Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis
Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis
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DOI：
10.2353/ajpath.2008.070918
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发表时间：
2008-03-01
影响因子：
6
通讯作者：
Klein, Robyn S.
中科院分区：
文献类型：
--
作者：
McCandless, Erin E.;Piccio, Laura;Klein, Robyn S.
血脑屏障（BBB）功能失调和白细胞的跨内皮迁移是多发性硬化（MS）活动性病变发展和传播的重要组成部分。动物研究表明，趋化因子CXCL 12在BBB的极化表达可防止白细胞外渗进入中枢神经系统（CNS），CXCL 12极性的破坏可促进自身反应性白细胞的进入和炎症。在本研究中，我们检测了MS和非MS患者CNS组织中CXCL 12及其受体CXCR 4的表达。在BBB的CXCL 12表达的免疫组织化学分析揭示了来自非MS患者的组织中的基底外侧定位和来自MS患者的组织中的未涉及的位点。相反，在活动性MS病变中，CXCL 12表达向血管腔重新分布，并与浸润性白细胞中的CXCR 4活化相关，如磷酸化CXCR 4特异性抗体所示。对中枢神经系统微血管系统CXCL 12表达的定量评估表明，CXCL 12再分布、白细胞浸润和组织学疾病严重程度之间存在正相关性。这些结果表明，CXCL 12正常功能定位浸润性白细胞;血管周围空间，防止CNS实质浸润。在所研究的患者队列中，BBB中CXCL 12表达模式的改变与MS特异性相关，可能促进表达CXCR 4的单核细胞进出血管周围空间的运输，并导致疾病进展。
Dysregulation of blood-brain barrier (BBB) function and transendothelial migration of leukocytes are essential components of the development and propagation of active lesions in multiple sclerosis (MS). Animal studies indicate that polarized expression of the chemokine CXCL12 at the BBB prevents leukocyte extravasation into the central nervous system (CNS) and that disruption of CXCL12 polarity promotes entry of autoreactive leukocytes and inflammation. in the present study, we examined expression of CXCL12 and its receptor, CXCR4, within CNS tissues from MS and non-MS patients. lmmunohistochemical analysis of CXCL12 expression at the BBB revealed basolateral localization in tissues derived from non-MS patients and at uninvolved sites in tissues from MS patients. In contrast, within active MS lesions, CXCL12 expression was redistributed toward vessel lumena and was associated with CXCR4 activation in infiltrating leukocytes, as revealed by phospho-CXCR4-specific antibodies. Quantitative assessment of CXCL12 expression by the CNS microvasculature established a positive correlation between CXCL12 redistribution, leukocyte infiltration, and severity of histological disease. These results suggest that CXCL12 normally functions to localize infiltrating leukocytes; to perivascular spaces, preventing CNS parenchymal infiltration. in the patient cohort studied, altered patterns of CXCL12 expression at the BBB were specifically associated with MS, possibly facilitating trafficking of CXCR4-expressing mononuclear cells into and out of the perivascular space and leading to progression of disease.