Amelioration of Brain Pathology and Behavioral Dysfunction in Mice With Lupus Following Treatment With a Tolerogenic Peptide

The Weizmann Institute of Science, Rehovot, Israel.
Arthritis & Rheumatology (Impact Factor: 7.76). 12/2009; 60(12):3744-54. DOI: 10.1002/art.25013
Source: PubMed


Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZBxNZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations.
Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed. The messenger RNA expression of SLE-associated cytokines and apoptosis-related molecules from the hippocampi was determined. Anxiety-like behavior was assessed by open-field tests and dark/light transfer tests, and memory deficit was assessed using a novel object recognition test.
Infiltration was evident in the hippocampi of the lupus-afflicted mice, and the presence of CD3+ T cells as well as IgG and complement C3 complex deposition was observed. Furthermore, elevated levels of gliosis and loss of neuronal nuclei immunoreactivity were also observed in the hippocampi of the mice with lupus. Treatment with hCDR1 ameliorated the histopathologic changes. Treatment with hCDR1 down-regulated the high expression of interleukin-1beta (IL-1beta), IL-6, IL-10, interferon-gamma, transforming growth factor beta, and the proapoptotic molecule caspase 8 in the hippocampi of the mice with lupus, and up-regulated expression of the antiapoptotic bcl-xL gene. Diseased mice exhibited increased anxiety-like behavior and memory deficit. Treatment with hCDR1 improved these parameters, as assessed by behavior tests.
Treatment with hCDR1 ameliorated CNS pathology and improved the tested cognitive and mood-related behavior of the mice with lupus. Thus, hCDR1 is a novel candidate for the treatment of CNS lupus.

Download full-text


Available from: Anat Elmann, Oct 18, 2015
  • Source
    • "Lupusprone mice (NZB/NZW mice) demonstrate infiltration of the hippocampus with inflammatory cells, immunoglobulin, complement and a variety of pro-inflammatory molecules. This pathology is characterized phenotypically by behaviors consistent with anxiety symptoms in a variety of behavioral tests (e.g., open field test) (Lapter et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder characterized by the production of autoantibodies. Approximately 30-50 % of patients produce autoantibodies directed against N-Methyl-D-aspartic acid receptors (NMDARs). Once they have gained access to brain tissue, these autoantibodies bind to the NR2A subunit of the NMDARs and synergize with glutamate to cause excitatory, non-inflammatory cell death or alter neuron function. Both humans with SLE and animal models of SLE have shown structural and functional damage to the amygdala. The amygdala is a brain region important for processing the emotional relevance of stimuli in the environment. It also serves to modulate perception, attention, and memory to facilitate the processing and learning of relevant stimuli. Research has linked amygdala damage to deficits in emotional memory and emotional behavior. Individuals with SLE often exhibit emotional dysregulation, such as lability and depression; however, the behavioral impact of possible amygdala dysfunction has yet to be studied in this population. The purpose of this review is to 1) examine possible associations between SLE, anti-NMDAR antibodies, amygdala damage, and emotional processing deficits and 2) to identify the clinical, social, and treatment implications for individuals with SLE who suffer from deficits in emotional processing.
    Preview · Article · Aug 2012 · Neuropsychology Review
  • Source

    Full-text · Article · Dec 2009 · Arthritis & Rheumatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: This meeting was dedicated to various autoimmune diseases and their mechanisms, diagnosis and therapies. The autoimmunity-promoting factors included genetic variations and environmental injuries. A broad array of cytokines, including the B-cell activating factor, and autoantibodies, including novel specificities, were discussed. Finally, new horizons in treatment, including tolerogenic peptides, intravenous immunoglobulin and B-cell-depleting agents, were presented.
    No preview · Article · Sep 2010 · Immunotherapy
Show more