Structural mechanisms of autoimmune diseases targeting cys-loop receptors

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Principal Investigator: Ryan E Hibbs
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $638,821
Funding agency: National Institute of Neurological Disorders and Stroke

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.

Terms: <3-D><3-Dimensional><3D><5-HT Receptors><5-Hydroxytryptamine Receptors><Address><Affect><Anions><Antibodies><Antibody Fragments><Antigenic Determinants><Assay><Autoantibodies><Autoimmune><Autoimmune Diseases><Autoimmune Diseases of the Nervous System><Autoimmune Mechanism><Autoimmune Process><Autoimmune Status><Autoimmune encephalitis><Autoimmune encephalopathy><Autoimmune neurologic condition><Autoimmunity><Binding><Binding Determinants><Bioassay><Biochemistry><Biological Assay><Biological Chemistry><Blood><Blood Reticuloendothelial System><Brain Inflammation><Cations><Cell Surface Proteins><Cerebrospinal Fluid><Chromatography><Clinical><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Detection><Development><Disease><Disorder><Dysautonomias><Electron Cryomicroscopy><Electrophysiology><Electrophysiology (science)><Encephalitis><Epilepsy><Epileptic Seizures><Epileptics><Epitopes><Family><Fc Receptor><Fluorescence><Foundations><Glycine Receptors><Human><Immunoglobulin Fragments><Ion Channel Gating><Ion Channel Gatings><Knowledge><Laboratories><Ligands><Link><Maps><Mediating><Modern Man><Molecular><Molecular Interaction><Molecular Sieve Chromatography><Muscle><Muscle Tissue><Muscle Weakness><Muscular Weakness><Myasthenia Gravis><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System><Nervous System Autoimmune Disorders><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurohumor Receptors><Neurologic Autoimmune Diseases><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological Disorders><Neuromediator Receptors><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Neuroregulator Receptors><Neurotransmitter Receptor><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Pathogenesis><Pathogenicity><Pathology><Patients><Proteins><Receptor Inhibition><Receptor Protein><Reporting><Research><Research Resources><Resolution><Resources><Sampling><Seizure Disorder><Seizures><Size Exclusion Chromatography><Structure><Testing><Work><antibody based detection><antibody detection><antibody receptor><autoimmune antibody><autoimmune condition><autoimmune disease in the nervous system><autoimmune disorder><autoimmune reactivity><autoimmune-driven neurological disease><autoimmunity disease><autoreactive antibody><autoreactivity><axon signaling><axon-glial signaling><axonal signaling><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><cerebral spinal fluid><crosslink><cryo-EM><cryoEM><cryogenic electron microscopy><depository><design><designing><detect antibodies><developmental><electrophysiological><epilepsia><epileptogenic><experience><experiment><experimental research><experimental study><experiments><glia signaling><glial signaling><interest><muscular><nerve signaling><neural signaling><neuro-autoimmune disorder><neurologic autoimmune disorder><neurological disease><neuromuscular><neuronal><neuronal signaling><neurotransmission><novel><receptor><receptor binding><receptor bound><receptor function><receptor internalization><repository><resolutions><self reactive antibody><serotonin receptor><spinal fluid><structural biology><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional>