van Nierop Gijsbert P, Mautner Josef, Mitterreiter Johanna G, Hintzen Rogier Q, Verjans Georges M G M
Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands/Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.
Helmholtz Zentrum München and Technical University, Munich, Germany.
Mult Scler. 2016 Mar;22(3):279-91. doi: 10.1177/1352458515588581. Epub 2015 Jun 3.
The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) may involve intrathecal EBV-specific T-cell responses targeting the virus or indirectly, autoantigens.
Compare the prevalence and fine-specificity of EBV-specific T-cells in the cerebrospinal fluid (CSF) of patients with MS (n = 12), clinically-isolated syndrome (CIS) (n = 17) and other neurological diseases (OND) (n = 13).
Intrathecal EBV-specific T-cell reactivity was assayed using CSF-derived T-cell lines (CSF-TCL) and autologous EBV-transformed B-cells (autoBLCL) as antigen-presenting cells (APC). EBV proteins recognized by autoBLCL-specific CD8 T-cells were identified using human leukocyte antigen class I (HLA-I)-negative monkey cells as artificial APC, co-transfected with 59 different EBV genes and the corresponding patient's HLA-I alleles that were involved in autoBLCL T-cell reactivity. Reactivity towards the MS-associated autoantigen αB-crystallin (CRYAB) was determined analogously.
CSF-TCL from CIS and MS patients had significantly higher frequencies of autoBLCL-reactive CD4 T-cells, compared to the OND patients. CIS patients also had significantly higher autoBLCL-reactive CD8 T cells, which correlated with reactive CD4 T-cell frequencies. AutoBLCL-specific CD8 T-cell responses of four CSF-TCL analyzed in detail were oligoclonal and directed to lytic EBV proteins, but not CRYAB endogenously expressed by autoBLCL.
Enhanced intrathecal autoBLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in two CSF-TCL, suggested a localized T-cell response to EBV in patients with MS. Our data warrant further characterization of the magnitude and breadth of intrathecal EBV-specific T-cell responses in larger patient cohorts.
爱泼斯坦-巴尔病毒（EBV）与多发性硬化症（MS）之间的关联可能涉及针对该病毒或间接针对自身抗原的鞘内EBV特异性T细胞反应。
比较MS患者（n = 12）、临床孤立综合征（CIS）患者（n = 17）和其他神经系统疾病（OND）患者（n = 13）脑脊液（CSF）中EBV特异性T细胞的患病率和精细特异性。
使用源自CSF的T细胞系（CSF-TCL）和自体EBV转化的B细胞（自体B淋巴母细胞系，autoBLCL）作为抗原呈递细胞（APC），检测鞘内EBV特异性T细胞反应性。使用人类白细胞抗原I类（HLA-I）阴性猴细胞作为人工APC，与59种不同的EBV基因和参与自体B淋巴母细胞系T细胞反应性的相应患者的HLA-I等位基因共转染，鉴定自体B淋巴母细胞系特异性CD8 T细胞识别的EBV蛋白。类似地测定对MS相关自身抗原αB-晶状体蛋白（CRYAB）的反应性。
与OND患者相比，CIS和MS患者的CSF-TCL中自体B淋巴母细胞系反应性CD4 T细胞频率显著更高。CIS患者的自体B淋巴母细胞系反应性CD8 T细胞也显著更高，这与反应性CD4 T细胞频率相关。详细分析的四个CSF-TCL的自体B淋巴母细胞系特异性CD8 T细胞反应是寡克隆的，并且针对裂解性EBV蛋白，但不针对自体B淋巴母细胞系内源性表达的CRYAB。
鞘内自体B淋巴母细胞系特异性T细胞反应性增强，在两个CSF-TCL中选择性地针对裂解性EBV蛋白，提示MS患者对EBV存在局部T细胞反应。我们的数据需要在更大的患者队列中进一步表征鞘内EBV特异性T细胞反应的强度和广度。
