NR2-reactive antibody decreases cell viability through augmentation of Ca(2+)  influx in systemic lupus erythematosus.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our findings indicate that NR2-reactive antibody decreases cell viability by Ca(2+)  influx in SLE through inhibition of the binding capacity of zinc.
Tokyo Women's Medical University, Shinjuku-Ku, Tokyo, Japan.
Takahisa
T
Gono
Takeshi
T
Takarada
Ryo
R
Fukumori
Yasushi
Y
Kawaguchi
Hirotaka
H
Kaneko
Masanori
M
Hanaoka
Yasuhiro
Y
Katsumata
Yukio
Y
Yoneda
Hisashi
H
Yamanaka
D000906:Antibodies / Q000097:blood / Q000494:pharmacology*; D000974:Antibodies, Antinuclear / Q000097:blood; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism* / Q000503:physiopathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D015032:Zinc / Q000494:pharmacology
D000906:Antibodies; D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D004247:DNA; D015032:Zinc; D002118:Calcium