Gahring L C, Twyman R E, Greenlee J E, Rogers S W
Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Mol Med. 1995 Mar;1(3):245-53.
Paraneoplastic syndromes are "remote" complications of cancer characterized clinically by neurological disease. The sera and cerebrospinal fluid (CSF) from patients with paraneoplastic neurological syndromes (PNS) frequently contain autoantibodies to ill-defined neuronal antigens. We report here that neuronal glutamate receptors are targets for autoantibodies found in the serum from some patients with well-characterized PNS.
We have analyzed the serum from seven patients with well-characterized PNS for the presence of autoreactive antibodies to non-NMDA glutamate receptor subunits. Autoantibodies were assessed using Western blot, immunohistochemistry, and immunocytochemistry. Whole-cell electrophysiological recordings were used to examine the effect of antibodies on glutamate receptors expressed by cortical neurons in culture.
Six of seven patients' serum contained autoantibodies to the non-NMDA glutamate receptor (GluR) subunits GluR1, GluR4, and/or GluR5/6. No patient had autoantibodies to GluR2, and only one patient exhibited weak immunoreactivity to GluR3. Electrophysiological analysis demonstrated that the serum from four of the six GluR-antibody-positive patients enhanced glutamate-elicited currents on cultured cortical neurons but had no effect on receptor function alone. Enhancement of glutamate-elicited currents was also produced by affinity-purified antibody to GluR5.
The occurrence of autoantibodies to specific neuronal neurotransmitter subunits in the sera of patients with PNS and the ability of these autoantibodies to modulate glutaminergic receptor function suggest that some paraneoplastic neurological injury could result from glutamate-mediated excitotoxicity.
副肿瘤综合征是癌症的“远隔”并发症，临床上以神经疾病为特征。副肿瘤性神经综合征（PNS）患者的血清和脑脊液（CSF）中经常含有针对不明神经元抗原的自身抗体。我们在此报告，神经元谷氨酸受体是一些具有明确特征的PNS患者血清中发现的自身抗体的靶标。
我们分析了7例具有明确特征的PNS患者的血清中是否存在针对非NMDA谷氨酸受体亚基的自身反应性抗体。使用蛋白质印迹法、免疫组织化学和免疫细胞化学评估自身抗体。采用全细胞膜片钳电生理记录来检测抗体对培养的皮质神经元表达的谷氨酸受体的影响。
7例患者中有6例血清含有针对非NMDA谷氨酸受体（GluR）亚基GluR1、GluR4和/或GluR5/6的自身抗体。没有患者有针对GluR2的自身抗体，只有1例患者对GluR3表现出微弱的免疫反应性。电生理分析表明，6例GluR抗体阳性患者中有4例的血清增强了培养的皮质神经元上谷氨酸诱发的电流，但单独对受体功能无影响。针对GluR5的亲和纯化抗体也产生了谷氨酸诱发电流的增强。
PNS患者血清中出现针对特定神经元神经递质亚基的自身抗体，以及这些自身抗体调节谷氨酰胺能受体功能的能力表明，一些副肿瘤性神经损伤可能是由谷氨酸介导的兴奋性毒性所致。
