Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms

Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise fro...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-10, Vol.107 (43), p.18569-18574
Main Authors: Faust, Thomas W., Chang, Eric H., Kowal, Czeslawa, Berlin, RoseAnn, Gazaryan, Irina G., Bertini, Eva, Zhang, Jie, Sanchez-Guerrero, Jorge, Fragoso-Loyo, Hilda E., Volpe, Bruce T., Diamond, Betty, Huerta, Patricio T., Scharff, Matthew D.
Format: Article
Language:English
Subjects:
Animal models
Animals
Antibodies
Antigens
Apoptosis
Autoantibodies
Autoantibodies - toxicity
Binding sites
Biological Sciences
Blood-brain barrier
Brain
Brain - immunology
Brain - physiopathology
Cognitive ability
Cross Reactions
Cross-reactivity
Emotions
Excitatory Postsynaptic Potentials
Excitotoxicity
Female
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Humans
Immunoglobulins
In Vitro Techniques
Lupus
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - physiopathology
Lupus Vasculitis, Central Nervous System - immunology
Lupus Vasculitis, Central Nervous System - physiopathology
Mice
Mice, Inbred BALB C
Mitochondria
Mitochondrial Membrane Transport Proteins - physiology
Mitochondrial Permeability Transition Pore
Models, Immunological
Models, Neurological
N methyl D aspartate receptors
N-Methyl-D-aspartic acid receptors
Neurological diseases
Neurological disorders
Neuromodulation
Neurons
Neurotoxicity
Neurotoxins - toxicity
Permeability
Proteins
Pyramidal cells
Receptor mechanisms
Receptors
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - immunology
Systemic lupus erythematosus
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Summary:Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross-reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood–brain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1006980107