發(fā)明疫苗或治療傳染病面臨的最主要問題在于，慢性傳染病能逐漸阻止免疫T細(xì)胞的反應(yīng)能力?，F(xiàn)在,，由美國(guó)Emory大學(xué)領(lǐng)導(dǎo)的研究人員領(lǐng)導(dǎo)的一個(gè)研究組揭示出了慢性病毒感染疾病逃脫免疫反應(yīng)的重要方式,。這項(xiàng)研究的結(jié)果發(fā)表近期的PNAS(《美國(guó)國(guó)家科學(xué)院院刊》)的網(wǎng)絡(luò)版上,。
研究人員通過使用小鼠模型，發(fā)現(xiàn)一種慢性淋巴細(xì)胞脈絡(luò)叢腦膜炎病毒（LCMV）能夠攻擊一種淋巴器官中被稱為纖維原網(wǎng)狀細(xì)胞（FRC）的基質(zhì)細(xì)胞,。而急性病毒則對(duì)FRC沒有影響,。
FRC為免疫細(xì)胞提供移動(dòng)和與淋巴器官（脾臟、淋巴結(jié)）中其它免疫細(xì)胞作用的三維網(wǎng)絡(luò),。FRC對(duì)于免疫反應(yīng)的發(fā)動(dòng)很重要,。科學(xué)家發(fā)現(xiàn)FRC感染的傳播將導(dǎo)致這一重要基質(zhì)細(xì)胞功能的破壞,。去年Emory科學(xué)家Rafi Ahmed領(lǐng)導(dǎo)的小組發(fā)現(xiàn)在老鼠中,，另一種針對(duì)慢性感染的免疫反應(yīng)路徑被中斷——這是稱為PD-1的阻斷慢性LCMV反應(yīng)的路徑,。
研究組發(fā)現(xiàn)FRC感染或許和之前發(fā)現(xiàn)的PD-1路徑有關(guān),。PD-1的主要配合體PD-L1在FRC感染后增加了。PD-1路徑或許會(huì)阻止CD8+T細(xì)胞和FRC之間的相互作用,，防止脾臟中FRC結(jié)構(gòu)的破壞,。這能幫助病毒持續(xù)感染FRC，造成慢性長(zhǎng)期的病毒存在。
淋巴細(xì)胞脈絡(luò)叢腦膜炎（lymphocytic choriomeningitis,LCM）是由淋巴細(xì)胞性脈絡(luò)叢腦膜炎病毒引起的中樞神經(jīng)系統(tǒng)感染,。癥狀輕者似感冒,，少數(shù)典型者可出現(xiàn)腦膜炎癥狀。一般病情輕,，病死率極低,。尸體檢查報(bào)告極少，故病理改變不詳,。
嚴(yán)重腦膜炎病例死亡后,，尸檢發(fā)現(xiàn)大腦皮質(zhì)、延髓,、橋腦和小腦皮質(zhì)有廣泛的血管周圍單核細(xì)胞浸潤(rùn),。用免疫熒光法在腦膜和腦皮質(zhì)的神經(jīng)細(xì)胞中檢出病毒抗原，說明病毒可以直接侵犯神經(jīng)細(xì)胞,。
本病是家鼠固有的病,，人因食入病鼠尿、糞污染的食物或吸入污染的塵埃而受染,。人類發(fā)病者不多,，但在世界分布較廣，歐洲,、美洲和亞洲等地均有發(fā)病,，中國(guó)也曾有過少數(shù)病例報(bào)告。此外,，實(shí)驗(yàn)室工作者也可能受染,。
淋巴細(xì)胞脈絡(luò)叢腦膜炎病毒屬沙粒病毒科。人類受染后,多表現(xiàn)為隱性感染,，也可以發(fā)病,。潛伏期為6～13日。有三種臨床表現(xiàn)：類似流感或非神經(jīng)系統(tǒng)感染,、無菌性腦膜炎和腦膜腦脊髓炎,。以前二者常見。類似流感型表現(xiàn)發(fā)熱,、倦怠,、食欲減退、頭痛,、肌痛,、流涕，有時(shí)咽痛,、關(guān)節(jié)痛,、咳嗽、畏光、嘔吐和出現(xiàn)皮疹,，伴有白細(xì)胞和血小板減少,。病程持續(xù)4～7日，可痊愈,。腦膜炎型開始時(shí)也有類似流感的癥狀,，但是在病程中可再度發(fā)熱,伴有頭痛、嘔吐和腦膜炎的體征,如頸強(qiáng)直和病理反射,。腦脊液的改變是淋巴細(xì)胞增加,，蛋白質(zhì)含量增高，腦脊液中含有病毒,。病程持續(xù)數(shù)周,，可以痊愈。極少數(shù)嚴(yán)重病人發(fā)生昏迷和死亡,。少數(shù)病人可以有后遺癥,，例如帕金森氏綜合征等。本病毒感染還可以引起畸胎,、流產(chǎn)和新生兒腦積水等,。
在發(fā)熱時(shí),血中有病毒。在中樞神經(jīng)系統(tǒng)感染時(shí),腦脊液中存在病毒,。檢測(cè)急性期血清和腦脊液中的IgM抗體,，可作為早期診斷的方法。中和抗體出現(xiàn)較晚,，持續(xù)時(shí)間較長(zhǎng),，滴度不高。
目前尚無特效療法,，可以采用對(duì)癥治療和支持療法,。滅鼠是預(yù)防本病的主要措施。
英文原文：http://www.physorg.com/news109333710.html
原始出處:
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
