Grygorczuk Sambor, Parczewski Miłosz, Świerzbińska Renata, Czupryna Piotr, Moniuszko Anna, Dunaj Justyna, Kondrusik Maciej, Pancewicz Sławomir
Department of the Infectious Diseases and Neuroinfections, Medical University in Białystok, ul. Żurawia 14, 15-540, Białystok, Poland.
Department of Infectious Diseases and Hepatology, Pomeranian Medical University in Szczecin, ul. Arkońska 4, 71-455, Szczecin, Poland.
J Neuroinflammation. 2017 Jun 24;14(1):126. doi: 10.1186/s12974-017-0898-2.
Host factors determining the clinical presentation of tick-borne encephalitis (TBE) are not fully elucidated. The peripheral inflammatory response to TBE virus is hypothesized to facilitate its entry into central nervous system by disrupting the blood-brain barrier with the involvement of a signaling route including Toll-like receptor 3 (TLR3) and pro-inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNFα), and interleukin-1 beta (IL-1β).
Concentrations of MIF, TNFα, and IL-1β were measured with commercial ELISA in serum and cerebrospinal fluid (CSF) from 36 hospitalized TBE patients, 7 patients with non-TBE meningitis, and 6 controls. The CSF albumin quotient (AQ) was used as a marker of blood-brain barrier permeability. Single nucleotide polymorphisms rs3775291, rs5743305 (associated with TLR3 expression), and rs755622 (associated with MIF expression) were assessed in blood samples from 108 TBE patients and 72 non-TBE controls. The data were analyzed with non-parametric tests, and p < 0.05 was considered significant.
The median serum and CSF concentrations of MIF and IL-1β were significantly increased in TBE group compared to controls. MIF concentration in serum tended to correlate with AQ in TBE, but not in non-TBE meningitis. The serum concentration of TNFα was increased in TBE patients bearing a high-expression TLR3 rs5743305 TT genotype, which also associated with the increased risk of TBE. The low-expression rs3775291 TLR3 genotype TT associated with a prolonged increase of CSF protein concentration. The high-expression MIF rs755622 genotype CC tended to correlate with an increased risk of TBE, and within TBE group, it was associated with a mild presentation.
The results point to the signaling route involving TLR3, MIF, and TNFα being active in TBE virus infection and contributing to the risk of an overt neuroinvasive disease. The same factors may play a protective role intrathecally contributing to the milder course of neuroinfection. This suggests that the individual variability of the risk and clinical presentation of TBE might be traced to the variable peripheral and intrathecal expression of the mediators of the inflammatory response, which in turn associates with the host genetic background.
决定蜱传脑炎（TBE）临床表现的宿主因素尚未完全阐明。据推测，TBE病毒引发的外周炎症反应通过包括Toll样受体3（TLR3）和促炎细胞因子巨噬细胞移动抑制因子（MIF）、肿瘤坏死因子-α（TNFα）和白细胞介素-1β（IL-1β）在内的信号通路破坏血脑屏障，从而促进病毒进入中枢神经系统。
采用商业酶联免疫吸附测定法（ELISA）检测36例住院TBE患者、7例非TBE脑膜炎患者和6例对照者血清及脑脊液（CSF）中MIF、TNFα和IL-1β的浓度。脑脊液白蛋白商（AQ）用作血脑屏障通透性的标志物。在108例TBE患者和72例非TBE对照者的血样中评估单核苷酸多态性rs3775291、rs5743305（与TLR3表达相关）和rs755622（与MIF表达相关）。数据采用非参数检验进行分析，p < 0.05被认为具有统计学意义。
与对照组相比，TBE组血清和脑脊液中MIF和IL-1β的中位数浓度显著升高。TBE患者血清中MIF浓度与AQ呈正相关趋势，而非TBE脑膜炎患者则无此相关性。携带高表达TLR3 rs5743305 TT基因型的TBE患者血清中TNFα浓度升高，并与TBE风险增加相关。低表达rs3775291 TLR3基因型TT与脑脊液蛋白浓度持续升高相关。高表达MIF rs755622基因型CC与TBE风险增加呈正相关趋势，且在TBE组内，与症状较轻相关。
结果表明，涉及TLR3、MIF和TNFα的信号通路在TBE病毒感染中激活，并导致明显的神经侵袭性疾病风险增加。相同因素可能在鞘内起保护作用，使神经感染病程较轻。这表明，TBE风险和临床表现的个体差异可能归因于炎症反应介质外周和鞘内表达的变化，而这又与宿主遗传背景相关。
