Project 3

Project Summary. Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. MG patients suffer from severe muscle weakness and increased muscle fatigability due to diminished neuromuscular signaling. MG is caused by autoantibodies that target components of the neuromuscular junction (NMJ). The most common subtype of autoantibody-mediated MG—comprising approximately 80% of the patient population—is characterized by pathogenic autoantibodies targeting the nicotinic acetylcholine receptor (AChR). There is a subset of MG patients that are termed seronegative MG (SNMG). SNMG is defined by the absence of detectable autoantibodies to the known NMJ targets. The mechanisms underlying the immunopathology SNMG are poorly understood. Consequently, the impact on these patients is considerable; optimal treatment paradigms and outcomes are uncertain due to a lack of data and a poor understanding of disease mechanisms. In addition, SNMG patients are often not included in clinical trials in which autoantibody positive MG patients participate. To address this knowledge gap, we will identify immune mechanisms driving SNMG. This will be achieved through the application of high-throughput autoantibody-discovery technologies that allow for the screening of exceptionally large human antigen libraries. In the second part of this project, we will define new mechanisms participating in the autoantibody- mediated pathology of MG patients. Autoantibodies can mediate pathology through natural killer (NK) cell- mediated antibody dependent cellular cytotoxicity (ADCC) and macrophage mediated antibody dependent cellular phagocytosis (ADCP). We will apply in vitro assays, which we have newly developed, to measure ADCC and ADCP in serum from patients representing several subsets of MG (EOMG, LOMG and treatment refractory). This study is designed to provide detailed insights into the molecular mechanisms used by autoantibodies to facilitate the pathology of the MG subtypes. In addition to providing valuable candidate biomarkers, these newly defined immunomechanisms are expected to impact treatment outcomes through informing application of biological therapeutics used to treat specific MG disease subsets.