Anti–Ribosomal P Protein Autoantibodies From Patients With Neuropsychiatric Lupus Impair Memory in Mice

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2015-01, Vol.67 (1), p.204-214
• Main Authors: Bravo‐Zehnder, Marcela, Toledo, Enrique M., Segovia‐Miranda, Fabián, Serrano, Felipe G., Benito, María J., Metz, Claudia, Retamal, Claudio, Álvarez, Alejandra, Massardo, Loreto, Inestrosa, Nibaldo C., González, Alfonso
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Antigens, Surface - metabolism; Apoptosis; Apoptosis - drug effects; Autoantibodies - adverse effects; Autoantibodies - blood; Autoantibodies - pharmacology; Blood-brain barrier; Blood-Brain Barrier - drug effects; Cells, Cultured; Disease Models, Animal; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Lupus; Lupus Vasculitis, Central Nervous System - immunology; Lupus Vasculitis, Central Nervous System - metabolism; Memory; Memory Disorders - etiology; Memory Disorders - immunology; Memory Disorders - metabolism; Mice; Mice, Inbred BALB C; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Ribosomal Proteins - immunology; Ribosomal Proteins - metabolism; Rodents; Young Adult
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.38900

Objective To define whether anti‐ribosomal P (anti‐P) autoantibodies from patients with neuropsychiatric systemic lupus erythematosus (NPSLE) impair the function of hippocampal neurons that express the neuronal surface P antigen (NSPA) when accessing the brain via circulating blood. Methods We used anti‐P antibodies from patients with NPSLE and rabbit‐generated anti‐P and anti‐NSPA antibodies. Primary hippocampal neurons from mice were analyzed to determine antibody cell surface binding (double immunofluorescence), intracellular calcium variations (Fura 2 AM), and apoptosis (caspase 3 activation). Hippocampal‐dependent spatial flexible memory was assessed in mice subjected to a water maze test 24 hours after an intravenous injection of anti‐P or anti‐NSPA, using lipopolysaccharide (LPS) to permeate the blood–brain barrier. Presence of antibodies and apoptosis in the hippocampus was studied using immunohistochemistry and TUNEL assays. Results Hippocampal neurons expressed NSPA on the cell surface, as revealed by anti‐P and anti‐NSPA staining colocalization, and responded to both anti‐P and anti‐NSPA by exhibiting increased intracellular calcium levels. Neuronal apoptosis was induced when anti‐P was directly injected by stereotaxis into the hippocampus or added to primary cultures. Upon LPS treatment, intravenously injected anti‐P impaired memory but did not elicit neuronal apoptosis in the hippocampus, where it was detectable in low amounts. Anti‐NSPA antibodies also impaired memory. Conclusion Anti‐P antibodies interact with NSPA on the surface of hippocampal neurons leading to apoptotic death or to functional perturbations, results that are likely dependent on the concentration of these antibodies. Circulating anti‐P can access the hippocampus and impair memory without requiring neuronal death when the blood–brain barrier is disrupted. NSPA can mediate antibody‐driven diffuse brain dysfunction, and anti‐P might contribute to the cognitive impairment that is frequently observed in SLE.