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Defining the autoimmune mechanisms driving human MOG antibody disease pathology

定义驱动人类 MOG 抗体疾病病理学的自身免疫机制

基本信息

批准号：
10748070
负责人：
Kevin C O'connor
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748070
关键词：
Address Adopted Adult Affect Antibodies Antigens Area Astrocytes Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Automobile Driving B cell repertoire B cell therapy B-Cell Antigen Receptor B-Lymphocyte Subsets B-Lymphocytes Binding Biological Assay Bladder CD19 gene Cell-Mediated Cytolysis Cells Central Nervous System Clinical Clinical Trials Clonality Cloning Complement Complement Activation Complement Inactivators Complement-Dependent Cytotoxicity Complex Mixtures Demyelinations Detection Diagnostic Dimensions Disease Disease Progression Disease model Elements Epitope Mapping Experimental Designs Flow Cytometry Frequencies Gene Expression Goals Human IgG autoantibodies IgG1 Immunoglobulin A Immunoglobulin G Immunoglobulin M Impaired cognition In Vitro Individual Inflammatory Infrastructure Intestines Investigation Knowledge Laboratories Libraries MS4A1 gene Measures Mediating Modeling Molecular Monitor Monoclonal Antibodies Motor Multiple Sclerosis Nature Neuromyelitis Optica Pathogenicity Pathology Patients Peripheral Blood Mononuclear Cell Phenotype Plasma Cells Plasmablast Prediction of Response to Therapy Production Property Public Health Qualifying Recombinants Role Serum Somatic Mutation Specificity Study of serum Syndrome Testing Therapeutic Therapeutic Intervention Tissue Stains Tissues Visual Work antibody-dependent cell cytotoxicity antigen binding aquaporin 4 autoreactive B cell biobank care providers central nervous system demyelinating disorder clinical phenotype clinically relevant experience experimental study glycosylation high dimensionality human monoclonal antibodies immunopathology mouse model novel novel strategies novel therapeutics oligodendrocyte-myelin glycoprotein pathogenic autoantibodies personalized therapeutic rituximab single-cell RNA sequencing therapeutic target tool water channel

项目摘要

Project Summary. Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) is an inflammatory demyelinating central nervous system condition. MOGAD is a newly defined autoimmune disease that has clinical phenotypic overlap with multiple sclerosis (MS) and aquaporin 4 (AQP4) autoantibody positive neuromyelitis optica spectrum disorder (NMOSD), but all three conditions are now recognized as being distinct. MOGAD is characterized by IgG1 subclass MOG-specific autoantibodies. Patients can present with visual, motor, ambulatory, bladder, bowel and/or cognitive dysfunction. The mechanisms by which MOG autoantibodies mediated pathology is not well understood. This is important to understand given the availability of therapeutics that can target these autoantibody effector functions. In addition, the specific B cell subtypes that express MOG autoantibodies have not been identified. This additional gap in our knowledge also presents consequences for MOGAD patient treatment, given that different therapeutic B cell depletion approaches are effective against distinct B cell subsets. To address these gaps in our understanding of this disease we will: (i) Generate human monoclonal MOG autoantibodies from patients; (ii) Use novel approaches to define and measure the different mechanisms of MOG autoantibody pathogenicity. Specifically focusing on complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), given that human IgG1 antibodies include these pathogenic mechanisms, and (iii) Perform deep single cell phenotyping on the specific B cells that express human MOG autoantibodies. To accomplish these aims, we have developed a unbiased high-throughput approach for producing MOG- specific human mAbs by cloning single B cells. This approach will afford production of a diverse MOG-specific mAb library. New approaches to study the different effector mechanisms of MOG autoantibody pathogenicity have also been developed. Specifically, we developed high-throughput flow cytometry assays to measure complement activity (CA), CDC, and ADCC of live cells expressing human MOG. These experiments will define how the specificity and molecular properties of MOG autoantibodies are associated with pathogenic effector function. Finally, we will define the phenotypes of autoantibody-producing B cell subsets using high dimensional flow cytometry and single cell RNA sequencing approaches. Overall, this investigation will: (i) provide a set of well-characterized human mAbs which will serve as tools for more accurate modeling of MOGAD pathology; (ii) identify the cellular contributors to autoantibody production (iii) and importantly for translational value, identify potential new therapeutic avenues for treating MOGAD through specifically targeting MOG autoantibody effector functions (with complement inhibitors) and/or production by autoreactive B cells through CD19 or CD20-mediated B cell depletion therapy.

项目摘要。髓鞘少突胶质细胞糖蛋白（MOG）抗体病（MOGAD）是一种炎症性疾病，中枢神经系统脱髓鞘疾病MOGAD是一种新定义的自身免疫性疾病，多发性硬化（MS）和水通道蛋白4（AQP 4）自身抗体阳性的临床表型重叠视神经肌萎缩症谱系障碍（NMOSD），但所有这三种条件现在被认为是不同的。 MOGAD的特征在于IgG 1亚类MOG特异性自身抗体。患者可以表现为视觉，运动、行走、膀胱、肠和/或认知功能障碍。MOG自身抗体的机制介导的病理学还没有被很好地理解。鉴于治疗方法的可用性，理解这一点很重要能够针对自身抗体效应子功能。此外，表达MOG的特定B细胞亚型尚未鉴定出自身抗体。我们知识中的这一额外差距也对以下方面产生了影响：考虑到不同的治疗性B细胞耗竭方法对MOGAD患者治疗有效，不同的B细胞亚群。为了解决我们对这种疾病的理解中的这些差距，我们将：患者的MOG自身抗体;（ii）使用新方法定义和测量不同的机制 MOG自身抗体的致病性。特别关注补体依赖性细胞毒性（CDC），抗体依赖性细胞毒性（ADCC），因为人IgG 1抗体包括这些致病性机制，和（iii）对表达人MOG的特异性B细胞进行深单细胞表型分析自身抗体为了实现这些目标，我们开发了一种无偏倚的高通量方法来生产MOG- 通过克隆单个B细胞来制备特异性人mAb。这种方法将提供一个不同的MOG特定的生产 mAb文库。研究MOG自身抗体致病性不同效应机制的新方法也已经开发了。具体来说，我们开发了高通量流式细胞术测定，补体活性（CA）、CDC和ADCC。这些实验将定义 MOG自身抗体的特异性和分子特性如何与致病性效应子相关功能最后，我们将使用高维度的方法定义产生自身抗体的B细胞亚群的表型。流式细胞术和单细胞RNA测序方法。总体而言，这项研究将：（i）提供一套充分表征的人单克隆抗体，其将作为工具， MOGAD病理学的更准确建模;（ii）识别自身抗体产生的细胞贡献者 (iii)对于翻译价值来说，重要的是，确定治疗MOGAD的潜在新治疗途径通过特异性靶向MOG自身抗体效应子功能（用补体抑制剂）和/或自身反应性B细胞通过CD 19或CD 20介导的B细胞耗竭疗法产生。