Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function.

OBJECTIVE: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. METHODS: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240µg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. RESULTS: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. INTERPRETATION: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.

Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis.

Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4+ T helper (TH) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive TH cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive TH cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis.

[Efficiency and specificity of the KAT-test for rapid diagnosis of falciparum malaria]. / Effektivnost' i spetsifichnost' KAT-testa pri ékspress-diagnostike tropicheskoi malarii.

A new rapid KAT Quick Malaria test for the diagnosis of falciparum malaria, which is based on the detection of a monoclonal antibody-antigen complex of malaria parasites, has been worked out by the KAT Medical CC in South Africa. The efficiency and specificity of the KAT test were compared with those of the microscopic method and with the ICT test for rapid diagnosis of P. falciparum and P. vivax. The polymerase chain reaction was used as a control test. Testing for malaria was performed on 98 blood samples from feverish patients in Vietnam and Tadjikistan and among the persons who had returned to Moscow from endemic regions. The efficiency of the KAT test for falciparum-malaria was found to be 100% versus 90.5% with ICT. The absence of cross-reactions with P. vivax and the presence of pseudopositive results of the KAT test for fever cases of non-malaria origin indicate its high specificity. There was no correlation between the rate of test line colouring and the level of parasitemia. The KAT test yielded positive results only when gametocytes were found in blood specimens.