Molecular and cellular mechanisms underlying anti-neuronal antibody mediated disorders of the central nervous system.
Over the last decade multiple autoantigens located on the plasma membrane of neurons have been identified. Neuronal surface antigens include molecules directly involved in neurotransmission and excitability. Binding of the antibody to the antigen may directly alter the target protein's function, resulting in neurological disorders. The often striking reversibility of symptoms following early aggressive immunotherapy supports a pathogenic role for autoantibodies to neuronal surface antigens. In order to better understand and treat these neurologic disorders it is important to gain insight in the underlying mechanisms of antibody pathogenicity. In this review we discuss the clinical, circumstantial, in vitro and in vivo evidence for neuronal surface antibody pathogenicity and the possible underlying cellular and molecular mechanisms. This review shows that antibodies to neuronal surface antigens are often directed at conformational epitopes located in the extracellular domain of the antigen. The conformation of the epitope can be affected by specific posttranslational modifications. This may explain the distinct clinical phenotypes that are seen in patients with antibodies to antigens that are expressed throughout the brain. Furthermore, it is likely that there is a heterogeneous antibody population, consisting of different IgG subtypes and directed at multiple epitopes located in an immunogenic region. Binding of these antibodies may result in different pathophysiological mechanisms occurring in the same patient, together contributing to the clinical syndrome. Unraveling the predominant mechanism in each distinct antigen could provide clues for therapeutic interventions.
Department of Biology, Division of Cell Biology, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. Electronic address: M.HvanCoevorden-Hameete@uu.nl.
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MH
van Coevorden-Hameete
Department of Biology, Division of Cell Biology, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. Electronic address: E.deGraaff@uu.nl.
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de Graaff
Department of Neurology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Electronic address: M.Titulaer@erasmusmc.nl.
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MJ
Titulaer
Department of Biology, Division of Cell Biology, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. Electronic address: C.Hoogenraad@uu.nl.
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Hoogenraad
Department of Neurology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Electronic address: P.Sillevissmit@erasmusmc.nl.
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Sillevis Smitt
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D002493:Central Nervous System Diseases / Q000276:immunology*; D006801:Humans; D007473:Ion Channels / Q000276:immunology; D009474:Neurons / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000276:immunology
D000906:Antibodies; D000941:Antigens; D007473:Ion Channels; D043562:Receptors, G-Protein-Coupled
Antibody; Autoimmune encephalitis; Cell surface antigen; Central nervous system; Ion channel; Neurotransmitter receptor