title: Anti-NR2 antibodies, blood-brain barrier, and cognitive dysfunction.
abstract: Cognitive dysfunction (CD) is one of the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). In animal models, antibodies to NR2 subunit of N-methyl D-aspartate receptor (anti-NR2) cause memory impairment, but only with blood-brain barrier (BBB) disruption or intrathecal administration. Several studies have failed to find association of aNR2 with CD, but none have assessed BBB integrity. S100B, an astrocyte-specific protein, has been used as biomarker of BBB disruption in traumatic brain injury and some neurodegenerative disorders. Antibodies to this immunologically privileged protein (anti-S100B) might indicate preceding BBB disruption. We hypothesized that aNR2 antibody is pathogenic in SLE patients only with BBB disruption. Demographic, clinical, and laboratory data was collected from patients with SLE. Total throughput score (TTS) of the Automated Neuropsychological Assessment Metrics (ANAM) was used as primary outcome measure. CD was defined as TTS < 1.5 SD below an age-, sex-, and race-matched RA population mean. Serum was analyzed by established ELISA techniques. Fifty-seven patients were evaluated and 12 had CD. Age, ethnicity, and family income were significantly different between the two groups (p < 0.05). In a multiple regression model adjusting for other variables, no significant effects of anti-NR2, S100B, or anti-S100B on TTS were found. Even at high levels of S100B and anti-S100B, no significant influence of anti-NR2 on TTS was found. The anti-NR2 was not associated with CD in SLE even in context of potential BBB disruption. This suggests that, if pathogenic, these antibodies may be produced intrathecally.
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Medical Sciences Building (MSB), University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0563, Cincinnati, OH, 45267, USA. gaurav.gulati@uc.edu.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gulati
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Iffland
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
authors.affiliation: Department of Biostatistics & Epidemiology, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, 45229, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Medical Sciences Building (MSB), University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0563, Cincinnati, OH, 45267, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Luggen
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood* / Q000737:chemistry; D001323:Autoantibodies / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000276:immunology*; D060825:Cognitive Dysfunction / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016682:Lupus Coagulation Inhibitor / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood* / Q000737:chemistry; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D015415:Biomarkers; D016682:Lupus Coagulation Inhibitor; D016194:Receptors, N-Methyl-D-Aspartate; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human
keywords: Anti-NR2 antibody; Anti-S100B antibody; Blood-brain barrier (BBB); Cognitive dysfunction; Lupus; Neuropsychiatric lupus; S100B protein; Systemic lupus erythematosus (SLE)