Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity
Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity
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DOI：
10.1038/mp.2013.110
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发表时间：
2014-10-01
影响因子：
11
通讯作者：
Ehrenreich, H.
中科院分区：
文献类型：
--
作者：
Hammer, C.;Stepniak, B.;Ehrenreich, H.
2007年，描述了一种与免疫球蛋白-G同种型抗NMDA受体自身抗体（NMDAR-AB）相关的多方面综合征，其不同程度地包括精神病、癫痫、认知能力下降和锥体外系症状。然而，NMDAR-AB 在复杂神经精神疾病与健康中的患病率和意义仍不清楚。我们检测了 2817 名受试者（1325 名健康受试者、1081 名精神分裂症受试者、263 名帕金森受试者和 148 名情感障碍受试者）的血清中是否存在 NMDAR-AB，进行了全基因组遗传关联研究，比较了 AB 携带者与非携带者，并评估了他们的流感 AB 状态。为了深入了解和记录 AB 功能，我们对血脑屏障缺陷 (ApoE(-/-)) 小鼠进行了体内实验，并在原代皮质神经元中进行了体外内吞测定。在 10.5% 的受试者中，检测到任何免疫球蛋白同种型的 NMDAR-AB（NR1 亚基），患者和健康对照之间的血清阳性率、滴度或体外功能没有差异。向小鼠施用提取的人血清仅影响注射 NMDAR-AB 阳性血清的 ApoE(-/-) 小鼠的基础活性和 MK-801 诱导的旷场活性，但不影响各自的对照。有神经外伤或出生并发症史的血清阳性精神分裂症患者（表明血脑屏障至少暂时受损）比具有类似病史的血清阴性患者有更多的神经系统异常。常见的基因变异（rs524991，P = 6.15E-08）以及既往甲型流感（P = 0.024）或乙型流感（P = 0.006）感染被确定为 NMDAR-AB 血清阳性的诱发因素。健康个体和患者的 NMDAR-AB 总体血清阳性率 >10% 出乎意料地高。然而，临床意义显然取决于与过去或现在血脑屏障功能扰动的关联。
In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P = 6.15E-08) as well as past influenza A (P = 0.024) or B (P = 0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.