Afonso Philippe Vicente, Ozden Simona, Prevost Marie-Christine, Schmitt Christine, Seilhean Danielle, Weksler Babette, Couraud Pierre-Olivier, Gessain Antoine, Romero Ignacio Andres, Ceccaldi Pierre-Emmanuel
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie and Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Institut Pasteur, Paris, France.
J Immunol. 2007 Aug 15;179(4):2576-83. doi: 10.4049/jimmunol.179.4.2576.
The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1alpha and TNF-alpha secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-kappaB pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.
血脑屏障（BBB）构成了血液与脑实质之间的界面，已证实在逆转录病毒相关神经脊髓病期间其会被破坏。人类T细胞白血病病毒1型（HTLV-1）相关脊髓病/热带痉挛性截瘫是一种缓慢进展的神经退行性疾病，其中，中枢神经系统中淋巴细胞浸润以及血浆蛋白通过脑内皮渗漏的现象证明了血脑屏障的破坏。利用体外人类血脑屏障模型，我们研究了HTLV-1感染的淋巴细胞诱导内皮细胞变化所涉及的细胞和分子机制。我们证明，与受感染淋巴细胞共培养会通过分泌白细胞介素-1α（IL-1α）和肿瘤坏死因子-α（TNF-α）导致细胞旁内皮通透性增加和跨细胞迁移。这种破坏与内皮细胞之间紧密连接的紊乱以及紧密连接蛋白（如闭合蛋白1）表达模式的改变有关。抑制核因子-κB（NF-κB）途径或肌球蛋白轻链激酶活性可预防这些变化。在一名HTLV-1相关脊髓病/热带痉挛性截瘫患者的脊髓组织切片中证实了这种紊乱。基于此血脑屏障模型，目前的数据表明，HTLV-1感染的淋巴细胞可诱导血脑屏障破坏，并可能是逆转录病毒相关神经脊髓病早期发生中枢神经系统浸润的原因。
