Regarding the causative diseases of ES patients

Regarding the causative diseases of ES, patients with unknown cause and those with encephalitis had significantly higher CSF levels of alk5 against GluN2B-NT2 and GluN2B-CT than the disease controls, but patients with genetic disorder and those with cortical dysplasia showed no significant difference compared with disease controls. Especially, in ES patients with unknown cause or preceding encephalitis, secondary immune-mediated pathophysiology may contribute to the production of antibodies to NMDA-type GluRs, and subsequent poor motor and cognitive outcomes. We previously reported that patients with antibodies against GluN2B by immunoblot in CSF during chronic stage after acute encephalopathy associated with influenza virus infection had higher frequency of epileptic seizures. Patients with partial epilepsy after acute encephalitis have higher antibodies against GluN2B-NT2, GluN2B-CT, GluN1-NT and GluN1-CT than patients without acute encephalitis. Antibodies to NMDA-type GluR were produced in the recovery stage of acute encephalitis by herpes simplex virus and trigger the brain autoimmunity. Neuronal death associated with acute encephalitis may induce the production of antibodies to neural molecules, and the antibodies may contribute to the ictogenesis, motor dysfunction, cognitive dysfunction, etc. To improve seizure outcomes in ES patients with unknown cause and encephalitis, immunological factors including antibodies against NMDA-type GluRs should be investigated to reveal secondary immunological pathogenesis. In patients with ES of unknown cause, we found that CSF level of antibodies against NMDA-type GluR showed evidence of correlation within a linear regression model until 25 months after the onset (Fig. 5-D). Several functions of antibodies against NMDA-type GluR have been reported, such as internalization of NMDA-type GluR complex,15, 16 apoptosis induction, and disrupted surface cross-talk. These pathophysiological mechanisms of the antibodies lead to hypo-function of NMDA-type GluR in synapse, and impair cognitive and motor learning. Recently, we have found that rabbit antibodies to human GluN2B-NT2 affected behavior and memory in passive transfer to mice hippocampi.19, 20 Patients of ES with higher levels of antibodies to GluN2B-NT2 & CT tend to have poor motor and cognitive outcomes, but not poor seizure outcome. The antibodies produced after onset of ES may affect the motor and cognitive outcomes via dysfunction of NMDA-type GluR. Prevention of antibody production in the chronic stage of ES may contribute to improvement of motor and cognitive outcomes. There has been considerable interest in immunopathology of ES, because ACTH therapy is effective in approximately 60% of the patients. Shiihara et al. reported that IL-1a, IL-5, IL-6, IL-15, IL-10 were high in patients with West syndrome before ACTH treatment, and that CD4+ T cells and CD3+ T cells were also high. Antibodies against voltage-gated potassium channel were found in a patient with infantile spasms. Suleiman et al. reported that 11 of 114 patients with childhood epilepsy had autoantibodies, and four had antibodies to NMDA-type GluR.
Funding This study was funded in part by grants-in-aid for Scientific Research I No. 23591238, 2451537 and 15K09634, Health and Labour Sciences Research Grants for Comprehensive Research on Disability Health and Welfare (H20-Mental-General-021); Research on rare and intractable disease （H26-Intractable-General-051）（H26-Intractable-General-024）（H26-Itaku-General-065）; and grants from Japan Epilepsy Research Foundation.
Disclosure or conflict of interest
Introduction High fidelity of protein translation is maintained in cells by a family of multi-domain enzymes known as aminoacyl-tRNA synthetases (aaRSs) [1]. While aminoacylation of tRNA is the primary function of the catalytic domain, the anticodon-binding domain recognizes the correct tRNA with additional contributions to optimize the aminoacylation step [2]. Glutamyl-tRNA synthetase (GluRS) and glutaminyl-tRNA synthetase (GlnRS), two members of this family, are grouped in the GlxRS subclass because of the shared evolutionary pathway of their catalytic domains [3], [4]. The catalytic domain of Glx subfamily is believed to be more ancient, having evolved from a common GluRS ancestor that contained only the catalytic domain [3], [4]. Anticodon binding domains of extant bacterial and eukaryotic/archeal GlxRS appeared independently at a later stage, with the anticodon-binding domain of bacterial GlnRS being acquired by an unique horizontal gene transfer event from the eukaryotic kingdom [3], [4].