视神经脊髓炎谱系疾病(NMOSD)是一类多复发、选择性损伤视神经和脊髓的自身免疫性疾病，除AQP-4自身抗体外，部分患者被检测到髓鞘少突胶质细胞糖蛋白（MOG）自身抗体,但MOG自身抗体的致病性至今仍是个悬而未解的临床问题。申请者在前期工作中，建立了已知最大的NMOSD样本库，申请了MOG自身抗体高特异检测方法的专利,证实了MOG自身抗体阳性患者IgG可介导补体依赖的细胞毒并可导致大鼠脱髓鞘损伤，表明了MOG自身抗体具有疾病发生相关性。患者来源IgG成分复杂,无法明确MOG自身抗体的致病性。本研究拟应用单细胞分选获得患者来源的浆细胞，扩增抗体基因，筛选并制备MOG重组单抗,于体外髓鞘模型和动物模型中验证MOG自身抗体是脱髓鞘发生及发展的关键因素；并探索阻断MOG抗体介导的补体依赖细胞毒对疾病的干预作用。研究MOG自身抗体在NMOSD中的致病机理对临床精确诊断及靶向性治疗将具有重要的

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory autoimmune disorders of the central nervous system that predominantly present with recurrent optic neuritis and transverse myelitis. The exact pathogenesis of NMOSD remains largely unknown. Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been described in patients with neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 antibodies (AQP4-IgG). However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. We previously developed a high sensitive cell-based assay for human MOG autoantibody detection (patent pending) and created the largest library of serum and DNA samples from NMOSD patients. We showed that total IgG from MOG-IgG seropositive patients with NMOSD initiated complement-dependent cytotoxicity and induced demyelination through passive antibody transfer in rat intracisternal injection model. Since MOG-specific autoantibodies are only a minor component of the serum IgG fraction, it remains unclear whether MOG-IgG contributes directly to disease pathogenesis or is a serologic marker of a broader autoimmune response. In this study, we plan to use fluorescence-activated cell sorting and single-cell reverse transcriptase polymerase chain reaction to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the peripheral lymphoid compartment of MOG-IgG seropositive patients. Monoclonal recombinant antibodies (rAbs) will be generated from the paired heavy and light chain sequences and tested for target MOG by cell-based assay. The effect of rAbs on CNS immunopathology will be investigated by in vitro demyelination model and passive antibody transfer in rat intracisternal injection model. Blocking complement-dependent cytotoxicity will be further investigated to evaluate whether it could be a potential therapeutic target for the clinical management of NMOSD. Identifying MOG autoantibody as a key component of NMOSD pathogenesis will improve diagnosis and treatment of NMOSD and offers a model for testing antibody and oligodendrocyte-targeted therapies in NMOSD.