IgG anti-NR2 glutamate receptor autoantibodies from patients with systemic lupus erythematosus activate endothelial cells.
OBJECTIVE
To investigate the possibility that IgG anti-NR2 glutamate receptor antibodies (anti-NR2) derived from patients with systemic lupus erythematosus (SLE) cause an immunologic interaction with endothelial cells (ECs) in the blood-brain barrier, resulting in inflammation of the blood-brain barrier, allowing the entrance of these autoantibodies into the cerebrospinal fluid.


METHODS
Purified IgG anti-NR2 antibodies from 14 patients with SLE were tested for their ability to bind to double-stranded DNA (dsDNA) and ECs, to modulate endothelial adhesion molecule expression and cytokine production by ECs, and to activate the NF-κB pathways in the ECs. Purified IgG from 5 normal subjects was used as a negative control.


RESULTS
Purified IgG anti-NR2 antibodies bound to dsDNA in an IgG-dose-dependent manner. This interaction up-regulated the expression of endothelial leukocyte adhesion molecule 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 on the EC surface and increased the production of interleukin-6 (IL-6) and IL-8, but not tumor necrosis factor α or IL-1β, by ECs. Purified IgG anti-NR2 also activated the degradation of cytoplasmic IκB, indicating the activation of NF-κB in the ECs.


CONCLUSIONS
EC activation through the NF-κB signaling pathway induced by IgG anti-NR2 antibodies in the central nervous system of SLE patients may lead to inflammation of the blood-brain barrier, initiating the pathogenesis of neuropsychiatric SLE.
Division of Rheumatology and Clinical Immunology, Jichi Medical University, 3311 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. takuyosh@jichi.ac.jp
Taku
T
Yoshio
Hiroshi
H
Okamoto
Shunsei
S
Hirohata
Seiji
S
Minota
D000328:Adult; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; C120997:NR2A NMDA receptor; D017452:Receptors, IgG; D016194:Receptors, N-Methyl-D-Aspartate; D004247:DNA