Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis
Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis
复制标题
DOI：
10.1016/j.cyto.2020.155226
复制
发表时间：
2020-11-01
期刊：
影响因子：
3.8
通讯作者：
Reinhold, Dirk
中科院分区：
文献类型：
--
作者：
Koertvelyessy, Peter;Goihl, Alexander;Reinhold, Dirk
生物体液中细胞因子或可溶性受体水平的变化可以提供有关相应疾病的免疫病理机制的信息。在这里，我们研究了自身免疫性脑炎（AE）患者在免疫抑制治疗前后的细胞因子模式，以鉴定可能的生物标志物候选者并寻找与脓毒症相关的病理机制。我们用抗富含亮氨酸的胶质瘤失活蛋白1（LGI 1）的抗体（ab）对7名AE患者和9名AE患者的脑脊液（CSF）和血清进行了测量，从马格德堡和柏林（德国）的两个三级AE中心招募相关蛋白样2（Caspr 2）ab。在马格德堡，治疗前和治疗后的样品可用于测量，在柏林队列中，样品在治疗开始后收集。首先，我们使用包含36种细胞因子或可溶性受体的人细胞因子阵列来筛选8例AE（治疗前和治疗后）、4例单纯疱疹病毒脑膜脑炎患者和4例无神经炎症的对照的CSF样品中的生物标志物。然后，选择CCL 2、CXCl 10、CXCl 13、IL-6和sICAM-1作为候选物，用特异性ELISA系统检测所有16例AE患者、14例无神经炎症的对照者和7例单纯疱疹病毒性脑膜炎患者的CSF和血清中CCL 2、CXCl 10、CXCl 13、IL-6和sICAM-1。采用改良兰金量表评价临床疗效。通过色谱法纯化来自马格德堡队列的LGI 1和Caspr 2 abs。免疫印迹分析结果显示，与LGI 1 AE患者和对照组相比，Caspr 2患者CSF中大多数候选参数水平均升高，但治疗前后细胞因子浓度无明显变化。因此，这些参数似乎不适合作为疾病的替代生物标志物。与对照样品相比，在Caspr 2 AE患者（CXCL 13和sICAM 1）的CSF中以及在Caspr 2（CXCL 10）和LGI 1 AE患者（CXCL 13）的血清中观察到显著更高的水平。Caspr 2 AE似乎引发比LGI 1 AE更高的免疫应答，这与每种类型疾病中涉及的AE特异性抗体的相应IgG亚类组合无关。
Changes in levels of cytokines or soluble receptors in biological fluids may provide information on immunological pathomechanisms underlying the respective diseases. Here, we studied cytokine patterns of patients with autoimmune encephalitis (AE) before and after immunosuppressive treatment in order to identify possible biomarker candidates and to look for putatively involved pathomechanisms.We performed measurements in Cerebrospinal fluid (CSF) and serum of 7 patients suffering from AE with antibodies (ab) against Leucine-rich glioma-inactivated-protein 1 (LGI1) and 9 AE patients with Contactin-associated protein-like 2 (Caspr2) ab recruited from two tertiary AE centers in Magdeburg and Berlin, Germany. In the Magdeburg samples before and after treatment were available for the measurements and in the Berlin cohort samples were collected after treatment was initiated.First, we used a human cytokine array comprising 36 cytokines or soluble receptors to screen for biomarkers in CSF samples of 8 AE (before and after treatment), 4 herpes-simplex virus meningoencephalitis patients and 4 controls without neuroinflammation. Next, CCL2, CXCl10, CXCl13, Il -6 and sICAM1 were chosen as candidates and measured in CSF and serum with specific ELISA systems in all 16 AE patients, 14 controls without neuroinflammation and 7 herpes-simplex virus meningitis patients. Clinical outcome was assessed via modified Rankin scale. LGI1 and Caspr2 abs from the Magdeburg cohort were purified by chromatography. IgG subclasses of these LGI1 or Caspr2 abs were identified by immunoblot analysis.The levels of most candidate parameters were higher in the CSF of Caspr2 than of LGI1 AE patients and controls, but there were no significant changes of cytokine concentrations before and after initiating treatment. Thus, these parameters seem unsuited as surrogate biomarkers of disease. Significantly higher levels were observed in the CSFs of Caspr2 AE patients (CXCL13 and sICAM1) as well as in the serum of Caspr2 (CXCL10) and LGI1 AE patients (CXCL13) in comparison to control samples.These results suggest that neuro-immunological pathomechanisms may differ between Caspr2 and LGI1 AE patients. Caspr2 AE seems to elicit a higher immune response than LGI1 AE, which has no correlation to the respective IgG subclass combination of AE specific abs involved in each type of disease.