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13 Antibody-mediated neuropsychiatric lupus
  1. B Diamond1,
  2. Y Arinuma1,
  3. F Yuichiro1,
  4. C Kowal1,
  5. J Nestor1,
  6. P Huerta2 and
  7. B Volpe3
  1. 1The Feinstein Insitute for Medical Research, Autoimmune and Musculoskeletal Diseases, Manhasset, USA
  2. 2The Feinstein Institute for Medical Research, Biomedical Science, Manhasset, USA
  3. 3The Feinstein Institute for Medical Research, Functional Neuroanatomy, Manhasset, USA

Abstract

Neuropsychiatric lupus manifestations, especially the common disorders of mood and cognition, can be mediated by cytokines or by antibodies. In particular, a subset of anti-DNA antibodies has been shown to bind the N-methyl d-aspartate receptor. The antibodies preferentially bind the active configuration of the receptor, augmenting the effects of ligand binding. Meta-analysis has confirmed that high serum titers of these antibodies, present in 30%–40% of SLE patients, are associated with cognitive impairment.

In a mouse model, antibody within the circulation is not harmful to the brain unless there is a breach in blood-brain barrier integrity. If there is an insult to the hippocampal vasculature, antibody gains access to hippocampal neurons and mediates tissue damage in 2 distinct stages. First, there is immediate antibody-mediated excitotoxicity causing neuronal loss. Second, after antibody is no longer present in the brain, there is microglial activation and dendritic pruning of surviving neurons. The brain injury that ensues leads to impairment in spatial cognition.

These studies suggest there are two distinct approaches to therapy; one might modulate the initial damage by neutralising the pathogenic antibodies or maintaining blood-brain barrier integrity, the other might mitigate the later damage by inhibiting microglial cells.

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