Glutamate Receptor Biology and its Clinical Significance in Neuropsychiatric Systemic Lupus Erythematosus

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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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References (79)

  • C. Kowal et al.

    Cognition and immunity; antibody impairs memory

    Immunity

    (2004)
  • R.G. Lahita

    Systemic lupus erythematosus: learning disability in the male offspring of female patients and relationship to laterality

    Psychoneuroendocrinology

    (1988)
  • J. Dalmau et al.

    Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

    Lancet Neurol

    (2008)
  • Y. Ganor et al.

    Autoimmune epilepsy: distinct subpopulations of epilepsy patients harbor serum autoantibodies to either glutamate/AMPA receptor GluR3, glutamate/NMDA receptor subunit NR2A or double-stranded DNA

    Epilepsy Res

    (2005)
  • N.J. Scolding et al.

    The neuropathology and pathogenesis of systemic lupus erythematosus

    Neuropathol Appl Neurobiol

    (2002)
  • The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

    Arthritis Rheum

    (1999)
  • J.G. Hanly et al.

    Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance

    J Rheumatol

    (2004)
  • J.G. Hanly et al.

    Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study

    Arthritis Rheum

    (2007)
  • P.E. Love et al.

    Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance

    Ann Intern Med

    (1990)
  • G. Sanna et al.

    Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies

    J Rheumatol

    (2003)
  • R.L. Brey et al.

    Neuropsychiatric syndromes in lupus: prevalence using standardized definitions

    Neurology

    (2002)
  • H. Ainiala et al.

    The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus

    Neurology

    (2001)
  • W.L. Sibbitt et al.

    The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus

    J Rheumatol

    (2002)
  • R.L. Brey et al.

    Neuropsychiatric systemic lupus erythematosus: miles to go before we sleep

    Neurology

    (2003)
  • J. Bleiberg et al.

    Factor analysis of computerized and traditional tests used in mild brain injury research

    Clin Neuropsychol

    (2000)
  • S. Menon et al.

    A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus

    Arthritis Rheum

    (1999)
  • E.Y. McLaurin et al.

    Predictors of cognitive dysfunction in patients with systemic lupus erythematosus

    Neurology

    (2005)
  • J.G. Hanly et al.

    A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus

    Arthritis Rheum

    (1999)
  • J.G. Hanly et al.

    Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study

    Arthritis Rheum

    (2008)
  • E. Trysberg et al.

    Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement

    Arthritis Rheum

    (2003)
  • K. Waterloo et al.

    Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow

    J Neurol

    (2001)
  • M.J. Jarek et al.

    Magnetic resonance imaging in systemic lupus erythematosus patients without a history of neuropsychiatric lupus erythematosus

    Arthritis Rheum

    (1994)
  • C.H. Kao et al.

    The role of FDG-PET, HMPAO-SPET and MRI in the detection of brain involvement in patients with systemic lupus erythematosus

    Eur J Nucl Med

    (1999)
  • M.K. Lim et al.

    Systemic lupus erythematosus: brain MR imaging and single-voxel hydrogen 1 MR spectroscopy

    Radiology

    (2000)
  • A.T. Kaell et al.

    The diversity of neurologic events in systemic lupus erythematosus. Prospective clinical and computed tomographic classification of 82 events in 71 patients

    Arch Neurol

    (1986)
  • J.S. Axford et al.

    Sensitivity of quantitative (1)H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus

    Ann Rheum Dis

    (2001)
  • E. Kozora et al.

    Cognition, MRS neurometabolites, and MRI volumetrics in non-neuropsychiatric systemic lupus erythematosus: preliminary data

    Cogn Behav Neurol

    (2005)
  • L. Lapteva et al.

    Anti-N-methyl-d-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus

    Arthritis Rheum

    (2006)
  • M.W. DiFrancesco et al.

    Functional magnetic resonance imaging assessment of cognitive function in childhood-onset systemic lupus erythematosus: a pilot study

    Arthritis Rheum

    (2007)
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