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Updated: Jun 8, 2026
06:56
Antibody Transfection into Neurons as a Tool to Study Disease Pathogenesis
Published on: September 26, 2012
Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms
Thomas W Faust1, Eric H Chang, Czeslawa Kowal
1Burke Cornell Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
Summary
Systemic lupus erythematosus (SLE) autoantibodies targeting the NMDA receptor (NMDAR) can cause cognitive and emotional dysfunction. Their concentration dictates whether they enhance or damage NMDAR function, leading to neuronal death.
Area of Science:
- Neuroimmunology
- Molecular Neuroscience
- Autoimmunity
Background:
- Autoantibodies (AAbs) in systemic lupus erythematosus (SLE) can cross-react with brain antigens.
- Neuropsychiatric symptoms in SLE are linked to autoantibodies targeting the NMDA receptor (NMDAR).
- The precise cellular mechanisms of NMDAR-reactive AAbs in SLE-related brain damage are not fully understood.
Purpose of the Study:
- To elucidate the cellular mechanisms by which NMDAR-reactive AAbs cause neuronal dysfunction and death.
- To investigate the concentration-dependent effects of these AAbs on NMDAR function.
- To establish a model linking AAb concentration to specific cellular responses in the brain.
Main Methods:
- Studied lupus AAbs cross-reacting with NR2A and NR2B subunits of the NMDAR in adult mouse models.
- Assessed the impact of NMDAR-reactive AAbs on NMDAR-mediated excitatory postsynaptic potentials.
- Investigated the effects of AAbs on mitochondrial permeability transition at varying concentrations.
- Confirmed the requirement of NMDAR activation for observed synaptic and mitochondrial effects.
Main Results:
- At low concentrations, NMDAR-reactive AAbs positively modulate NMDAR function, increasing excitatory postsynaptic potentials.
- At high concentrations, these AAbs induce excitotoxicity via enhanced mitochondrial permeability transition.
- NMDAR activation is essential for both the synaptic potentiation and the mitochondrial effects.
- Other synaptic receptors remain unaffected by the NMDAR-reactive AAbs.
Conclusions:
- NMDAR-reactive AAbs trigger graded cellular alterations in the brain, dependent on their local concentration.
- These mechanisms explain transient and permanent neuropsychiatric symptoms in SLE patients.
- The study provides a mechanistic model for AAb-induced neurotoxicity in SLE.
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