Structural mechanisms of autoimmune diseases targeting cys-loop receptors

Project Summary/Abstract Autoimmunity against neuronal receptors causes an array of diseases. Cys-loop receptors are a class of neuronal receptors targeted in autoimmune diseases including myasthenia gravis, autoimmune encephalitis, and autoimmune autonomic ganglionopathy. Myasthenia gravis is the longest studied; antibodies against the neuromuscular nicotinic acetylcholine receptor were described in 1974. Autoimmune autonomic ganglionopathy was first identified in 2000 as being associated with antibodies against the ganglionic nicotinic acetylcholine receptors. Most recently, autoimmune encephalitis was associated with antibodies against the related GABAA receptor. Mechanisms underlying autoimmune pathology are poorly understood but are often attributed to receptor cross-linking and internalization. However, other mechanisms that include direct inhibition of neurotransmission are increasingly reported. We have access to blood and cerebrospinal fluid from patients suffering from myasthenia gravis, autoimmune autonomic ganglionopathy, and autoimmune encephalitis. Here we propose to identify and clone autoimmune antibodies that target Cys-loop receptors. We will examine functional receptor inhibition by patient-derived antibodies using electrophysiology. We will produce antibody fragments to determine structures of the antibody-receptor complexes from different autoimmune diseases. These structures combined with functional interrogation will illuminate conserved and divergent mechanisms of autoimmune disease in this important protein superfamily. This work will lay the foundation for expansion to other targets of the Cys-loop receptor family and beyond.