N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G (IgG) is thought to be among the most frequent antineuronal antibodies in clinically asymptomatic individuals. Whether maternal antibodies in asymptomatic NMDAR-IgG carriers reach the fetal brain and affect fetal development promoting neurodevelopmental disorders remain unknown. In this issue of Annals of Neurology, Jurek et al establish a murine model of in utero exposure to human NMDAR antibodies to determine whether maternal autoantibodies are a risk factor for impaired brain development in the neonate. NMDAR encephalitis is the most frequent antibodyassociated encephalitis. Evidence suggests that maternal immune responses against distinct neuronal proteins could influence development of autism spectrum disorder, learning disability, and schizophrenia. Maternal transfer of antibodies occurs during the early stage of the second trimester of gestation, when the blood–brain barrier is still permeable, creating a critical window for potentially harmful antineuronal antibodies to compromise fetal brain development. The seroprevalence of up to 1% creates a considerable subgroup of asymptomatic pregnant women at risk of transferring the NMDAR antibodies to the fetus. Antibodies against the NR1 (GluN1) subunit of the NMDAR bind and crosslink the receptor, eventually leading to receptor internalization. The resulting alteration in postsynaptic currents and impairment of long-term potentiation lead to a characteristic clinical phenotype of progressive psychiatric symptoms, cognitive impairment, seizures, and speech problems. To assess gestational antibody transfer, the authors established a mouse model of in utero exposure to human monoclonal NR1 antibodies. Recombinant human monoclonal NR1-reactive IgG antibodies, previously cloned from 2 female patients with acute NMDAR encephalitis, were injected into the peritoneum at gestational days 13 and 17. Control mice were injected with an isotype-matched control antibody. Jurek et al observed that antibodies transferred across the placenta and bound to synaptic structures within the neonatal brain. Furthermore, NMDAR density was reduced and electrophysiological properties were altered in early postnatal life. Mortality was increased in NR1 antibody–exposed offspring. Surprisingly, maternal anti-NMDAR antibodies delayed neurodevelopment in neonates, reduced anxiety behavior, and impaired prepulse inhibition in adult offspring. To translate these finding from a murine model to a clinical setting, the authors compared serum anti-NR1 IgG reactivity by flow cytometry in mothers of children with psychiatric disorders to those of mothers with healthy children. NMDAR antibody titers were slightly higher in the mothers of affected children, suggesting that asymptomatic mothers of affected children may transmit antibodies vertically to the unborn fetus, predisposing their offspring to a spectrum of psychiatric disorders. Diaplacental antibody transfer is a key mechanism of maternal immune protection of the fetus. Maternal IgG is transferred via neonatal Fc-receptor at the beginning of the second trimester (Fig). However, only limited data are available regarding gestational transfer of maternal antibodies in diseases with antineuronal antibodies. Maternal–fetal antibody transfer has been shown to have deleterious effects in murine models of anti-NR2B (GluN2B) antibodies, anti-Caspr2 antibodies, and anti–fetal brain antibodies from mothers of children with autism spectrum disorder. Pathogenic mechanisms of these transferred antibodies include disruption of NMDAR currents and NMDAR hypofunction. One could envisage that NMDAR hypofunction at a critical gestational age could lead to persistent neurologic deficits that predispose to neuropsychiatric disorders that may occur long after antibody clearance. However, there are several issues that need to be addressed. First, although the elevation in NMDAR antibodies in asymptomatic mothers was statistically significant, it was quite small. Thus, it is important to replicate the findings in this investigation and confirm the effect size. The authors provide evidence that diaplacentally transmitted NMDAR antibodies accumulate

中文翻译：

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母体抗 N-甲基-D-天冬氨酸受体抗体是否促进儿童神经精神疾病的发展？

N-甲基-D-天冬氨酸受体（NMDAR）免疫球蛋白G（IgG）被认为是临床无症状个体中最常见的抗神经元抗体之一。无症状 NMDAR-IgG 携带者中的母体抗体是否到达胎儿大脑并影响胎儿发育，促进神经发育障碍仍然未知。在本期神经病学年鉴中，Jurek 等人建立了子宫内暴露于人 NMDAR 抗体的小鼠模型，以确定母体自身抗体是否是新生儿大脑发育受损的危险因素。NMDAR 脑炎是最常见的抗体相关脑炎。有证据表明，母体针对不同神经元蛋白的免疫反应可能会影响自闭症谱系障碍、学习障碍和精神分裂症的发展。抗体的母体转移发生在妊娠中期的早期阶段，此时血脑屏障仍然是可渗透的，这为潜在有害的抗神经元抗体破坏胎儿大脑发育创造了一个关键窗口。高达 1% 的血清阳性率产生了相当多的无症状孕妇亚组，这些亚组有将 NMDAR 抗体转移给胎儿的风险。针对 NMDAR 的 NR1 (GluN1) 亚基的抗体与受体结合并交联，最终导致受体内化。由此产生的突触后电流的改变和长时程增强的损害导致进行性精神症状、认知障碍、癫痫发作和言语问题的特征性临床表型。为了评估妊娠抗体转移，作者建立了子宫内暴露于人单克隆 NR1 抗体的小鼠模型。之前从 2 名患有急性 NMDAR 脑炎的女性患者中克隆的重组人单克隆 NR1 反应性 IgG 抗体在妊娠第 13 天和第 17 天被注射到腹膜中。对照小鼠注射了同种型匹配的对照抗体。Jurek 等人观察到抗体通过胎盘转移并与新生儿大脑内的突触结构结合。此外，在出生后早期，NMDAR 密度降低，电生理特性发生改变。暴露于 NR1 抗体的后代的死亡率增加。令人惊讶的是，母体抗 NMDAR 抗体延迟了新生儿的神经发育，减少了焦虑行为，并削弱了成年后代的前脉冲抑制。为了将这些发现从小鼠模型转化为临床环境，作者通过流式细胞术比较了患有精神疾病的儿童的母亲与健康儿童的母亲的血清抗 NR1 IgG 反应性。NMDAR 抗体滴度在受影响儿童的母亲中略高，这表明受影响儿童的无症状母亲可能会将抗体垂直传播给未出生的胎儿，使其后代易患一系列精神疾病。胎盘抗体转移是母体免疫保护胎儿的关键机制。母体 IgG 在妊娠中期开始时通过新生儿 Fc 受体转移（图）。然而，关于抗神经元抗体疾病中母体抗体的妊娠转移的可用数据有限。母胎抗体转移已被证明对患有自闭症谱系障碍儿童的母亲的抗 NR2B (GluN2B) 抗体、抗 Caspr2 抗体和抗胎儿脑抗体的小鼠模型具有有害影响。这些转移抗体的致病机制包括破坏 NMDAR 电流和 NMDAR 功能减退。人们可以设想，NMDAR 在关键胎龄时功能减退可能会导致持续的神经功能缺损，从而导致在抗体清除后很长时间内可能发生的神经精神疾病。但是，有几个问题需要解决。首先，尽管无症状母亲的 NMDAR 抗体升高具有统计学意义，但幅度很小。因此，重要的是复制本调查中的发现并确认效应大小。