hIgG1-G396R和HLA协同上调MOG-IgG1致MOG脑脊髓炎的机制研究

髓鞘少突胶质细胞糖蛋白（MOG）脑脊髓炎（MOG-ES）是新确定的神经免疫疾病。我们发现MOG-ES有别于多发性硬化和视神经脊髓炎（Neurosci Bull，Accepted；Eur J Neurol，PMID30153357），但其致病性抗MOG自身抗体（MOG-IgG）产生机制未明。我们还发现自身免疫疾病与遗传相关（J Neurol Neurosurg Psychiatry，PMID30636700），因此进一步进行全外显子关联分析发现hIgG1-G396R和HLA-DQB1*04:01基因与MOG-ES呈正相关并有协同效应，且都促进IgG1产生。由此我们推测两者协同引起MOG特异性B细胞产生高水平MOG-IgG1，增加MOG-ES易感性。本研究基于hIgG1-G396R和HLA-DQB1*04:01双敲入小鼠，阐明MOG-IgG产生的分子机制。将为MOG-ES的精准医疗提供干预靶点

Myelin oligodendrocyte glycoprotein (MOG) encephalomyelitis (MOG-ES) is a new neuroimmunological disease. Our previous studies found that MOG-ES is different from multiple sclerosis and neuromyelitis optica (Neurosci Bull, Accepted; Eur J Neurol, PMID 30153357), but the mechanism leading to the production of anti-MOG autoantibodies remains unclear. We have also found the influence of genetic factors on autoimmune diseases (J Neurol Neurosurg Psychiatry, PMID 30636700), so we conducted the Whole Exome Sequencing research and found that rs117518546 variant (hIgG1-G396R) and HLA-DQB1*04:01 were both positively related with MOG-ES and they had synergy. It has been proven that both genetic variants are associated with IgG1 production. Therefore, we propose for the first time a new mechanism for the susceptibility to MOG-ES:hIgG1-G396R and HLA-DQB1*04:01 promote the MOG-specific B cells which increase the production of high levels of MOG-IgG1,leading to increased susceptibility to MOG-ES.The aim of this study is to explore the molecular mechanism of MOG-IgG production based on double-knock in mice of hIgG1-G396R and HLA-DQB1*04:01.This study will lay an important foundation for future targeted treatment.