyzed by flow cytometry. CD4 T cells, T helper (Th) cells including Th1, Th2, and Th17 were analyzed by intracellular staining of cytokines. Regulatory T cells (T, Foxp3), CD45RAFoxp3 T and subpopulation naive T (CD45RAFoxp3), effector T (CD45RAFoxp3) and non-suppressive T (CD45RAFoxp3) proportions were determined.
The mean onset age of each group, ranging from 9.9 to 13.8, and sex ratio, were similar between MOGR, MOGNR, MS and control patients as analyzed by one-way ANOVA and Chi-square test. When comparing unstimulated to rh-MOG stimulated T cells, a significant increase in the proportion of Th2 and Th17 cells was observed in MOGAD. Increase of Th17 cells was significant in MOGNR (means: 0.63 ± 0.15 1.36 ± 0.43; Wilcoxon-test = 0.03) but not in MOGR. CD4 T were significantly increased in MOGNR (means: 3.51 ± 0.7 4.59 ± 1.33; Wilcoxon-test = 0.046) while they decreased in MOGR. CD45RAFoxp3 T were significantly decreased in MOGR (means: 2.37 ± 0.23 1.99 ± 0.17; paired t-test = 0.021), but not in MOGNR. MOGR showed the highest ratio of effector T/non suppressive-T which was significantly higher than in MOGNR.
Our findings suggest that CD4 Th2 and Th17 cells are involved in the pathophysiology of MOGAD in children. The opposite response of T to rh-MOG in MOGNR, where CD4 T increased, and in MOGR, where CD45RAFoxp3 T decreased, suggests a probable loss of tolerance toward MOG autoantigen in MOGR which may explain relapses in this recurrent pediatric autoimmune disease.
髓鞘少突胶质细胞糖蛋白（MOG）抗体相关疾病（MOGAD）占儿科获得性脱髓鞘综合征（ADS）的 25%；其中 40%可能会复发，类似于多发性硬化症（MS），这是一种复发性神经退行性 ADS，MOG-Abs 为阴性。
鉴定 MOGAD、MS 和对照患者之间，以及 MOGAD 的复发和非复发亚组之间的 MOG 抗原免疫反应差异。
选择了三组患者：MOGAD（n=12，其中 5 例为复发型（MOGR），7 例为非复发型（MOGNR））、MS（n=10）和对照组患者（n=7）。在首次脱髓鞘事件时采集外周血单核细胞（PBMC），在重组人（rh）-MOG 蛋白（10μg/ml）存在或不存在的情况下培养 48 小时，以进行特异性刺激或阴性对照。通过流式细胞术分析 T 细胞免疫表型。通过细胞内细胞因子染色分析 CD4 T 细胞、Th1、Th2 和 Th17 等 Th 细胞。通过 CD45RAFoxp3 T 细胞和幼稚 T（CD45RAFoxp3）、效应 T（CD45RAFoxp3）和非抑制性 T（CD45RAFoxp3）比例来确定调节性 T 细胞（T、Foxp3）。
通过单因素方差分析和卡方检验分析，各组的平均发病年龄（9.9-13.8 岁）和性别比例在 MOGR、MOGNR、MS 和对照组患者之间相似。与未刺激的 rh-MOG 刺激的 T 细胞相比，MOGAD 中观察到 Th2 和 Th17 细胞比例显著增加。MOGNR 中 Th17 细胞增加显著（均值：0.63±0.15 vs. 1.36±0.43；Wilcoxon 检验=0.03），但在 MOGR 中没有。MOGNR 中 CD4 T 细胞显著增加（均值：3.51±0.7 vs. 4.59±1.33；Wilcoxon 检验=0.046），而 MOGR 中 CD4 T 细胞减少。MOGR 中 CD45RAFoxp3 T 细胞显著减少（均值：2.37±0.23 vs. 1.99±0.17；配对 t 检验=0.021），但在 MOGNR 中没有。MOGR 中效应 T/非抑制性 T 的比例最高，明显高于 MOGNR。
我们的研究结果表明，CD4 Th2 和 Th17 细胞参与了儿童 MOGAD 的病理生理学。MOGNR 中 T 对 rh-MOG 的反应与 MOGR 相反，MOGNR 中 CD4 T 增加，而 MOGR 中 CD45RAFoxp3 T 减少，这表明 MOGR 中可能对 MOG 自身抗原失去了耐受性，这可能解释了这种复发性儿科自身免疫性疾病的复发。
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