Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions.
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 alpha, 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 alphaB-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 alpha was not altered.


CONCLUSIONS
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.
Koning
Nathalie
N
Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. n.koning@nin.knaw.nl
Bö
Lars
L
Hoek
Robert M
RM
Huitinga
Inge
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D051928:CD47 Antigen; D008263:Macrophage Migration-Inhibitory Factors