日本血吸虫病患者肝脏病理损害的免疫学诊断方法的建立及相关机制探讨
摘要
血吸虫病是当前我国乃至世界最严重的寄生虫病之一,全球感染人数超过2亿。在我国,日本血吸虫病是一种流行广泛,危害严重的传染病,迄今仍然是我国主要公共卫生问题之一。日本血吸虫感染后,沉积在肝脏内的虫卵引起以虫卵肉芽肿为主的免疫病理损害,进一步引起进行性发展的肝脏纤维化,并最终导致肝硬化、门脉高压症等,是对宿主最严重的免疫损伤,甚至危及生命。因此,监测血吸虫病人肝脏免疫病理损伤进程、研究血吸虫病肝脏免疫病理损伤的机制对于治疗血吸虫病人是非常迫切和必要的。然而,现行的以B超检测为主的方法因其不能检测出血吸虫引起的早期肝脏纤维化、而且使用受偏远的农村和山区地区经济和电力供应等方面的因素限制以及不适用于大规模的流行病学筛查等,导致其在现场使用具有很大的局限性,因此研发一种较为简单的免疫学方法,在血吸虫感染早期即可检测宿主对血吸虫感染免疫应答的强弱、丛而在血吸虫感染早期即可估测特定患者今后可能引起免疫病理损害的进展速度和/或程度,或用于感染后动态监测患者免疫病理损害进程与程度,并可能在流行区人群中低成本、大规模地反复应用的检测方法是非常重要的。
我们在实验中发现,日本血吸虫感染小鼠的血清SjHSP60-IgG及其亚型IgG1抗体滴度与对应的肝脏单个虫卵肉芽肿面积呈正相关；日本血吸虫感染家兔的血清SjHSP60-IgG抗体滴度与对应的肝脏单个虫卵肉芽肿面积也呈正相关,且在家兔的慢性感染模型中(感染23周)也观察到家兔肝脏中的胶原纤维Ⅲ和a-SMA的表达水平与血清中的SjHSP60-IgG抗体滴度呈正相关。在注射四氯化碳模拟肝脏综合免疫病理损伤的日本血吸虫感染小鼠中发现,其血清SjHSP60-IgG抗体水平明显高于单纯日本血吸虫感染小鼠。在血吸病流行区粪检阳性的日本血吸虫病人中发现血清SjHSP60-IgG及其亚型IgG1抗体滴度与各对应患者的肝脏超声病理指标亦呈正相关。上述结果均表明日本血吸虫感染宿主的血清SjHSP60-IgG及其亚型IgG1抗体水平与肝脏肉芽肿和纤维化程度呈正相关,从而提示血清SjHSP60-IgG及其亚型IgG1抗体水平可以作为评价日本血吸虫患者肝脏病理程度的一个指标,具有潜在的临床应用价值。
然而,宿主血清中SjHSP60抗体水平与其肝脏免疫病理损伤程度呈正相关的免疫学机制还不清楚。在我们的后续研究中发现,日本血吸虫感染的Tfh细胞缺陷小鼠(ICOSL敲除鼠)的血清SjHSP60抗体水平极低,从而提示SjHSP60抗体产生依赖于Tfh细胞。为阐明是否是日本血吸虫感染过程中诱导产生的Tfh细胞在促进SjHSP60抗体生成的同时也促进肝脏病理的形成,从而导致了血清SjHSP60抗体水平与肝脏免疫病理损伤程度呈正相关,我们进行了深入的机制研究,并获得了如下结果：我们发现日本日本血吸虫感染小鼠8周后,随着肝脏虫卵肉芽肿的发展,小鼠脾脏、淋巴结和肝脏中Tfh细胞比例显著升高,初步提示了Tfh细胞可能参与了肝脏虫卵肉芽肿的形成。随后我们发现,Tfh细胞缺陷小鼠在感染日本血吸虫后肝脏虫卵肉芽肿反应显著减轻,而其接受过继转移的Tfh细胞后,虫卵肉芽肿反应加重并回复至正常水平,从而证明Tfh细胞确能促进虫卵肉芽肿的形成。我们还发现Tfh细胞可以被直接募集到肝脏中参与促进虫卵肉芽肿的形成。
随后,我们探讨了日本血吸虫感染小鼠体内Tfh细胞形成的相关机制,首次发现巨噬细胞可以通过细胞-细胞接触的方式诱导CD4+T细胞分化成Tfh细胞,并且巨噬细胞表面的ICOSL分子对于诱导Tfh细胞是必须的。我们还发现CD40/CD40L信号可以通过上调巨噬细胞表面的ICOSL的表达而促进Tfh的诱导。
总之,本研究首次发现了日本血吸虫感染小鼠的巨噬细胞通过细胞-细胞接触、并依赖于其表面ICOSL分子诱导Tfh细胞产生,来参与虫卵肉芽肿形成并促进血清SjHSP60抗体产生,最终导致了宿主血清SjHSP60抗体水平与肝脏免疫病理损伤程度呈正相关。我们的研究结果不仅解释了SjHSP60抗体和肝脏免疫病理呈相关性的免疫学现象,还首次发现了Tfh细胞参与肉芽肿形成这一新功能并阐述了巨噬细胞诱导Tfh细胞形成的新机制,从而有助于更好地了解和认识Tfh细胞在生理和疾病中的作用,也为以Tfh细胞诱导过程与功能发挥为干预靶标的新型治疗方法的研发奠定理论基础。
Schistosomiasis remains a major public health problem in many developing countries in tropical and subtropical regions. Much of the symptomatology of schistosomiasis is attributed to the egg-induced granulomatous inflammatory response and associated fibrosis, which are the primary causes of morbidity in infected individuals and in some cases will ultimately be lethal. Yet it is still a better outcome for both parasite and its hosts than the alternative of pervasive liver tissue damage caused by unsequestered egg toxins. Evaluation of the pathogenic level of hepatic fibrosis and understanding the mechanism of granuloma formation are crucial for better schistomiasis treatment.
This study was performed to determine whether the level of antibody to Schistosoma japonicum heat shock protein60(SjHSP60) could be associated with the extent of the hepatic fibrosis in infected mice, rabbits and patients. We found that the titers of total IgG and the subtype IgG1anti-SjHSP60antibodies in infected mice, rabbits and human patients were significantly higher than that of the controls., and the titers of total IgG and the subtype IgG1anti-SjHSP60antibodies were positively correlated with the extent of hepatic pathology in infected mice, rabbits and patients. Furthermore, the grades of collagen III and a-SMA, but not collagen I expression were positively associated with the level of serum SjHSP60IgG antibody in infected rabbits compared to the controls. Moreover, the titer of total IgG anti-SjHSP60antibody in infected mice with CCl4was higher than that of the infected mice without CCl4, although little change in the level of SjHSP60IgGl antibody was detected in infected mice treated with or without CCl4. These data suggest that SjHSP60antibody has diagnostic and prognostic utility for progression in schistosomiasis.
However, the mechanisms underlying the correlation of the level of SjHSP60antibody with the extent of hepatic fibrosis in schistosomiasis remain unknown. To address this issue, we infected ICOSL KO mice with S. japonicum. We found that Tfh cells play a central role in the production of Sj HSP60antibody during infection. Furthermore, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation during S.japonicum infection, and identified a novel function of macrophages in Tfh cells induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling.
Our findings indicated that SjHSP60IgG and IgGl antibody levels were positively correlated with the extent of hepatic fibrosis and that the level of SjHSP60antibody may be biomarkers for the evaluation of the pathogenic level of hepatic fibrosis in Schistosoma japonicum-infected patients and uncovered a previously unappreciated role of Tfh cells in liver pathogenesis in schistosomiasis and macrophages in Tfh cell differentiation, which contributes to a deeper understanding and may help to design better treatment of the schistosomiasis.
我们在实验中发现,日本血吸虫感染小鼠的血清SjHSP60-IgG及其亚型IgG1抗体滴度与对应的肝脏单个虫卵肉芽肿面积呈正相关；日本血吸虫感染家兔的血清SjHSP60-IgG抗体滴度与对应的肝脏单个虫卵肉芽肿面积也呈正相关,且在家兔的慢性感染模型中(感染23周)也观察到家兔肝脏中的胶原纤维Ⅲ和a-SMA的表达水平与血清中的SjHSP60-IgG抗体滴度呈正相关。在注射四氯化碳模拟肝脏综合免疫病理损伤的日本血吸虫感染小鼠中发现,其血清SjHSP60-IgG抗体水平明显高于单纯日本血吸虫感染小鼠。在血吸病流行区粪检阳性的日本血吸虫病人中发现血清SjHSP60-IgG及其亚型IgG1抗体滴度与各对应患者的肝脏超声病理指标亦呈正相关。上述结果均表明日本血吸虫感染宿主的血清SjHSP60-IgG及其亚型IgG1抗体水平与肝脏肉芽肿和纤维化程度呈正相关,从而提示血清SjHSP60-IgG及其亚型IgG1抗体水平可以作为评价日本血吸虫患者肝脏病理程度的一个指标,具有潜在的临床应用价值。
然而,宿主血清中SjHSP60抗体水平与其肝脏免疫病理损伤程度呈正相关的免疫学机制还不清楚。在我们的后续研究中发现,日本血吸虫感染的Tfh细胞缺陷小鼠(ICOSL敲除鼠)的血清SjHSP60抗体水平极低,从而提示SjHSP60抗体产生依赖于Tfh细胞。为阐明是否是日本血吸虫感染过程中诱导产生的Tfh细胞在促进SjHSP60抗体生成的同时也促进肝脏病理的形成,从而导致了血清SjHSP60抗体水平与肝脏免疫病理损伤程度呈正相关,我们进行了深入的机制研究,并获得了如下结果：我们发现日本日本血吸虫感染小鼠8周后,随着肝脏虫卵肉芽肿的发展,小鼠脾脏、淋巴结和肝脏中Tfh细胞比例显著升高,初步提示了Tfh细胞可能参与了肝脏虫卵肉芽肿的形成。随后我们发现,Tfh细胞缺陷小鼠在感染日本血吸虫后肝脏虫卵肉芽肿反应显著减轻,而其接受过继转移的Tfh细胞后,虫卵肉芽肿反应加重并回复至正常水平,从而证明Tfh细胞确能促进虫卵肉芽肿的形成。我们还发现Tfh细胞可以被直接募集到肝脏中参与促进虫卵肉芽肿的形成。
随后,我们探讨了日本血吸虫感染小鼠体内Tfh细胞形成的相关机制,首次发现巨噬细胞可以通过细胞-细胞接触的方式诱导CD4+T细胞分化成Tfh细胞,并且巨噬细胞表面的ICOSL分子对于诱导Tfh细胞是必须的。我们还发现CD40/CD40L信号可以通过上调巨噬细胞表面的ICOSL的表达而促进Tfh的诱导。
总之,本研究首次发现了日本血吸虫感染小鼠的巨噬细胞通过细胞-细胞接触、并依赖于其表面ICOSL分子诱导Tfh细胞产生,来参与虫卵肉芽肿形成并促进血清SjHSP60抗体产生,最终导致了宿主血清SjHSP60抗体水平与肝脏免疫病理损伤程度呈正相关。我们的研究结果不仅解释了SjHSP60抗体和肝脏免疫病理呈相关性的免疫学现象,还首次发现了Tfh细胞参与肉芽肿形成这一新功能并阐述了巨噬细胞诱导Tfh细胞形成的新机制,从而有助于更好地了解和认识Tfh细胞在生理和疾病中的作用,也为以Tfh细胞诱导过程与功能发挥为干预靶标的新型治疗方法的研发奠定理论基础。
Schistosomiasis remains a major public health problem in many developing countries in tropical and subtropical regions. Much of the symptomatology of schistosomiasis is attributed to the egg-induced granulomatous inflammatory response and associated fibrosis, which are the primary causes of morbidity in infected individuals and in some cases will ultimately be lethal. Yet it is still a better outcome for both parasite and its hosts than the alternative of pervasive liver tissue damage caused by unsequestered egg toxins. Evaluation of the pathogenic level of hepatic fibrosis and understanding the mechanism of granuloma formation are crucial for better schistomiasis treatment.
This study was performed to determine whether the level of antibody to Schistosoma japonicum heat shock protein60(SjHSP60) could be associated with the extent of the hepatic fibrosis in infected mice, rabbits and patients. We found that the titers of total IgG and the subtype IgG1anti-SjHSP60antibodies in infected mice, rabbits and human patients were significantly higher than that of the controls., and the titers of total IgG and the subtype IgG1anti-SjHSP60antibodies were positively correlated with the extent of hepatic pathology in infected mice, rabbits and patients. Furthermore, the grades of collagen III and a-SMA, but not collagen I expression were positively associated with the level of serum SjHSP60IgG antibody in infected rabbits compared to the controls. Moreover, the titer of total IgG anti-SjHSP60antibody in infected mice with CCl4was higher than that of the infected mice without CCl4, although little change in the level of SjHSP60IgGl antibody was detected in infected mice treated with or without CCl4. These data suggest that SjHSP60antibody has diagnostic and prognostic utility for progression in schistosomiasis.
However, the mechanisms underlying the correlation of the level of SjHSP60antibody with the extent of hepatic fibrosis in schistosomiasis remain unknown. To address this issue, we infected ICOSL KO mice with S. japonicum. We found that Tfh cells play a central role in the production of Sj HSP60antibody during infection. Furthermore, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation during S.japonicum infection, and identified a novel function of macrophages in Tfh cells induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling.
Our findings indicated that SjHSP60IgG and IgGl antibody levels were positively correlated with the extent of hepatic fibrosis and that the level of SjHSP60antibody may be biomarkers for the evaluation of the pathogenic level of hepatic fibrosis in Schistosoma japonicum-infected patients and uncovered a previously unappreciated role of Tfh cells in liver pathogenesis in schistosomiasis and macrophages in Tfh cell differentiation, which contributes to a deeper understanding and may help to design better treatment of the schistosomiasis.
引文
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