McCandless Erin E, Piccio Laura, Woerner B Mark, Schmidt Robert E, Rubin Joshua B, Cross Anne H, Klein Robyn S
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Am J Pathol. 2008 Mar;172(3):799-808. doi: 10.2353/ajpath.2008.070918. Epub 2008 Feb 14.
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. Immunohistochemical 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.
血脑屏障（BBB）功能失调以及白细胞的跨内皮迁移是多发性硬化症（MS）活动性病灶发展和扩散的重要组成部分。动物研究表明，趋化因子CXCL12在血脑屏障处的极化表达可防止白细胞渗入中枢神经系统（CNS），而CXCL12极性的破坏会促进自身反应性白细胞的进入和炎症反应。在本研究中，我们检测了MS患者和非MS患者中枢神经系统组织中CXCL12及其受体CXCR4的表达。对血脑屏障处CXCL12表达的免疫组织化学分析显示，在非MS患者来源的组织以及MS患者组织中未受累部位，CXCL12呈基底外侧定位。相比之下，在活动性MS病灶内，CXCL12表达重新分布至血管腔，并与浸润白细胞中的CXCR4激活相关，这通过磷酸化CXCR4特异性抗体得以揭示。中枢神经系统微血管对CXCL12表达的定量评估表明，CXCL12重新分布、白细胞浸润与组织学疾病严重程度之间呈正相关。这些结果表明，CXCL12通常起到将浸润白细胞定位到血管周围间隙的作用，从而防止中枢神经系统实质浸润。在所研究的患者队列中，血脑屏障处CXCL12表达模式的改变与MS特异性相关，可能促进表达CXCR4的单核细胞进出血管周围间隙，并导致疾病进展。
