Immunity and behavior: Antibodies alter emotion

Abstract

Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.amygdala ͉ anti-NMDA receptor antibody ͉ anti-DNA antibody ͉ fear conditioning ͉ systemic lupus erythematosus

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

“…4, Upper Right and Lower Right). In agreement with the competitive ELISA data, the neuroprotective dose of FISLE-412 was ≈2 logs less than the dose of DWEYS peptide needed to achieve similar neuroprotection (23). These data suggest that FISLE-412 will maintain its neutralizing capacity within the complex environment of whole tissues or organs.…”

“…Similarly, gestating mice that harbor anti-dsDNA/NMDAR antibodies in their circulation give birth to offspring with impaired brain development (25) because the BBB does not form until the end of gestation and the fetal brain is exposed in utero to the maternal antibody. Of therapeutic importance, the D-isoform of the DWEYS peptide can protect tissue against antibody binding: In vivo administration of D-DWEYS peptide blocks renal and brain deposition of anti-dsDNA/NMDAR antibodies and ameliorates ongoing disease in mouse lupus models (12,23,24). These studies underscore the principle that antidsDNA/NMDAR antibodies are pathogenic in lupus and suggest a possible clinical utility for a molecule with properties of the DWEYS peptide.…”

“…In humans, elevated titers of cross-reactive anti-dsDNA/ NMDAR antibodies are present in the serum of 40% of lupus patients and their presence in CSF of lupus patients correlates with CNS manifestations of neuropsychiatric lupus (NPSLE), which afflicts up to 80% of lupus patients (15,(18)(19)(20)(21)(22). Moreover, human anti-dsDNA/NMDAR antibodies have been eluted from postmortem brain tissue, and such antibodies isolated from lupus patient sera can cause brain damage (e.g., cognitive or behavioral dysfunction) in mice (23,24). Similarly, gestating mice that harbor anti-dsDNA/NMDAR antibodies in their circulation give birth to offspring with impaired brain development (25) because the BBB does not form until the end of gestation and the fetal brain is exposed in utero to the maternal antibody.…”

Disruption of Type I-IFN Signaling Decreases Autoimmune Development and Kidney Damage, But Not Anxiety-Like Behaviors in Lupus NZB Mice

“…There was a report that the IgG prepared from lupus patient's cross-reacts with dsDNA and the N-methyl-aspartate receptor (NMDA) receptor [26]. The antibodies, when injected into the mice, caused neuronal apoptosis and elicited learning deficits [27,28]. Treatment of pregnant mice with the antibody against the NR2-specific NMDA receptor can disrupt the Representative kidney sections from 9-month old NZB and NZB/IFNARKO mice stained with PAS and counterstained with hematoxylin.…”

Actualización en lupus neuro-psiquiátrico con énfasis en déficit cognitivo

“…La frecuencia va de 10% a 30% [38][39][40] . Juegan un papel en alteraciones conductuales relacionadas con fallas de memoria en modelos animales 41 , sin embargo, no se dispone hasta ahora de información que apoye esta hipó-tesis en humanos 38,40,42 . Su presencia en el líquido céfalo raquídeo (LCR) sería más importante en términos etiopatogénicos que en el suero 43 .…”