Association of anti-NMDAR2 antibodies with the pathogenesis of neuropsychiatric systemic lupus erythematosus

首先，探讨SLE患者脑脊液和血清中抗NMDAR2抗体(抗NR2)与神经精神性SLE(NPSLE)的关系。收集80例系统性红斑狼疮患者的脑脊液和血清标本。分为4组，1组为中枢神经系统神经综合征组，2组为弥漫性精神/神经心理综合征组，3组为复杂表现组(中枢神经系统神经综合征+弥漫性精神/神经心理综合征组)，4组为非NPSLE组。以合成的DWEYSVWLSN多肽为抗原，用酶联免疫吸附试验检测脑脊液和血清中抗NR2抗体的效价。血清Ig G、抗NR2抗体与NPSLE的发生无明显相关性。脑脊液中抗NR2抗体与NPSLE的发生密切相关，尤其是复杂的临床表现。NPSLE患者脑脊液中抗NR2抗体滴度与血清中脑脊液抗体滴度、脑脊液中抗P抗体滴度均呈显著正相关。检测了14例SLE患者脑脊液中抗NR2抗体与双链DNA结合、与EC结合、调节EC表面黏附分子表达及细胞因子产生的能力。以纯化的5名正常对照的免疫球蛋白G作为阴性对照。纯化的抗NR2与dsDNA结合呈剂量依赖关系。它们与EC结合，刺激黏附分子表达上调，IL-6和IL-8的产生明显高于正常对照组。提示抗NR2抗体作为抗dsDNA抗体可能与EC表面结合，从而激活SLE中的EC。中枢神经系统EC的这种事件可能导致血脑屏障的破坏，从而导致NPSLE的发生和发展。

Firstly it was investigated whether IgG anti-NMDAR2 antibodies (anti-NR2) in the cerebrospinal fluid (CSF) and serum of patients with SLE are related to neuropsychiatric SLE (NPSLE). CSF and serum samples from 80 patients with SLE were used. They were divided into 4 groups (1^<st> group : neurologic syndromes of the central nervous system(CNS), 2^<nd> group : diffuse psychiatric/neuropsychological syndromes, 3^<rd> group : complex presentations (neurologic syndromes of the CNS+diffuse psychiatric/neuropsychological syndromes) and 4^<th> group : non-NPSLE). CSF and serum IgG anti-NR2 titers were measured by ELISA using synthetic DWEYSVWLSN peptide as the antigen. Serum IgG anti-NR2 were not significantly associated with the presence of NPSLE. CSF IgG anti-NR2 were significantly associated with the presence of NPSLE, especially complex presentations. CSF IgG anti-NR2 titers were significantly positive-correlated with each of serum CSF IgG anti-NR2 titers and CSF IgG anti-P titers in patients with NPSLE. These results suggest that the presence of IgG anti-NR2 in the CSF of patients with SLE may be associated with the appearance and development of NPSLE, especially complex presentations.Secondly purified IgG anti-NR2 of 14 patients with SLE were tested for their ability to 1)bind to ds DNA, 2)bind to EC, 3)modulate adhesion molecule expression on EC surface and cytokine production from EC. Purified IgG of 5 normal controls were used as negative controls. Purified anti-NR2 bound to dsDNA with IgG-dose-dependence. They bound to EC and stimulated the up-regulation of adhesion molecule expression and IL-6 and IL-8 production more significantly than IgG of normal controls. These results suggest the possibility that anti-NR2 as anti-dsDNA antibodies may bind to EC surface and activate EC in SLE. Such events on EC in the central nervous system may lead to the damage of blood-brain barrier, resulting in the appearance and development of NPSLE.