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Neuronal autoantigens—pathogenesis, associated disorders and antibody testing

Abstract

The discovery of disorders that are associated with antibodies to neuronal cell-surface proteins has led to a paradigm shift in our understanding of CNS autoimmunity. These disorders can occur in patients with or without cancer—often children or young adults who develop psychosis, catatonic or autistic features, memory problems, abnormal movements, or seizures that were previously considered idiopathic. The autoantigens in such cases have crucial roles in synaptic transmission, plasticity and peripheral nerve excitability. Patients can be comatose or encephalopathic for months and yet fully recover with supportive care and immunotherapy. By contrast, disorders in which the antibodies target intracellular antigens, and in which T-cell-mediated irreversible neuronal degeneration occurs, show a considerably poorer response to treatment. In this article, we review the various targets of neuronal antibodies, focusing predominantly on autoantigens located on the cell surface or synapses—namely, N-methyl-D-aspartate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, γ-aminobutyric acid receptors, leucine-rich glioma-inactivated protein 1, contactin-associated protein-like 2, and metabotropic glutamate receptors. We also provide an algorithm to identify and assess antibodies that bind to cell-surface and synaptic antigens.

Key Points

  • Antibodies that target neuronal antigens are becoming increasingly recognized

  • Antibodies to intracellular neuronal antigens may mark a T-cell response that targets neurons

  • Antibodies to cell-surface and synaptic antigens are associated with seizures and psychosis, as well as disorders of memory, behaviour, cognition and movement; such antibodies may be directly pathogenic

  • Many patients with antibodies to cell-surface antigens respond to treatment

  • Assessment of clinical phenotype and analysis of serum and cerebrospinal fluid are crucial for identification of known and novel autoantibodies

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Figure 1: Autoantigens and mechanisms of neuronal dysfunction.
Figure 2: Caspr2 interaction with juxtaparanodal proteins.
Figure 3: Algorithm for identification and assessment of antibodies to neuronal cell-surface antigens.

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Acknowledgements

This work is supported in part by grants to J. Dalmau from the NIH (RO1NS077851 and RO1MH094741), the National Cancer Institute (RO1CA089054), Fundació la Marató TV3 and Fondo de Investigaciones Sanitarias (FIS, PI11/01780), and Euroimmun. This work is also supported in part by grants to E. Lancaster from the National Organization for Rare Disorders and the Dana Foundation.

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Both authors contributed to researching data for the article, discussion of the content, writing the article, and review and/or editing of the manuscript before submission.

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Correspondence to Eric Lancaster.

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E. Lancaster receives grant support from Lundbeck and Talecris. J. Dalmau is a patent holder of antibody tests from the University of Pennsylvania, and receives grant support from Euroimmun.

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Lancaster, E., Dalmau, J. Neuronal autoantigens—pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8, 380–390 (2012). https://doi.org/10.1038/nrneurol.2012.99

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