The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071285
The Journal of Experimental Medicine, Vol. 204, No. 13, 3221-3234
The Rockefeller University Press, 0022-1007 $30.00
© Matus et al.
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ARTICLE

 Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis

Soledad Matus1,2,4, Patricia V. Burgos1,2,4, Marcela Bravo-Zehnder1,2,4, Regine Kraft6, Omar H. Porras5, Paula Farías3, L. Felipe Barros5, Fernando Torrealba3, Loreto Massardo1, Sergio Jacobelli1, and Alfonso González1,2,4

1 Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, 2 Centro de Regulación Celular y Patología, and 3 Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
4 Millennium Institute for Fundamental and Applied Biology, Santiago 7780272, Chile
5 Centro de Estudios Científicos, Casilla 1469, Valdivia, Chile
6 Max-Delbrück-Center, 13092 Berlin, Germany

CORRESPONDENCE Alfonso González: agonzara{at}med.puc.cl

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.

Abbreviations used: {alpha}-hP11 and {alpha}-hP4, affinity-purified human anti-P against a synthetic P peptide of 11 or 4 residues, respectively; anti-P, antiribosomal-P protein; BBB, blood–brain barrier; CNS, central nervous system; NMDAR,N-methyl-D-aspartate receptor; NP, neuropsychiatric; NSPA, neuronal surface P antigen; SLE, systemic lupus erythematosus.

S. Matus and P.V. Burgos contributed equally to this study.

P.V. Burgos's present address is Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.


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