Cellular, synaptic, and circuit effects of antibodies in autoimmune CNS synaptopathies.
Recently, clinicians have identified overlapping but distinguishable encephalitides, each associated with antibodies in serum and cerebrospinal fluid directed against specific cell surface proteins. The antibody targets identified to date are proteins that modulate cell physiology, synaptic transmission, and circuit function. Clinical and laboratory evidence suggests that the anti-cell surface antibodies are not simply markers of disease, but are pathogenic. Patient antibodies to N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or gamma-aminobutyric acid-A (GABAA) receptors cause a loss of cognate receptors from synapses, while recent work has shown that antibodies to GABAB receptors directly antagonize receptor activity. Despite the distinct mechanisms by which patient antibodies abrogate the function of their targets, the resulting pathophysiology leads to abnormal circuit activity and plasticity, which manifests as patient signs and symptoms. Understanding the underlying synaptic and circuit mechanisms of patient autoantibody action may enable clinicians to develop diagnostics and therapies unique to each synaptic autoimmunity subtype, thereby improving patient identification and outcomes.
Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Ankit
A
Jain
Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Neuroscience and Pain Research Unit, Pfizer, Inc., Cambridge, MA, USA. Electronic address: rita.balice-gordon@pfizer.com.
Rita
R
Balice-Gordon
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology; D013569:Synapses / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000276:immunology
D001323:Autoantibodies; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid
Autoimmune encephalitis; anti-NMDA receptor encephalitis; autoimmune synaptopathy; synaptic autoimmunity