Glutamate Receptor Biology and its Clinical Significance in Neuropsychiatric Systemic Lupus Erythematosus
Section snippets
NPSLE
Before 1999, characterization of CNS events in lupus was hampered by confusing terminology and differences among studies in attribution and methods of ascertainment. A consensus conference convened by the American College of Rheumatology (ACR) in 1999 to facilitate clinical and basic research of NPSLE resulted in the elucidation of 19 different neuropsychiatric syndromes attributable to SLE (Box 1).3 Case definitions, reporting standards, and diagnostic criteria were provided by the group.
Mechanistic studies of NPSLE
The etiopathogenesis of cognitive impairment and mood disorder remain a mystery. Studies of serum antibodies and cytokines have failed to show a reproducible signal that predicts the development of diffuse NPSLE symptoms in the CNS or that correlates with the presence of these symptoms. For example, serum antiphospholipid antibodies have been shown to correlate with cognitive decline in some studies but not in others.10, 15, 16, 17, 18 Numerous studies of serum antineuronal and antiribosomal
Antibodies and the brain
In SLE, tissue injury is initiated by antibodies. This observation is true in the kidneys, skin, blood vessels, and in all organs for which there is an appreciation of pathogenesis and inflammatory pathways. For decades it has been known that the serum of many patients with SLE contains brain-reactive antibodies. The specific antigens that are recognized by these antibodies were not identified, nor was their functionality known. Additionally, no correlations were found between the presence of
Antibodies to the N-Methyl-D-Aspartate Receptor and function of the NMDAR
Our own interest is in a subset of anti-DNA antibodies that cross-reacts with a consensus pentapeptide present in the NR2A and NR2B subunits of the NMDAR.
Many anti-DNA antibodies derived from patients with lupus and from some spontaneous mouse models of SLE are of the IgG isotype and display extensive somatic mutation in variable region sequences.42 These are characteristics of the molecular signature of a T-cell–dependent, germinal center matured B-cell response. Generally, protein antigens
Regional brain effects of anti-NMDAR antibodies: murine models of cognitive and behavioral effects
To study the potential effects of anti-NMDAR antibody on cognition we immunized mice with a multimeric form of the DWEYS peptide. These mice develop anti-DNA/anti-NMDAR cross-reactive antibodies. Although these antibodies are present in the circulation, there is no evidence of brain pathology and no alteration of learning or memory, presumably because the endothelial cells in the brain microvasculature form a blood-brain barrier (BBB) that is impenetrable to antibody.58 There are, however,
Anti-NMDAR antibodies and SLE
Multiple studies performed on cohorts in Asia, Europe, and North America report that approximately 40% to 50% of patients have antibody reactivity to the DWEYS peptide. This reactivity is only observed in patients with anti-DNA antibody and, when the peptide-reactive antibodies are purified, they display cross-reactivity to DNA.60 Many studies have attempted to correlate the presence of these antibodies in serum with aspects of NPSLE. Two cross-sectional studies found correlations with
Anti-NMDAR antibodies and brain tissue
In addition to serum and CSF, anti-NMDAR antibody may be found in brain tissue. We have eluted anti-NMDAR antibody from postmortem brain tissue of a patient with SLE who died with severe cognitive deficits.69 The eluted antibody displays neurotoxic effects when injected into a mouse brain. In several other brains, it has been possible to discern antibody bound to neurons and colocalizing with NMDARs.69 It is clear that, under some circumstances, brain parenchyma is exposed to anti-NMDAR
Anti-NMDAR antibodies and fetal brain development
It has been reported in several small studies that the children of women with SLE have an increased frequency of learning disorders.70, 71, 72, 73, 74 These disabilities are not related to birth weight or prematurity. Only one study has asked whether the offspring of male patients with SLE are similarly affected, and it found no evidence for this.74 These observations suggest that the in utero environment might be a major contributor to abnormal fetal brain development. It is known that, after
Non-SLE anti-NMDAR antibodies
Anti-NMDAR antibodies and their toxic effects are not limited to SLE. Anti-NMDAR encephalitis is a recently described syndrome characterized by diffuse cerebral dysfunction with acute organic psychiatric disturbances progressing to seizures, dyskinesias, autonomic instability, abnormal cardiac conduction, decreased level of consciousness, and central hypoventilation.76 This syndrome is highly associated with ovarian teratomas but can occur in the absence of tumor.77 It has also been implicated
Summary
Studies to date show that cross-reactive anti-DNA/anti-NMDAR antibodies are present in serum, CSF, and brain tissue of a significant number of patients with SLE. Using a mouse model, it has been possible to show that these antibodies can cause cognitive or behavioral impairments. The nature of the brain dysfunction depends on the region of the brain exposed to antibody, which, in turn, is influenced by the agent breaching the BBB. These studies explain why serum titers of a pathologic
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All authors contributed equally.