Immunity and behavior: Antibodies alter emotion
Immunity and behavior: Antibodies alter emotion
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DOI：
10.1073/pnas.0510055103
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发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
Diamond, B
中科院分区：
文献类型：
--
作者：
Huerta, PT;Kowal, C;Diamond, B
系统性红斑狼疮是一种自身免疫性疾病，大多数患者表达结合双链 DNA 的抗体。最近的研究表明，狼疮抗体的一个子集可以与 NMDA 受体的 NR2A 和 NR2B 亚基发生交叉反应。这种受体在整个大脑的神经元中表达，但在海马、杏仁核和下丘脑的细胞内密度最高。中枢神经系统中的神经元通常受到血脑屏障 (BBB) 的保护，免受脑反应性抗体的影响；然而，屏障完整性的破坏会使神经元暴露于潜在致病性的抗体中。此前，我们已经证明，用 DNA 肽模拟表位免疫的小鼠会产生与 DNA 和 NMDA 受体发生交叉反应的狼疮样抗体。此外，在通过脂多糖治疗消除血脑屏障后，免疫小鼠表现出海马神经元损伤，并随之而来的记忆障碍。鉴于肾上腺素的升高会增加脑血流量并可能导致血脑屏障渗漏，我们决定研究肾上腺素是否可以作为抗体介导的神经毒性的许可剂。在这里，我们表明，给予肾上腺素以打开血脑屏障的肽免疫小鼠，其外侧杏仁核中的神经元丢失，并出现一种行为障碍，其特征是对恐惧调节范式的反应不足。因此，用于打开血脑屏障的药物决定了哪个大脑区域容易受到神经毒性抗体的影响，而渗透脑组织的抗体不仅会导致认知能力的变化，还会导致情绪行为的变化。
Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.