Phares Timothy W, Fabis Marzena J, Brimer Christine M, Kean Rhonda B, Hooper D Craig
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
J Immunol. 2007 Jun 1;178(11):7334-43. doi: 10.4049/jimmunol.178.11.7334.
Elevated blood-brain barrier (BBB) permeability is associated with both the protective and pathological invasion of immune and inflammatory cells into CNS tissues. Although a variety of processes have been implicated in the changes at the BBB that result in the loss of integrity, there has been no consensus as to their induction. TNF-alpha has often been proposed to be responsible for increased BBB permeability but there is accumulating evidence that peroxynitrite (ONOO(-))-dependent radicals may be the direct trigger. We demonstrate here that enhanced BBB permeability in mice, whether associated with rabies virus (RV) clearance or CNS autoimmunity, is unaltered in the absence of TNF-alpha. Moreover, the induction of TNF-alpha expression in CNS tissues by RV infection has no impact on BBB integrity in the absence of T cells. CD4 T cells are required to enhance BBB permeability in response to the CNS infection whereas CD8 T cells and B cells are not. Like CNS autoimmunity, elevated BBB permeability in response to RV infection is evidently mediated by ONOO(-). However, as opposed to the invading cells producing ONOO(-) that have been implicated in the pathogenesis of CNS inflammation, during virus clearance ONOO(-) is produced without pathological sequelae by IFN-gamma-stimulated neurovascular endothelial cells.
血脑屏障（BBB）通透性升高与免疫和炎性细胞进入中枢神经系统（CNS）组织的保护性及病理性侵袭均相关。尽管多种过程都与血脑屏障的变化有关，这些变化导致其完整性丧失，但对于这些变化的诱导因素尚无共识。肿瘤坏死因子-α（TNF-α）常被认为是血脑屏障通透性增加的原因，但越来越多的证据表明，过氧亚硝酸盐（ONOO⁻）依赖性自由基可能是直接触发因素。我们在此证明，在小鼠中，无论与狂犬病病毒（RV）清除还是中枢神经系统自身免疫相关，血脑屏障通透性增强在缺乏TNF-α的情况下并未改变。此外，在没有T细胞的情况下，RV感染诱导中枢神经系统组织中TNF-α表达对血脑屏障完整性没有影响。响应中枢神经系统感染时，需要CD4 T细胞来增强血脑屏障通透性，而CD8 T细胞和B细胞则不需要。与中枢神经系统自身免疫一样，响应RV感染时血脑屏障通透性升高显然是由ONOO⁻介导的。然而，与参与中枢神经系统炎症发病机制的产生ONOO⁻的侵袭细胞不同，在病毒清除过程中，IFN-γ刺激的神经血管内皮细胞产生ONOO⁻而无病理后遗症。
