Cognition and immunity; antibody impairs memory.
Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.
Kowal
Czeslawa
C
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
DeGiorgio
Lorraine A
LA
Nakaoka
Tsukasa
T
Hetherington
Hoby
H
Huerta
Patricio T
PT
Diamond
Betty
B
Volpe
Bruce T
BT
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D007107:Immune System / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy / Q000276:immunology*; D009682:Magnetic Resonance Spectroscopy; D008559:Memantine / Q000494:pharmacology; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000276:immunology* / Q000628:therapy; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000276:immunology
D008070:Lipopolysaccharides; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine