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Fast-acting autoantibodies muscle in on encephalitis

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Science Immunology  06 Dec 2019:
Vol. 4, Issue 42, eaba3068
DOI: 10.1126/sciimmunol.aba3068

Abstract

Autoantibodies that recognize the glycine receptor mediate pathology by directly interrupting glycinergic neurotransmission that manifests as a disorder characterized by muscle stiffness and spasms.

Patients with autoimmune encephalitis display symptoms that can include changes to thought, perception, and memory, and they can experience seizures and abnormal movements. This presentation has often led to patients being categorized as having psychiatric disorders. Some of these cases were found to have autoantibodies directed against neurological antigens and accordingly, could be successfully treated with immunomodulatory therapy. Thus, an emerging paradigm demonstrates that autoimmunity underlies the pathology in a number of disorders previously deemed as psychiatric or neurologic. Anti-glycine receptor (GlyR) autoantibodies are present in patients with progressive encephalitis rigidity and myoclonus (PERM) or stiff person syndrome (SPS). These patients experience muscle rigidity, painful spasms, and stimulus-triggered responses displaying characteristics of exaggerated startling. If left untreated, these disorders can lead to disability and death. Not all autoantibodies are pathogenic and treatment with immunomodulatory drugs can have adverse effects. Consequently, it is important to determine the pathogenic mechanisms to inform treatment decisions.

Crisp et al. identified three PERM and one SPS patient who had detectable circulating GlyR autoantibodies. Patient-derived immunoglobulin disrupted neurotransmission as evaluated by whole-cell patch clamp studies. The authors noted that divalent autoantibodies that target central nervous system (CNS) neurotransmitter receptors in other disorders exert their pathogenicity by cross-linking and internalizing receptors; a process that requires considerable time (hours) to manifest. Observing the rapid (15 min) pathogenic affect with patient-derived autoantibodies, the authors tested monovalent Fab versions of the autoantibodies—which cannot cross-linkthe antigen—and demonstrated that they retained pathogenic capacity. These findings indicate GlyR autoantibodies exert their pathogenic function through blocking the receptor function rather than cross-linking.

These findings have profound impact for patients and their care providers. The unambiguous demonstration of an autoimmune-based pathology in these patients provides justification for treatment with immunomodulatory therapies. B cell depletion or reduction of circulating immunoglobulin with FcRn inhibitors represent viable candidate treatment strategies that were not previously considered for these disorders. Finally, it will be of great interest to learn more details about the autoimmune mechanisms. Identifying the autoimmune B cell phenotype, IgG subclass effector functions, and the role of T cells will provide insight into the immunopathology that may lead to patient-tailored treatment approaches.

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