Myelin oligodendrocyte glycoprotein antibody disease: incidence, prevalence, outcome prediction and immunopathology

项目总结/摘要 髓鞘少突胶质细胞糖蛋白抗体病（MOGAD）的发作可使患者失明， 瘫痪或昏迷，并与其他脱髓鞘疾病，如多发性硬化症（MS） 和水通道蛋白-4（AQP 4）-IgG阳性视神经肌病谱系障碍（NMOSD）是至关重要的， 临床过程、治疗和预后的主要差异。MOGAD的主要知识差距阻碍了 患者护理和理解其发病机制的障碍。没有MOGAD发生率， 流行率数据和对全球流行病学的有限了解直接影响到何时 订购MOG-IgG、医疗保健规划、临床试验设计和风险因素识别。缺乏 关于MOG-IgG滴度和持续性影响治疗的预后价值的前瞻性美国数据 决策临床医生使用脑脊液（CSF）中的MOG-IgG来诊断MOGAD，但关于其 与已建立的血清MOG-IgG的效用相比，诊断效用有限。MRI数据有限 进化和免疫病理学阻碍了我们对MOGAD发病机制的理解。长期目标是 更好地诊断、治疗和理解MOGAD。本提案的目的是确定 和MOGAD的患病率，MOG-IgG检测的预后价值，CSF MOG-IgG的诊断效用， MRI病变的演变和免疫病理学。核心假设（由申请人支持） 初步数据）是MOGAD流行病学与美国的AQP 4-IgG相似，但因地区而异， 血清MOG-IgG持久性和高滴度预测复发，CSF MOG-IgG缺乏诊断效用， MOGAD MRI病变比MS更容易消退，MOGAD的免疫病理学特征可以 被定义。理由是这些发现将直接影响患者护理，促进临床试验准备， 增强对发病机制的理解，并导致新治疗方法的开发。假设是 通过追求三个具体目标进行测试：1）确定基于人群的发病率，患病率和 在世界多个地区，MOGAD与AQP 4-IgG和MS的频率; 2）确定预后 MOG-IgG滴度和持久性的值，评估CSF MOG-IgG的效用并比较MRI演变与MS 3）明确MOGAD的免疫病理学特征，并与MS和AQP 4-IgG进行比较 NMOSD。为了做到这一点，我们将利用最大的临床，血清流行病学和病理生物库， 脱髓鞘疾病该方法是创新的，因为它使用了一种新的活细胞流式细胞术 由申请人团队开发的基于MOG-IgG的测定。这项拟议的研究意义重大，因为它是 预计将指导资源分配，通过提供诊断指导直接影响患者护理， 治疗方法并深入了解发病机制。最终，免疫病理学的知识可能会导致 开发类似于AQP 4-IgG NMOSD病理学中补体沉积的新型治疗方法 导致2期和3期试验显示依库珠单抗（一种补体抑制剂）的疗效和安全性。

PROJECT SUMMARY/ABSTRACT Attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can render a patient blind, paralyzed or comatose and distinguishing it from other demyelinating diseases such as multiple sclerosis (MS) and aquaporin-4(AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD) is crucial given the major differences in clinical course, treatment and prognosis. Major knowledge gaps in MOGAD are hindering patient care and a barrier to understanding its pathogenesis. The absence of MOGAD incidence and prevalence data and limited knowledge on its epidemiology worldwide directly impacts decisions on when to order MOG-IgG, healthcare planning, clinical trial design and identification of risk factors. The lack of prospective USA data regarding the prognostic value of MOG-IgG titer and persistence impacts treatment decisions. MOG-IgG in cerebrospinal fluid (CSF) is used by clinicians to diagnose MOGAD, yet data on its diagnostic utility is limited compared to the established utility of serum MOG-IgG. The limited data on MRI evolution and immuno-pathology hinders our understanding of MOGAD pathogenesis. The long-term goal is to better diagnose, treat, and understand MOGAD. The objective of this proposal is to determine the incidence and prevalence of MOGAD, the prognostic value of MOG-IgG testing, the diagnostic utility of CSF MOG-IgG, the evolution of MRI lesions and the immunopathology. The central hypotheses (supported by the applicants preliminary data) is that MOGAD epidemiology is similar to AQP4-IgG in the USA but varies by region, that serum MOG-IgG persistence and high titer predict relapse, that CSF MOG-IgG lacks diagnostic utility, that MOGAD MRI lesions resolve more often than MS and that immuno-pathological characteristics of MOGAD can be defined. The rationale is that these findings will directly impact patient care, facilitate clinical trial readiness, enhance understanding of pathogenesis, and lead to development of novel treatments. The hypothesis will be tested by pursuing three specific aims: 1) To determine the population-based incidence, prevalence and frequency of MOGAD versus AQP4-IgG and MS across multiple world regions; 2) To identify the prognostic value of MOG-IgG titer and persistence, assess the utility of CSF MOG-IgG and compare MRI evolution to MS and AQP4-IgG NMOSD; 3) To define the immuno-pathology of MOGAD and compare it to MS and AQP4-IgG NMOSD. To do this we will utilize the largest clinical, sero-epidemiologic and pathologic biobank of demyelinating disease in the world. The approach is innovative because it uses a novel live-cell flow cytometry based MOG-IgG assay developed by the team of applicants. The proposed research is significant because it is expected to guide resource allocation, directly impact patient care by providing guidance on diagnostics and therapeutics and give insight into pathogenesis. Ultimately, the knowledge of immunopathology may lead to the development of novel treatments similar to how complement deposition in AQP4-IgG NMOSD pathology led to phase 2 and 3 trials showing efficacy and safety of eculizumab (a complement inhibitor).