Friday, December 8, 2023
12/8/2023
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.
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