Abstract：
Human Borna disease virus 1 (BoDV-1) encephalitis is a severe emerging disease with a very high case-fatality rate. While the clinical disease, case definitions, diagnostic algorithms and neuropathology have been described, very little is known about the immunological processes of human BoDV-1 encephalitis. Here, we analyzed serum and cerebrospinal fluid (CSF) samples from 10 patients with fatal BoDV-1 encephalitis for changes of different cytokines, chemokines, growth factors and other biomarkers over time. From one of these individuals, also autoptic formalin-fixed brain tissue was analyzed for the expression of inflammatory biomarkers by mRNA levels and immunostaining; in a further patient, only formalin-fixed brain tissue was available and examined in addition. A marked and increasing immune activation from the initial phase to the last phase of acute BoDV-1 encephalitis is shown in serum and CSF, characterized by cytokine concentration changes (IFNγ, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-13, IL-18, TGF-β1) with a predominantly pro-inflammatory pattern over time. IFNγ production was demonstrated in endothelial cells, astrocytes and microglia, IL-6 in activated microglia, and TGF-β1 in endothelial cells, activated astrocytes and microglia. This was paralleled by an increase of chemokines (CCL-2, CCL-5, CXCL-10, IL-8) to attract immune cells to the site of infection, contributing to inflammation and tissue damage. Pathologically low growth factor levels (BDNF, β-NGF, PDGF) were seen. Changed levels of arginase and sTREM further fostered the pro-inflammatory state. This dysbalanced, pro-inflammatory state likely contributes importantly to the fatal outcome of human BoDV-1 encephalitis, and might be a key target for possible treatment attempts.
摘要：
人类博尔纳病病毒1（BoDV-1）脑炎是一种严重的新兴疾病，病死率很高。而临床疾病,案例定义，已经描述了诊断算法和神经病理学，对人类BoDV-1脑炎的免疫过程知之甚少。这里,我们分析了10例致命的BoDV-1脑炎患者的血清和脑脊液（CSF）样本中不同细胞因子的变化，趋化因子,随着时间的推移，生长因子和其他生物标志物。从这些人中的一个，还通过mRNA水平和免疫染色分析了自体福尔马林固定的脑组织中炎症生物标志物的表达；在另一个患者中，只有福尔马林固定的脑组织可用,并进行了额外检查.从急性BoDV-1脑炎的初始阶段到最后阶段，血清和CSF中显示出明显且增加的免疫激活，以细胞因子浓度变化为特征(IFNγ，IL-5，IL-6，IL-9，IL-10，IL-12p40，IL-13，IL-18，TGF-β1）随着时间的推移具有主要的促炎模式。IFNγ的产生在内皮细胞中得到证实，星形胶质细胞和小胶质细胞，活化小胶质细胞中的IL-6，和内皮细胞中的TGF-β1，激活的星形胶质细胞和小胶质细胞。这与趋化因子（CCL-2，CCL-5，CXCL-10，IL-8）的增加平行，以吸引免疫细胞到感染部位。导致炎症和组织损伤。病理性低生长因子水平（BDNF，β-NGF,PDGF）。精氨酸酶和sTREM水平的改变进一步促进了促炎状态。这种失衡，促炎状态可能对人类BoDV-1脑炎的致命后果有重要贡献，并且可能是可能的治疗尝试的关键目标。
