Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis.
The interesting observation was made 20 years ago that psychotic manifestations in patients with systemic lupus erythematosus are associated with the production of antiribosomal-P protein (anti-P) autoantibodies. Since then, the pathogenic role of anti-P antibodies has attracted considerable attention, giving rise to long-term controversies as evidence has either contradicted or confirmed their clinical association with lupus psychosis. Furthermore, a plausible mechanism supporting an anti-P-mediated neuronal dysfunction is still lacking. We show that anti-P antibodies recognize a new integral membrane protein of the neuronal cell surface. In the brain, this neuronal surface P antigen (NSPA) is preferentially distributed in areas involved in memory, cognition, and emotion. When added to brain cellular cultures, anti-P antibodies caused a rapid and sustained increase in calcium influx in neurons, resulting in apoptotic cell death. In contrast, astrocytes, which do not express NSPA, were not affected. Injection of anti-P antibodies into the brain of living rats also triggered neuronal death by apoptosis. These results demonstrate a neuropathogenic potential of anti-P antibodies and contribute a mechanistic basis for psychiatric lupus. They also provide a molecular target for future exploration of this and other psychiatric diseases.
Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile.
Soledad
S
Matus
Patricia V
PV
Burgos
Marcela
M
Bravo-Zehnder
Regine
R
Kraft
Omar H
OH
Porras
Paula
P
Farías
L Felipe
LF
Barros
Fernando
F
Torrealba
Loreto
L
Massardo
Sergio
S
Jacobelli
Alfonso
A
González
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology* / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D012270:Ribosomes / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D001323:Autoantibodies; D000939:Epitopes; D010455:Peptides; D011506:Proteins; D002118:Calcium