Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis.
Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis.
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DOI：
10.1002/ana.24195
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发表时间：
2014-07
影响因子：
11.2
通讯作者：
Balice-Gordon, Rita J.
中科院分区：
文献类型：
--
作者：
Moscato, Emilia H.;Peng, Xiaoyu;Jain, Ankit;Parsons, Thomas D.;Dalmau, Josep;Balice-Gordon, Rita J.
一种严重但可治疗的免疫介导的脑炎与血清和脑脊液（CSF）中针对N-甲基-D-天冬氨酸受体（NMDAR）GluN 1亚基的抗体有关。海马神经元长时间暴露于抗NMDAR脑炎患者的抗体导致NMDAR的突触定位和功能可逆性降低。然而，抗体的急性效应、内化受体的命运、受影响的神经元类型以及神经元是否发展代偿性稳态机制尚不清楚，并且是本研究的重点。分离的海马神经元培养物和啮齿动物脑切片用于免疫细胞化学、生理和分子研究。患者抗体与整个啮齿动物大脑中的NMDAR结合，并降低兴奋性和抑制性海马神经元中的NMDAR簇密度。它们迅速增加表面NMDAR簇的内化速率，与受体活性无关。这种内化可能解释了观察到的NMDAR介导的电流减少，因为没有检测到直接阻断的证据。一旦内化，抗体结合的NMDAR通过再循环内体和溶酶体运输，类似于NMDAR诱导的NMDAR内吞作用。抗体负责受体内化，因为它们从CSF中的耗尽消除了海马神经元中的这些作用。我们发现，虽然抗NMDAR抗体不会诱导谷氨酸受体基因表达的代偿性变化，但它们会导致兴奋性海马神经元上抑制性突触密度的降低。我们的数据支持由免疫球蛋白诱导的受体内化驱动的抗体介导的疾病发病机制。抗体介导的表面NMDAR下调涉及稳态突触可塑性机制，这可能无意中导致疾病进展。《神经病学年鉴》2014;76：108-119
A severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study. Dissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies. Patient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of receptor activity. This internalization likely accounts for the observed decrease in NMDAR-mediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons. Our data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression. Ann Neurol 2014;76:108–119
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