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Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions

Authors

  • Nathalie Koning MSc,

    Corresponding author
    1. Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
    2. Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
    • Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, the Netherlands
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  • Lars Bö MD, PhD,

    1. Department of Neuropathology, VU Medical Center, Amsterdam, the Netherlands
    2. Haukeland University Hospital, Department of Neurology, Bergen, Norway
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  • Robert M. Hoek PhD,

    1. Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
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  • Inge Huitinga PhD

    1. Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
    2. Netherlands Brain Bank, Amsterdam, the Netherlands
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Abstract

Objective

Inflammatory and demyelinating activity of activated resident macrophages (microglia) and recruited blood-borne macrophages are considered crucial in multiple sclerosis (MS) lesion development. The membrane glycoproteins CD200 and CD47, highly expressed on neurons, are mediators of macrophage inhibition via their receptors CD200R and signal-regulatory protein α, respectively, on myeloid cells. We determined the expression pattern of immune inhibitory molecules in relation to genes involved in macrophage activation and MS lesion pathology.

Methods

Laser dissection microscopy was combined with real-time polymerase chain reaction to quantitatively study these gene expression patterns in specific subareas (rim, center, and normal-appearing white matter) of chronic active and inactive MS lesions.

Results

Hallmarks of MS pathology were confirmed by messenger RNA expression patterns of glial fibrillary acidic protein, neurofilament (NF), myelin basic protein, growth factors, chemokines and receptors, and macrophage activation markers, although expression of osteopontin and αB-crystallin was decreased. CD200 and CD47 were downregulated in the center of chronic active and inactive MS lesions. CD47 expression was also decreased in the rim of chronic active lesions, where complement expression was increased. This expression profile was also found in normal-appearing white matter surrounding these lesions, but not surrounding inactive lesions. Expression of CD200R and signal-regulatory protein α was not altered.

Interpretation

These data suggest that diminished immune inhibition via decreased CD200 and CD47 expression contributes to a disturbed equilibrium in macrophage and microglia activation in MS lesions. Furthermore, this may result in a proinflammatory predisposition in the area surrounding chronic active lesions, thereby contributing to axonal injury, demyelination, and possible lesion expansion. Ann Neurol 2007

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