摘要： 研究背景 新型隐球菌性脑膜炎是新型隐球菌感染脑膜和（或）脑实质引起的中枢神经系统感染性疾病，其发生、发展和转归在一定程度上取决于患者自身免疫功能，尤其与辅助性T 细胞亚群Th1/Th2 免疫应答失衡有关。本研究旨在探讨新型隐球菌性脑膜炎患者中枢神经系统局部Th1 和Th2免疫应答作用。方法 采用酶联免疫吸附试验定量检测脑脊液Th1 细胞因子［干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）］和Th2 细胞因子［白细胞介素-10（IL-10）］水平，并动态监测脑脊液细胞学变化。结果 脑膜炎组患者脑脊液Th1 细胞因子IFN-γ、TNF-α为（11.17 ± 1.50）和（18.74 ± 2.97）pg/ml，低于对照组的（17.69 ± 2.34）和（28.83 ± 3.55）pg/ml（均P = 0.000），Th2 细胞因子IL-10 为（43.65 ± 10.12）pg/ml，高于对照组的（7.80 ± 1.30）pg/ml（P = 0.000）；急性期IFN-γ、TNF-α为（11.17 ± 1.50）和（18.74 ± 2.97）pg/ml，低于稳定期的（17.70 ± 2.34）和（22.93 ± 1.53）pg/ml（均P = 0.000），IL-10 为（43.65 ± 10.12）pg/ml，高于稳定期的（22.93 ± 7.39）pg/ml（P = 0.000）。脑膜炎组患者脑脊液IFN-γ/IL-10、TNF-α/IL-10 比值低于对照组（均P = 0.000），急性期亦低于稳定期（均P = 0.000）。结论 Th2 免疫应答模式在新型隐球菌性脑膜炎急性期起重要作用，至稳定期转变为以Th1 为主的免疫反应。提示Th1/Th2 免疫应答失衡与新型隐球菌性脑膜炎发病机制密切相关。

关键词: 脑膜炎, 隐球菌性, 脑脊髓液, T 淋巴细胞, 辅助诱导, 干扰素Ⅱ型, 肿瘤坏死因子α, 白细胞介素10

Abstract: Background  Cryptococcal meningitis (CM) is the most common fungal infection of central nervous system, caused by Cryptococcus neoformans infection of the meninges. The development and prognosis of CM depend on the patient's own immune function to some extent, and are relative to the imbalance of helper T lymphocyte (Th1/Th2). This study aims to explore the hidden role of the local Th1/ Th2 immune response in the pathophysiological process of CM.  Methods  The levels of Th1 cytokines interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and Th2 cytokine interleukin-10 (IL-10) in the cerebrospinal fluid (CSF) were detected by enzyme-linked immunosorbent assay (ELISA). CSF cytology changes were monitored dynamically to understand the outcome status of patients with CM.  Results  The levels of IFN-γ and TNF-α in CM patients [(11.17 ± 1.50) and (18.74 ± 2.97) pg/ml, respectively] were significantly lower than that in control patients [(17.69 ± 2.34) and (28.83 ± 3.55) pg/ml; P = 0.000, for all]. However, the levels of IL-10 in CM patients [(43.65 ± 10.12) pg/ml] were significantly higher than that in control patients [(7.80 ± 1.30) pg/ml, P = 0.000]. The CSF IFN-γ and TNF-α levels in acute phase of CM patients [(11.17 ± 1.50) pg/ml and (18.74 ± 2.97) pg/ml, respectively] were significantly lower than that in stable phase of CM patients [(17.70 ± 2.34) and (22.93 ± 1.53) pg/ml; P = 0.000, for all]. On the other hand, the levels of IL-10 were significantly higher in the acute phase than that in stable phase [(43.65 ± 10.12) and (22.93 ± 7.39) pg/ml, respectively; P = 0.000]. The ratios of Th1/Th2 were used to assess the contribution of Th1/Th2 immunity in acute and stable phase of CM patients. The ratios of IFN-γ/IL-10 and TNF-α/IL-10 measured in acute phase of CM patients were significantly lower than that in control patients (P = 0.000, for all). These ratios in acute phase patients were also significantly lower than that in stable phase patients (P = 0.000, for all).  Conclusions  In acute phase, the Th2 response is dominant in patients with CM. However, the immune response shifts towards to Th1 response in the stable phase, providing direct evidence that the imbalance of Th1-Th2 cytokines is related to the pathogenesis of CM.

Key words: Meningitis, cryptococcal, Cerebrospinal fluid, T-lymphocytes, helper-inducer, Interferon type Ⅱ, Tumor necrosis factor-alpha, Interleukin-10