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Autoantibodies and cognitive impairment in systemic lupus erythematosus
Arthritis Res Ther volume 6, Article number: 32 (2004)
Many patients with systemic lupus erythematosus experience cognitive decline as their disease progresses. The pathogenic mechanisms include thrombosis, vasculitis, and drug toxicity. We have demonstrated that a subset of anti-DNA antibodies cross-reacts with N-methyl-D-aspartate NMDA receptors and can cause excitotoxic cell death. In mice with high serum titers of these antibodies, there is no evidence of brain damage until there is a breach in the blood–brain barrier. With a break in the blood–brain barrier induced by administration of lipopolysaccharide, the antibodies bind preferentially to hippocampal neurons that express N-methyl-D-aspartate receptors at high density. The antibodies mediate a noninflammatory apoptotic cell death. By 1 week following lipopolysaccharide administration, there is a 30% loss of hippocampal neurons. At 1 month there is no further loss of neurons, suggesting that the blood–brain barrier closes and the antibodies have no further access to brain tissue.
Mice experiencing hippocampal damage from antibody show decreased N-acetyaspartate in the hippocampus by magnetic resonance spectroscopy. An abnormal metabolism is detectable only in the hippocampus, confirming the selectivity of the damage. These mice also display impaired performance on tasks of memory function that are dependent on the integrity of the hippocampus. Thus, these studies provide a new model for cognitive impairment in systemic lupus and suggest that antibodies may mediate, through noninflammatory mechanisms, changes in cognitive function.
This work was funded by the Lupus Research Institute and the National Institutes of Health.
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Kowal, C., DeGiorgio, L., Huerta, P. et al. Autoantibodies and cognitive impairment in systemic lupus erythematosus. Arthritis Res Ther 6, 32 (2004) doi:10.1186/ar1367
- Systemic Lupus Erythematosus
- Cognitive Impairment
- NMDA Receptor