发明疫苗或治疗传染病面临的最主要问题在于，慢性传染病能逐渐阻止免疫T细胞的反应能力。现在，由美国Emory大学领导的研究人员领导的一个研究组揭示出了慢性病毒感染疾病逃脱免疫反应的重要方式。这项研究的结果发表近期的PNAS(《美国国家科学院院刊》)的网络版上。
研究人员通过使用小鼠模型，发现一种慢性淋巴细胞脉络丛脑膜炎病毒（LCMV）能够攻击一种淋巴器官中被称为纤维原网状细胞（FRC）的基质细胞。而急性病毒则对FRC没有影响。
FRC为免疫细胞提供移动和与淋巴器官（脾脏、淋巴结）中其它免疫细胞作用的三维网络。FRC对于免疫反应的发动很重要。科学家发现FRC感染的传播将导致这一重要基质细胞功能的破坏。去年Emory科学家Rafi Ahmed领导的小组发现在老鼠中，另一种针对慢性感染的免疫反应路径被中断——这是称为PD-1的阻断慢性LCMV反应的路径。
研究组发现FRC感染或许和之前发现的PD-1路径有关。PD-1的主要配合体PD-L1在FRC感染后增加了。PD-1路径或许会阻止CD8+T细胞和FRC之间的相互作用，防止脾脏中FRC结构的破坏。这能帮助病毒持续感染FRC，造成慢性长期的病毒存在。
淋巴细胞脉络丛脑膜炎（lymphocytic choriomeningitis,LCM）是由淋巴细胞性脉络丛脑膜炎病毒引起的中枢神经系统感染。症状轻者似感冒，少数典型者可出现脑膜炎症状。一般病情轻，病死率极低。尸体检查报告极少，故病理改变不详。
严重脑膜炎病例死亡后，尸检发现大脑皮质、延髓、桥脑和小脑皮质有广泛的血管周围单核细胞浸润。用免疫荧光法在脑膜和脑皮质的神经细胞中检出病毒抗原，说明病毒可以直接侵犯神经细胞。
本病是家鼠固有的病，人因食入病鼠尿、粪污染的食物或吸入污染的尘埃而受染。人类发病者不多，但在世界分布较广，欧洲、美洲和亚洲等地均有发病，中国也曾有过少数病例报告。此外，实验室工作者也可能受染。
淋巴细胞脉络丛脑膜炎病毒属沙粒病毒科。人类受染后,多表现为隐性感染，也可以发病。潜伏期为6～13日。有三种临床表现：类似流感或非神经系统感染、无菌性脑膜炎和脑膜脑脊髓炎。以前二者常见。类似流感型表现发热、倦怠、食欲减退、头痛、肌痛、流涕，有时咽痛、关节痛、咳嗽、畏光、呕吐和出现皮疹，伴有白细胞和血小板减少。病程持续4～7日，可痊愈。脑膜炎型开始时也有类似流感的症状，但是在病程中可再度发热,伴有头痛、呕吐和脑膜炎的体征,如颈强直和病理反射。脑脊液的改变是淋巴细胞增加，蛋白质含量增高，脑脊液中含有病毒。病程持续数周，可以痊愈。极少数严重病人发生昏迷和死亡。少数病人可以有后遗症，例如帕金森氏综合征等。本病毒感染还可以引起畸胎、流产和新生儿脑积水等。
在发热时,血中有病毒。在中枢神经系统感染时,脑脊液中存在病毒。检测急性期血清和脑脊液中的IgM抗体，可作为早期诊断的方法。中和抗体出现较晚，持续时间较长，滴度不高。
目前尚无特效疗法，可以采用对症治疗和支持疗法。灭鼠是预防本病的主要措施。
英文原文：http://www.physorg.com/news109333710.html
原始出处:
Published online before print September 18, 2007, 10.1073/pnas.0702579104
PNAS | September 25, 2007 | vol. 104 | no. 39 | 15430-15435
BIOLOGICAL SCIENCES / IMMUNOLOGY
Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection
Scott N. Mueller*, Mehrdad Matloubian, Daniel M. Clemens, Arlene H. Sharpe, Gordon J. Freeman¶,||, Shivaprakash Gangappa**, Christian P. Larsen**, and Rafi Ahmed*,
*Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322; Department of Medicine, Division of Rheumatology, University of California, San Francisco, CA 94143; Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, CA 90095; Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115; ¶Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; ||Department of Medicine, Harvard Medical School, Boston, MA 02115; and **Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322
Edited by James P. Allison, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved August 10, 2007 (received for review March 19, 2007)
Many chronic viral infections are marked by pathogen persistence and a generalized immunosuppression. The exact mechanisms by which this occurs are still unknown. Using a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate viral targeting of fibroblastic reticular cells (FRC) in the lymphoid organs. The FRC stromal networks are critical for proper lymphoid architecture and function. High numbers of FRC were infected by LCMV clone 13, which causes a chronic infection, whereas few were infected by the acute strain, LCMV Armstrong. The function of the FRC conduit network was altered after clone 13 infection by the action of CD8+ T cells. Importantly, expression of the inhibitory programmed death ligand 1, which was up-regulated on FRC after infection, reduced early CD8+ T cell-mediated immunopathology and prevented destruction of the FRC architecture in the spleen. Together, this reveals an important tropism during a persistent viral infection. These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection.
immunopathology | stromal cells | viral infection
