Autoantibodies against the N-Methyl-d-Aspartate Receptor Subunit NR1: Untangling Apparent Inconsistencies for Clinical Practice.
Autoantibodies against the N-Methyl-d-Aspartate Receptor Subunit NR1: Untangling Apparent Inconsistencies for Clinical Practice.
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DOI：
10.3389/fimmu.2017.00181
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ehrenreich H
中科院分区：
文献类型：
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作者：
Ehrenreich H
这篇观点综述提供了关于 N-甲基-d-天冬氨酸受体 1 (NMDAR1) 自身抗体 (AB) 的看似矛盾的工作的综合图片。根据目前的知识状况，它为有关免疫抑制治疗的临床决策过程提供了建议。一般而言，脑抗原导向的AB和特别是NMDAR1-AB属于包括人类在内的哺乳动物预先存在的自身免疫系统。特定的自身免疫反应性 B 细胞可能会受到各种潜在刺激物（例如微生物组、感染或肿瘤）的反复（也许是短暂的）增强，并且在整个生命周期中受到不太有效的抑制（逐渐丧失耐受性），这可能解释了随着衰老而血清阳性率增加的原因（80 岁人类中 NMDAR1-AB > 20%）。 (I) 当 AB 特异性浆细胞在大脑中定居并在鞘内产生大量脑抗原导向的 AB 时，和/或 (II) 在血脑屏障 (BBB) 受损的情况下，例如在受伤、感染、炎症或遗传易感性（APOE4 单倍型）时，就会出现病理生理学意义，从而允许循环 AB 大量进入大脑。关于 NMDAR1-AB，已证明免疫球蛋白 (Ig) 类别（IgM、IgA 和 IgG）对体外神经元的功能影响和体内脑症状的诱发。在脑部炎症的情况下，鞘内产生和类别转换为 IgG 可能会引起脑脊液 (CSF) 和血清中 NMDAR1-AB（和其他脑抗原导向的 AB）水平升高，导致称为“抗 NMDAR 脑炎”的严重综合征，然后需要在病因性脑炎治疗（如果有）的基础上进行免疫抑制治疗。然而，阴性 CSF NMDAR1-AB 结果不能排除血清 NMDAR1-AB 对中枢神经系统的慢性影响，因为大脑充当“免疫沉淀器”，特别是在 BBB 受损的情况下。在任何怀疑针对脑抗原的循环 AB 产生症状后果的情况下，在考虑免疫抑制之前，应通过 CSF 分析（白蛋白商作为替代）和磁共振成像来评估 BBB 的渗漏。
This viewpoint review provides an integrative picture of seemingly contradictory work published on N-methyl-d-aspartate receptor 1 (NMDAR1) autoantibodies (AB). Based on the present state of knowledge, it gives recommendations for the clinical decision process regarding immunosuppressive treatment. Brain antigen-directed AB in general and NMDAR1-AB in particular belong to a preexisting autoimmune repertoire of mammals including humans. Specific autoimmune reactive B cells may get repeatedly (perhaps transiently) boosted by various potential stimulants (e.g., microbiome, infections, or neoplasms) plus less efficiently suppressed over lifespan (gradual loss of tolerance), likely explaining the increasing seroprevalence upon aging (>20% NMDAR1-AB in 80-year-old humans). Pathophysiological significance emerges (I) when AB-specific plasma cells settle in the brain and produce large amounts of brain antigen-directed AB intrathecally and/or (II) in conditions of compromised blood–brain barrier (BBB), for instance, upon injury, infection, inflammation, or genetic predisposition (APOE4 haplotype), which then allows substantial access of circulating AB to the brain. Regarding NMDAR1-AB, functional effects on neurons in vitro and elicitation of brain symptoms in vivo have been demonstrated for immunoglobulin (Ig) classes, IgM, IgA, and IgG. Under conditions of brain inflammation, intrathecal production and class switch to IgG may provoke high NMDAR1-AB (and other brain antigen-directed AB) levels in cerebrospinal fluid (CSF) and serum, causing the severe syndrome named “anti-NMDAR encephalitis,” which then requires immunosuppressive therapy on top of the causal encephalitis treatment (if available). However, negative CSF NMDAR1-AB results cannot exclude chronic effects of serum NMDAR1-AB on the central nervous system, since the brain acts as “immunoprecipitator,” particularly in situations of compromised BBB. In any case of suspected symptomatic consequences of circulating AB directed against brain antigens, leakiness of the BBB should be evaluated by CSF analysis (albumin quotient as proxy) and magnetic resonance imaging before considering immunosuppression.