Gono Takahisa, Takarada Takeshi, Fukumori Ryo, Kawaguchi Yasushi, Kaneko Hirotaka, Hanaoka Masanori, Katsumata Yasuhiro, Yoneda Yukio, Yamanaka Hisashi
Tokyo Women's Medical University, Shinjuku-Ku, Tokyo, Japan.
Arthritis Rheum. 2011 Dec;63(12):3952-9. doi: 10.1002/art.30616.
Anti-N-methyl-D-aspartate (anti-NMDA) receptor subunit NR2-reactive antibody may play a crucial role in neuronal manifestations of systemic lupus erythematosus (SLE). However, how NR2-reactive antibody acts as a critical modulator of the NMDA receptor is unknown. This study was undertaken to investigate the biologic function of NR2-reactive antibody in patients with SLE.
The study included 14 patients with SLE, 9 of whom had NR2-reactive antibody. We analyzed the effects of NR2-reactive antibody on cell viability and intracellular Ca(2+) level. We also investigated the efficacy of zinc as a modulator of the intracellular Ca(2+) level in the presence of NR2-reactive antibody.
There was a significant inverse correlation between the NR2-reactive antibody titer and cell viability (R(2) = 0.67, P < 0.0001; n = 23), and there was a significant association between the NR2-reactive antibody titer and the intracellular Ca(2+) level in NR1/NR2a-transfected HEK 293 cells (R(2) = 0.69, P < 0.0001). Intracellular Ca(2+) levels were significantly higher in cells incubated with IgG derived from NR2-reactive antibody-positive SLE patients than in those incubated with IgG derived from NR2-reactive antibody-negative SLE patients (P = 0.0002). The addition of zinc decreased the intracellular Ca(2+) level in a dose-dependent manner. NR2-reactive antibody-positive SLE IgG weakened the efficacy of zinc as a negative modulator of the intracellular Ca(2+) level.
Our findings indicate that NR2-reactive antibody decreases cell viability by Ca(2+) influx in SLE through inhibition of the binding capacity of zinc.
抗N-甲基-D-天冬氨酸（抗-NMDA）受体亚基NR2反应性抗体可能在系统性红斑狼疮（SLE）的神经表现中起关键作用。然而，NR2反应性抗体如何作为NMDA受体的关键调节因子尚不清楚。本研究旨在探讨SLE患者中NR2反应性抗体的生物学功能。
该研究纳入了14例SLE患者，其中9例有NR2反应性抗体。我们分析了NR2反应性抗体对细胞活力和细胞内Ca(2+)水平的影响。我们还研究了在存在NR2反应性抗体的情况下锌作为细胞内Ca(2+)水平调节剂的效果。
NR2反应性抗体滴度与细胞活力之间存在显著的负相关（R(2)=0.67，P<0.0001；n=23），并且在NR1/NR2a转染的HEK 293细胞中，NR2反应性抗体滴度与细胞内Ca(2+)水平之间存在显著关联（R(2)=0.69，P<0.0001）。与来自NR2反应性抗体阳性SLE患者的IgG孵育的细胞中的细胞内Ca(2+)水平显著高于与来自NR2反应性抗体阴性SLE患者的IgG孵育的细胞（P=0.0002）。锌的添加以剂量依赖性方式降低细胞内Ca(2+)水平。NR2反应性抗体阳性的SLE IgG削弱了锌作为细胞内Ca(2+)水平负调节剂的效果。
我们的研究结果表明，NR2反应性抗体通过抑制锌的结合能力，使SLE中的Ca(2+)内流降低细胞活力。
