UT Southwestern researchers capture first image of antibody attacking neuron receptors

picture: Autoimmune encephalitis occurs when antibodies or T cells go bad and attack the brain. In this study, UTSW researchers and colleagues from Berlin used cryo-electron microscopy to determine the atomic structure of autoantibodies bound to GABAA receptors. The receptor is an important protein in the brain and a target in autoimmune encephalitis.
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Credit: UT Southwestern Medical Center

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Using the UT Southwestern Cryo-Electron Microscopy Facility, researchers have for the first time captured images of autoantibodies bound to nerve cell surface receptors, revealing the physical mechanisms behind neurological autoimmune disease. His findings, published in Cell, could lead to new ways to diagnose and treat autoimmune conditions, the study authors said.

“We are entering a new era of understanding how autoimmune diseases work in the central nervous system,” says Colleen M. Noviello, Ph.D., Assistant Professor of Neuroscience at UTSW who specializes in obtaining cryo-electron microscopy (cryo-EM). ) images up to atomic resolution. Dr. Noviello led the research with Ryan Hibbs, Ph.D., Associate Professor of Neuroscience and Biophysics, Effie Marie Cain Scholar in Medical Research, and Investigator Peter O’Donnell Jr. Brain Institute and Harald Prüss of the Universitätsmedizin Berlin.

Researchers have studied autoimmune diseases — a class of conditions in which the immune system attacks healthy parts of the body — for decades. However, the first autoimmune disease to target nerve receptor proteins was discovered just 15 years ago, Dr. Noviello explained. Since then, researchers have reported the presence of several other diseases that fall into this category. These include autoimmune encephalitis, a condition characterized by the sudden onset of severe symptoms including psychosis, seizures, movement disorders, impaired consciousness, and problems with the autonomic nervous system, which controls involuntary body functions.

Researchers in Germany recently identified a patient, then 8 years old, whose autoimmune encephalitis appeared to be caused by antibodies attacking the GABAA receptor, a protein that resides on the surface of synapses – special structures that connect brain cells. The role of these receptors is to inhibit the firing of neurons, balancing the electrical signals requested by excitatory receptors to maintain healthy signals between nerve cells.

After confirming that the two types of antibodies derived from the immune cells of these young patients easily bind to the GABAA receptor, Drs. Noviello, Hibbs, and their colleagues in the Hibbs lab performed cryo-EM — a technique that freezes proteins in place to obtain high-resolution microscopic images — for each antibody that binds to the receptor. The UTSW cryo-EM facility, opened in 2016 with support from the Cancer Prevention and Research Institute of Texas (CPRIT), provides 3D images of biological molecules at up to atomic resolution.

The images show that, both together and separately, the antibodies prevent the GABA receptor from inhibiting nerve signals, causing neurons to become electrically overexcited and causing brain inflammation, cell death, and the seizure characteristics of autoimmune encephalitis. Screening for these antibodies could lead to a better diagnosis of the condition, says Dr. Novello; also, finding ways to block interactions between these antibodies and their targets could lead to better ways to treat them.

Because the understanding of autoimmune nervous system diseases is still in its infancy, Dr. Hibbs said that he, Dr. Noviello, and their colleagues plan to make these perturbation studies using cryo-EM the focus of future Hibbs laboratory research. The team has worked closely with Steven Vernino, MD, Ph.D., Professor of Neurology, Vice Chair of Education and Faculty, and Distinguished Professor of Teaching; and Nancy Monson, Ph.D., Associate Professor of Neurology and Immunology, to study more autoimmune conditions that affect the central nervous system.

Dr. Vernino holds the Rex Griswold Distinguished Professorship in Multiple System Atrophy and Dr. Bob and Jean Smith Foundation Distinguished Chair in Neuromuscular Disease Research.

Other UTSW researchers who contributed to the study include Jinfeng Teng.

This study was supported by grants from The Welch Foundation (I-1812), National Institutes of Health (DA047325), German Research Foundation (FOR3004, PR 1274/3-1, and PR 1274/5-1), Helmholtz Association (HIL- A03), and the German Federal Ministry of Education and Research (Connect-Generate 01GM1908D). Single-particle cryo-EM data were collected at the UTSW Cryo-Electron Microscope Facility, supported by the CPRIT Core Facility Support Award RP170644.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with outstanding clinical care and education. The institute’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. A full-time faculty of more than 2,900 are responsible for innovative medical advances and are committed to rapidly translating science-driven research into new clinical treatments. UT Southwestern doctors provide care in more than 80 specialties to more than 100,000 inpatients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits per year.

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