Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.

中文翻译：

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人髓磷脂少突胶质细胞糖蛋白抗体脱髓鞘反应的表征。

近年来，针对髓磷脂少突胶质细胞糖蛋白（MOG Ab）的人类自身抗体与涉及视神经，脊髓和大脑的单相和复发性中枢神经系统脱髓鞘有关。随着人们认识到多发性硬化症在治疗和预后方面的差异，MOG Ab检测的临床意义变得越来越清晰，但仍需要对人类MOG Ab进行深入表征，以应对患者诊断，治疗和预后方面的关键挑战。本文中，我们研究了139名和148名MOG抗体血清阳性儿童和成人（基线时n = 287例患者，纵向样本130例，脑脊液样本22例）中MOG Ab的表位，结合敏感性和亲和力。MOG胞外域也被固定以确定MOG Ab的亲和力。MOG Ab反应是免疫球蛋白G1亚型，是外周而不是鞘内起源。在15％的儿科和18％的成人血清中检测到高亲和力的MOG Ab。超过75％的儿科和成人MOG Ab靶向Proline42周围的显性细胞外抗原区域。MOG Ab滴度随疾病进展而波动，但对脯氨酸42的亲和力和反应性保持稳定。复发过程的成年人本质上表现出对脯氨酸42的免疫反应性降低，并且MOG Ab反应更为多样，这一特征可用于预测复发。在更严重的表型和活动性疾病期间观察到更高的MOG Ab滴度，支持了MOG Ab的致病作用。观察到MOG的构象变化时，MOG Ab血清阳性丧失了，这极大地影响了复发性疾病（通常被认为更为严重）的检测灵敏度。在检测与疾病相关的自身抗体时，应仔细考虑自身抗原的结合特性。