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...

Full description

Saved in:
Bibliographic Details
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
Format: Article
Language:English
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20180776