## 2 Mechanisms of Cognitive Dysfunction  
### Anti-N-methyl-d-aspartate Receptor Subunit NR2A/B Antibodies  
Anti-N-methyl-d-aspartate (NMDA) receptor subunit NR2A/B antibodies have been demonstrated in the sera of 30%-40% of SLE patients [32]. It appears to be a convincing candidate to mediate cognitive dysfunction in SLE patients, fulfilling four of the six stringent pathogenicity criteria outlined for autoantibodies [33]. In the pioneering work by [PERSON] which aimed to determine cross-reactiveantigens for anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies, the nephritogenic mouse monoclonal anti-dsDNA antibody (R4A antibody) was reacted with a phage peptide display library harboring random 10 amino acid inserts encoded by random 30-base pair insets [34, 35]. A consensus sequence for the R4A antibody, D/E-W-D/E-Y-S/G, was identified in 36 phage clones [34]. Of these, 23 phage clones had identical DWEYSVWLSN amino acid sequences [34]. A protein database search found that the D/E-W-D/E-Y-S/G consensus sequence was found in some bacterial antigens but more surprisingly, also present in the \(N\)-terminal domains of mouse, rat and human NR2A and NR2B subunits but not in NR2C and NR2D subunits [35, 36, 37, 38]. The \(N\)-terminal domains of NR2A and NR2B subunits are composed of approximately the first 350 amino acids of the protein [39]. The D/E-W-D/E-Y-S/G consensus sequence is localized to residues 283-287 (sequence DWDYS) of the NR2A subunit and residues 284-288 (sequence EWDYG) of the NR2B subunit [2]. The evidence that R4A antibody cross-reacts with NR2A and NR2B subunits of NMDA receptors prompted researchers to search for similar antigenic specificities in the polyclonal anti-dsDNA antibodies of SLE patients. [PERSON] demonstrated that anti-NR2A/B antibodies isolated from the sera of four SLE patients, using a DWEYSVWLSN peptide-conjugated sepharose column, cross-reacted with dsDNA on ELISA [36]. [PERSON] demonstrated that affinity-purified anti-NR2A/B antibodies from 14 SLE patients cross-reacted with dsDNA in a dose-dependent manner [40]. Using an octameric DWEYSVWLSN peptide for inhibition ELISA experiments, 20%-75% inhibition was observed when the sera of 10 SLE patients were investigated for inhibition of binding of anti-dsDNA antibodies to dsDNA [41]. _In vitro_ and _in vivo_ experiments, using affinity-purified anti-NR2A/B antibodies, revealed that (i) adding anti-NR2A/B antibodies to neuronal cultures caused apoptotic cell death; (ii) injecting anti-NR2A/B antibodies sterotaxically into C57 BL/6 mice hippocampus caused neuronal loss in the hippocampus; and (iii) intravenous administration of anti-NR2A/B antibodies into BALB/c mice with LPS treatment led to binding of these antibodies to the hippocampal neurons and caused neuronal damage [36, 38]. In addition, IgG eluted from the brain of a SLE patient who had progressive and profound cognitive impairment showed cross-reactivity to dsDNA and DWEYS peptide on ELISA and mediated hippocampal neuronal damage when injected sterotaxically into a BALB/c mouse hippocampus [38]. Anti-NR2A/B antibodies from 14 SLE patients, affinity-purified using a DWEYSVWLSN peptide-conjugated sepharose column, up-regulated the expression of endothelial leukocyte adhesion molecule 1, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 on endothelial cells via the activation of NF-kB signaling pathway [40]. Expression of these endothelial cell adhesion molecules mirrored the effects of interleukin (IL)-1\(\upbeta\) in a time course experiment [40]. Several studies have indicated the presence and functionality of the NMDA receptors on brain microvascular endothelial cells (BMECs) of the BBB, suggesting the possibility of anti-NR2A/B antibodies activating BMECs through NMDA receptors [40, 42]. The concentration of anti-NR2A/B antibodies measured in the CSF of 32 SLE patients with NPSLE ranged from 10 \(\upmu\)g/mL to higher than 300 \(\upmu\)g/mL [2].