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PNAS:慢性病毒攻击淋巴器官基质细胞网的方式

来源:生物谷 2007-09-26 09:24

   生物谷报道: 治疗感染类疾病以及发明疫苗面临的最主要问题在于,慢性感染疾病能阻止免疫T细胞的反应能力。由Emory大学领导的研究小组最近发现了慢性病毒感染疾病逃脱免疫反应的重要方式。结果发表在最新的在线版《美国国家科学院院刊》(Proceedings  of  the  National  Academy  of  Science,PNAS)上。

    利用老鼠模型,科学家发现一种慢性淋巴脉络丛脑炎病毒(LCMV)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没有作用。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。 

   目前负责实验的是Ahmed实验室的博士后Scott  N.  Mueller。小组同时还包括来自Emory移植中心和医学院、California大学San  Francisco分校(UCSF)、Los  Angeles分校(UCLA)、哈佛医学院、Dana-Farber癌症中心的科学家。  小组发现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。( 教育部科技发展中心)

   原文链接: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

 Fig. 1. Reticular pattern of virus infection in the spleen after CL-13 infection. (A) Spleens from mice infected with LCMV Armstrong (Arm) or CL-13 3 days earlier were stained for LCMV antigen, counterstained with Mayer's hematoxylin, and examined via microscopy. (B) Spleens and LN (Right) stained for ER-TR7 (green) and LCMV (red) on days 1–30 after infection. White regions indicate colocalization. [Magnification: x20 (spleen) and x10 (LN). Scale bars: 100 µm (spleen) and 400 µm (LN).]

全文链接:http://www.pnas.org/cgi/content/full/104/39/15430?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=PD-1&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&fdate=//&resourcetype=HWCIT

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