Abstract
Over the last two decades, the discovery of antibodies directed against neuronal surface antigens (NSA-Abs) in patients with different forms of encephalitis has provided a basis for immunotherapies in previously undefined disorders. Nevertheless, despite the circumstantial clinical evidence of the pathogenic role of these antibodies in classical autoimmune encephalitis, specific criteria need to be applied in order to establish the autoimmune nature of a disease. A growing number of studies have begun to provide proof of the pathogenicity of NSA-Abs and insights into their pathogenic mechanisms through passive transfer or, more rarely, through active immunization animal models. Moreover, the increasing evidence that NSA-Abs in the maternal circulation can reach the fetal brain parenchyma during gestation, causing long-term effects, has led to models of antibody-induced neurodevelopmental disorders. This review summarizes different methodological approaches and the results of the animal models of N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibody-mediated disorders and discuss the results and the limitations. We also summarize recent experiments that demonstrate that maternal antibodies to NMDAR and CASPR2 can alter development in the offspring with potential lifelong susceptibility to neurological or psychiatric disorders.
Highlights
Over the last two decades, it has become clear that antibodies against neuronal surface antigens, receptor-gated ion channels of ion-channel-associated proteins, can reach the brain to cause a group of disorders referred to as antibody-mediated or autoimmune encephalitis (AE) [1]
Icv injection of purified plasmapheresis IgG from individuals with NMDAR-Ab encephalitis (NMDARE) induced, in association with a subthreshold dose of the chemo-convulsant pentylenetetrazol (PTZ), more frequent and severe seizures than a single injection of IgG from control individuals [(39); see Figure 3]; cognitive and other features were not examined in these mice
In a more recent study, EEG recordings of mice infused intraventricularly for 14 days with cerebrospinal fluid (CSF) N-methyl-d-aspartate receptor (NMDAR)-Abs showed a higher frequency of seizures compared with control mice, associated with variable behavior ranging from sleeping or normal exploratory activity to freezing and myoclonic jerks [42]
Summary
Over the last two decades, it has become clear that antibodies against neuronal surface antigens, receptor-gated ion channels of ion-channel-associated proteins, can reach the brain to cause a group of disorders referred to as antibody-mediated or autoimmune encephalitis (AE) [1]. Developed human-derived monoclonal antibodies to the NMDAR have produced similar pathogenic effects in vivo and in vitro and offer a promising less-limited resource (compared to human CSF and IgG) for future experimental studies [43].
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