Encephalitis associated with N-methyl-D-aspartate receptor antibodies can have a devastating impact on patients’ cognitive and psychiatric function. Researchers at Johns Hopkins University, Baltimore, studied 320 patients with clinical manifestations of the disesase to explore the cellular mechanisms by which antibodies cause the loss of NMDA receptors.

Anti-NMDA receptor antibodies trigger symptoms of memory loss, deficits in learning and cognition, and psychosis in patients with anti-NMDA receptor encephalitis by crosslinking and internalizing synaptic NMDA receptor clusters, according to findings in recent in vitro and in vivo experiments.

Ethan G. Hughes, Ph.D., who is now a postdoctoral fellow at Johns Hopkins University, carried out a study with his colleagues at the University of Pennsylvania, Philadelphia. Among patients with clinical manifestations of the disease, they found that purified anti-NR1 antibodies reduced the surface and total cluster density of NMDA receptors on cultured hippocampal neurons in a titer-dependent fashion. (The NR1 epitope is one of two protein subunits that form the NMDA receptor.) The researchers cultured the neurons with cerebrospinal fluid (CSF) samples that had been obtained at two different time points of the disease in two patients. In one of the patients, they found that CSF taken from the patient at symptom presentation had a higher titer of anti-NR1 antibodies than was present during symptom improvement; whereas in the second patient, they found that the CSF obtained during symptom worsening had a higher antibody titer than at symptom presentation. Periods in which anti-NR1 antibody titers were higher also had greater declines in NMDA receptor surface and total cluster density (J. Neurosci. 2010;30:5866-75).

Further experiments with hippocampal neurons cultured with CSF or purified anti-NR1 antibodies demonstrated that the patients’ antibodies “dramatically reduced” the synaptic localization of NMDA receptor clusters in a titer-dependent fashion without affecting the overall structural integrity of excitatory neurons, synapses, or other synaptic proteins or receptors. The density of the NMDA receptor clusters returned to baseline levels 4 days after the antibodies were removed, demonstrating the reversibility of the antibodies’ effects. Whole-cell patch recordings found that the antibodies decreased only NMDA receptor–mediated currents and not those mediated by other receptors. The patients’ antibodies promoted the internalization of the receptors by binding to, capping, and cross-linking them.

In addition to the study of patients with the disease, the researchers directly infused human anti-NR1 antibodies into the hippocampus of adult rats for 2 weeks. They found that the antibodies had bound to the rat hippocampus in a predictable pattern that was dependent on NMDA receptor density and similar to the pattern seen in patients with anti-NMDA receptor encephalitis. The density of NMDA receptor clusters had declined significantly in regions where the antibodies had been deposited, similar to what was observed in sections of the hippocampus in two patients who died from anti-NMDA receptor encephalitis.

The fact that many patients who develop anti-NMDA receptor encephalitis are first admitted to psychiatric institutions with schizophrenia-like symptoms suggests that NMDA receptor hypofunction underlies the symptoms of anti-NMDA receptor encephalitis and many manifestations of schizophrenia, Dr. Hughes and his colleagues wrote. The research was funded by grants from the National Institutes of Health.

Dr. Jonathan Carter, an associate professor of neurology at the Mayo Clinic College of Medicine and a consultant in the department of neurology at the Mayo Clinic Arizona, commented that anti-NMDA receptor encephalitis is the first of several “autoimmune synaptic encephalopathies” that have been described within the last 5 years.

Other similar disorders with different receptor targets include anti-AMPA receptor encephalitis and anti-GABA receptor encephalitis, he noted, adding that these disorders share certain clinical features such as female predominance, frequent association with neoplasm, and presentation with psychosis, behavioral changes, or intractable seizures. Importantly, these disorders are treatable and reversible if recognized early and treated aggressively with immunosuppressive therapies and removal of the neoplasm if present.

“The experiments of Dr. Hughes and his associates elegantly clarify the cellular and synaptic mechanisms of anti-NMDA receptor encephalitis using both in vitro and in vivo models. They demonstrate that antibodies from patient sera or CSF reversibly reduce synaptic NMDA receptor clusters by binding, crosslinking, and internalizing NMDA receptors without damaging synaptic connections or the number or structural integrity of these synapses. Furthermore, this reduction in synaptic NMDA receptors shows a linear correlation with the titer of anti-NMDA receptor antibodies. Patient antibodies also reduce synaptic NMDA receptor currents, and reduce NMDA receptor cluster density in rodent and human hippocampus slices in vivo,” Dr. Carter said.

This report solidly establishes the role of anti-NMDA receptor antibodies in the pathogenesis of this disorder, creating a new paradigm of central nervous system synaptic autoimmunity, Dr. Carter added. The reversibility of this process is also encouraging for clinicians who may see and treat patients with these disorders, which are likely highly underrecognized at present. The challenge for the future will be to translate these basic science advances into effective treatments for these disorders, and to recognize new forms and presentations of this widening family of autoimmune synaptic encephalopathies, he said.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

N-甲基-D-天门冬氨酸(NMDA)受体抗体相关性脑炎对患者的认知与精神功能具有破坏性的影响。巴尔的摩约翰霍普金斯大学的研究者们研究了320例具有此病临床表现的患者，旨在探讨抗体导致NMDA受体减少的细胞学机制。

 

最近一项体内和体外试验表明，抗NMDA受体抗体通过交联和内化突触的NMDA受体簇，导致抗NMDA受体脑炎患者出现记忆力丧失、学习及认知能力缺陷和精神病的症状。

 

约翰霍普金斯大学的博士后研究员Ethan G. Hughes博士及其在费城宾夕法尼亚大学的同事们完成了一项研究：在具有抗NMDA受体脑炎临床表现的患者中，他们发现纯化的抗NR1抗体能减少在培养的海马神经细胞表面的及总的NMDA受体簇密度(NR1抗原决定簇是组成NMDA受体的两个蛋白质亚单位之一)，并呈滴度依赖性。研究者们在2例位于两个不同疾病阶段的患者的脑脊液(CSF)标本中培养神经元。他们发现，其中1例患者脑脊液抗NR1抗体在症状发作时比症状改善时滴度高；而在另外1例患者，症状恶化时比症状发作时滴度高。在抗NR1抗体滴度高的阶段，NMDA受体簇表面和总密度也较低[J. Neurosci. 2010;30:5866-75]。

 

脑脊液培养的海马神经细胞或纯化抗NR1抗体的进一步实验表明，患者们的抗体“极大地减少”了NMDA受体簇的突触位点，具有滴度依赖性，但不影响兴奋性神经细胞、突触、其他突触蛋白或受体的结构完整性。在抗体去除4天后，NMDA受体簇密度重回到基线水平，显示了抗体影响的可逆性。全细胞膜片记录发现只有NMDA受体介导而不是其他受体介导的电流才会引起抗体减少。患者的抗体通过结合、加帽、交联增加了受体的内化。

 

除了对患者的研究外，研究者们直接向成年大鼠海马输注人抗NR1抗体2周。他们发现，抗体通过一种可预测的形式结合了大鼠海马，此形式取决于NMDA受体浓度，与抗NMDA受体脑炎患者的模式相似。在抗体沉积的地方NMDA受体簇滴度显著下降，与死于抗NMDA受体脑炎的2例患者海马部位的发现近似。

 

Hughes博士及其同事们写道：多数抗NMDA受体脑炎患者因类似精神分裂症的表现而首先被收入精神病治疗机构，此事实表明了NMDA受体功能减退是抗NMDA受体脑炎以及许多精神分裂症表现的基础。此研究由美国国立卫生研究院资助。

 

梅奥临床医学院神经病学副教授、亚利桑那梅奥诊所神经学系顾问Jonathan Carter博士评价说：在几种“自身免疫性突触性脑病”中，抗NMDA受体脑炎是近5年内最早被描述的一种。

 

他提到，其他与不同的靶受体有关的类似疾病还包括抗AMPA受体脑炎和抗GABA受体脑炎。他指出，这些疾病有一定的临床特点，如女性发病率高，常伴有肿瘤、精神病表现、行为改变或难治性的痫性发作。重要的是，如果能够早期识别、积极进行免疫抑制治疗，并切除可能存在的肿瘤，则这些疾病是可治疗的，也是可逆的。

 

Carter博士说：“Hughes博士及其同事的研究用体内及体外试验非常好地明确了抗AMPA脑炎的细胞和突触作用机制，他们揭示了，患者血清或脑脊液中的抗体通过结合、交联和内化NMDA受体，能可逆性地减少突触NMDA受体簇，而并不损害突触处细胞连接或这些突触的数量及结构完整性。而且，突触NMDA受体的减少与抗NMDA受体抗体滴度呈直线相关。患者的抗体也会减少突触NMDA受体电流，在啮齿动物体内和人体海马切片中减少NMDA受体簇密度。”

 

Carter博士还说，此研究牢固地确立了抗NMDA受体抗体在此疾患发病机制中的地位，开辟了中枢神经系统突触自身免疫性疾病的一个新研究思路。他说，此疾病的可逆性也是一个令进行此病诊治的临床医生们振奋的好消息，似乎他们目前还远远没有意识到这一点。未来将要面临的挑战是，将这些基本的科学进展转化成治疗这些疾病的有效方案，并发现自身免疫性突触性脑病这个日益庞大的家族中新的类型和表现方式。

 

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