Koning Nathalie, Bö Lars, Hoek Robert M, Huitinga Inge
Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Ann Neurol. 2007 Nov;62(5):504-14. doi: 10.1002/ana.21220.
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.
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.
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.
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.
活化的常驻巨噬细胞（小胶质细胞）和募集的血源性巨噬细胞的炎症和脱髓鞘活性被认为在多发性硬化症（MS）病变发展中起关键作用。神经元上高表达的膜糖蛋白CD200和CD47分别是通过其在髓样细胞上的受体CD200R和信号调节蛋白α抑制巨噬细胞的介质。我们确定了与巨噬细胞活化和MS病变病理学相关基因的免疫抑制分子表达模式。
激光显微切割术与实时聚合酶链反应相结合，定量研究慢性活动性和非活动性MS病变特定亚区域（边缘、中心和外观正常的白质）中的这些基因表达模式。
胶质纤维酸性蛋白、神经丝（NF）、髓鞘碱性蛋白、生长因子、趋化因子及其受体以及巨噬细胞活化标志物的信使核糖核酸表达模式证实了MS病理学特征，尽管骨桥蛋白和αB-晶状体蛋白的表达降低。慢性活动性和非活动性MS病变中心的CD200和CD47下调。慢性活动性病变边缘的CD47表达也降低，而补体表达增加。在这些病变周围外观正常的白质中也发现了这种表达谱，但在非活动性病变周围未发现。CD200R和信号调节蛋白α的表达未改变。
这些数据表明，CD200和CD47表达降低导致免疫抑制减弱，这有助于MS病变中巨噬细胞和小胶质细胞活化的平衡失调。此外，这可能导致慢性活动性病变周围区域的促炎倾向，从而导致轴突损伤、脱髓鞘以及可能的病变扩展。
