Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus

Abstract

Objective: To determine the prevalence of autoantibodies directed against an epitope of the glutamate/Nmethyl-D-aspartic acid (NMDA) receptor subunit NR2A (which is highly expressed in human brain) in the sera of lupus patients, and to investigate the possible correlation of these antibodies with clinical and serological manifestations of systemic lupus erythematosus (SLE). Methods: Sera were obtained from 109 consecutive SLE patients. Controls were 65 patients with myasthenia gravis, 19 with autoimmune polyendocrine syndrome type I (APS I), and 65 healthy donors. A 15 amino acid long peptide based on a sequence within the NR2A subunit of the NMDA/glutamate receptor was synthesised. Antibodies to this peptide were determined by enzyme linked immunosorbent assay. Antibodies against double stranded DNA (dsDNA) were measured by Chrithidia luciliae assay. Disease activity was determined using the SLE disease activity index (SLEDAI). Results: Sera of 34/109 SLE patients (31%) reacted specifically with the NR2A peptide compared with only 4/65 myasthenia gravis patients (6.1%, p,0.001), 1/19 APS I patients (5.3%, p,0.02), and 3/65 healthy controls (4.6%, p,0.001). No correlation was found between the presence of NR2A and dsDNA or anti-cardiolipin specific autoantibodies. In addition, no significant correlation was observed between the presence of NR2A specific antibodies and the SLEDAI score or any lupus related clinical manifestations. Conclusions: A significant number of SLE patients (31%) have NR2A specific antibodies that do not correlate with anti-dsDNA antibodies. Additional studies of lupus patients with neurological disorders should elucidate the role of NR2A specific antibodies in lupus related CNS manifestations.

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

“…Mice immunized with a multimerized configuration of DWEYS produce antidsDNA/NMDAR antibodies, display glomerular Ig deposition, and exhibit neuronal damage after a breach of the blood-brain barrier (BBB) that allows transit of these antibodies into the CNS (17). In humans, elevated titers of cross-reactive anti-dsDNA/ NMDAR antibodies are present in the serum of 40% of lupus patients and their presence in CSF of lupus patients correlates with CNS manifestations of neuropsychiatric lupus (NPSLE), which afflicts up to 80% of lupus patients (15,(18)(19)(20)(21)(22). Moreover, human anti-dsDNA/NMDAR antibodies have been eluted from postmortem brain tissue, and such antibodies isolated from lupus patient sera can cause brain damage (e.g., cognitive or behavioral dysfunction) in mice (23,24).…”

Blood Biomarkers of Ischemic Stroke

“…However, NMDA-R antibodies have also been associated with hypertension, atherosclerosis, prior stroke, epilepsy, systemic lupus erythematosus and encephalitis. Thus, the specificity of these antibodies to patients with acute ischemic stroke remains uncertain [15][16][17][18].…”

Models of Systemic Lupus Erythematosus: Development of Autoimmunity Following Peptide Immunizations of Noninbred Pedigreed Rabbits

“…Recently, anti-NR2 Abs have also been suggested to cause brain pathology and cognitive dysfunction (40). Finally, in some SLE patients showing signs of NL, serum Abs that may bind NR2a and NR2b receptors were found (41,42).…”