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Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors

Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and...

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Published in:The Journal of experimental medicine 2018-10, Vol.215 (10), p.2554-2566
Main Authors: Nestor, Jacquelyn, Arinuma, Yoshiyuki, Huerta, Tomás S, Kowal, Czeslawa, Nasiri, Elham, Kello, Nina, Fujieda, Yuichiro, Bialas, Alison, Hammond, Tim, Sriram, Uma, Stevens, Beth, Huerta, Patricio T, Volpe, Bruce T, Diamond, Betty
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cited_by cdi_FETCH-LOGICAL-c450t-7d45835364bddd8bdf62ba6607097c4e7df3e8da8186bcc4f65342c9640292a43
cites cdi_FETCH-LOGICAL-c450t-7d45835364bddd8bdf62ba6607097c4e7df3e8da8186bcc4f65342c9640292a43
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container_issue 10
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container_title The Journal of experimental medicine
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creator Nestor, Jacquelyn
Arinuma, Yoshiyuki
Huerta, Tomás S
Kowal, Czeslawa
Nasiri, Elham
Kello, Nina
Fujieda, Yuichiro
Bialas, Alison
Hammond, Tim
Sriram, Uma
Stevens, Beth
Huerta, Patricio T
Volpe, Bruce T
Diamond, Betty
description Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.
doi_str_mv 10.1084/jem.20180776
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subjects Angiotensin-Converting Enzyme Inhibitors - pharmacology
Animals
Antibodies, Antinuclear - immunology
Autoantibodies - immunology
Autoantibodies - toxicity
Brain - immunology
Brain - pathology
Female
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - pathology
Memory Disorders - chemically induced
Memory Disorders - drug therapy
Memory Disorders - immunology
Memory Disorders - pathology
Mice
Mice, Inbred BALB C
Microglia
Neurons - immunology
Neurons - pathology
Receptors, N-Methyl-D-Aspartate - immunology
title Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors
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