Fas／FasL（配体）与免疫相关性疾病

Ｆａｓ抗原与Ｆａｓ抗原配体（ＦａｓＬ）交联后,能传导细胞凋亡信号,引起Ｆａｓ抗原表达细胞的凋亡。目前已发现,多种组织细胞能分别表达Ｆａｓ和ＦａｓＬ,有些甚至能同时表达Ｆａｓ与ＦａｓＬ在调节免疫功能、维持机体内环境的平衡方面起着重要的作用,其异常表达常与多种免疫性疾病的发生和发展有关。本文主要就近年来有关Ｆａｓ／ＦａｓＬ与免疫相关性疾病的关系作一综述。     

Fas/FasL系统与慢性心力衰竭

Fas和FasL是细胞表面蛋白,与机体的分化发育、免疫调控密切相关。Fas/FasL系统在慢性心力衰竭的发生发展过程中参与免疫炎性反应、诱导心肌细胞凋亡、促进心肌细胞肥大增生、加剧心肌缺血再灌注损伤等过程。     

Fas／FasL与免疫性疾病

Ｆａｓ配体是一种细胞表面分子。它属于肿瘤坏死因子家族成员，并能与其受体Ｆａｓ抗原结合，从而诱导Ｆａｓ阳性的细胞凋亡，多种细胞表达Ｆａｓ，而Ｆａｓ主要由活化的Ｔ细胞表达。     

Fas/FasL(配体)与免疫相关性疾病

Ｆａｓ抗原与Ｆａｓ抗原配体（ＦａｓＬ）交联后,能传导细胞凋亡信号,引起Ｆａｓ抗原表达细胞的凋亡。目前已发现,多种组织细胞能分别表达Ｆａｓ和ＦａｓＬ,有些甚至能同时表达Ｆａｓ和ＦａｓＬ。Ｆａｓ与ＦａｓＬ在调节免疫功能、维持机体内环境的平衡方面起着重要的作用,其异常表达常与多种免疫性疾病的发生和发展有关。本文主要就近年来有关Ｆａｓ／ＦａｓＬ与免疫相关性疾病的关系作一综述。     

白血病中Fas／FasL系统诱导的细胞凋亡作用

Fas／FasL系统是研究最深入的介导细胞凋亡的途径，当Fas与FasL结合时，可直接引起Fas^ 细胞的凋亡。但是在白血病的发病过程中，尽管高表达Fas，似乎仍存在着血细胞的凋亡不足。许多研究表明，白血病细胞对Fas／FasL途径介导的凋亡不敏感或存在抵抗也是导致白血病耐药的原因之一，白血病的Fas抗性与多种因素有关，对它们的研究可为白血病的治疗提供新的方法。     

Fas／FasL与免疫性疾病

Ｆａｓ配体（ＦａｓＬ）是一种细胞表面分子，它属于肿瘤坏死因子家族成员，并能与其受体Ｆａｓ抗原（Ｆａｓ）结合，从而诱导Ｆａｓ阳性的细胞凋亡。多种细胞表达Ｆａｓ，而ＦａｓＬ主要由活化的Ｔ细胞表达。在免疫系统，Ｆａｓ／ＦａｓＬ不仅参与Ｔ细胞介导的细胞毒作用，而且具有下调免疫反应的作用。Ｆａｓ／ＦａｓＬ功能异常能导致淋巴细胞增生性疾病和促进自身免疫性疾病，而其功能过强可能导致组织损害。     

Fas/FasL系统与肿瘤的免疫逃逸

最近的研究揭示肿瘤细胞通过表达FasL反击免疫系统 ,消除体内抗肿瘤T细胞 ,并且抵抗Fas/FasL系统介导的凋亡 ,从而使肿瘤成为机体的免疫豁免部位而逃逸免疫系统的攻击。Fas反击作为肿瘤免疫逃逸新机制的阐明为临床工作及肿瘤的免疫治疗提供了新策略     

Fas／FasL与免疫逃逸

Ｆａｓ／ＦａｓＬ相互作用引发细胞凋亡。近几年研究显示,与凋亡相关的Ｆａｓ／ＦａｓＬ系统在肿瘤免疫逃逸中有重要作用,许多肿瘤组织内均有高水平的ＦａｓＬ的表达,而表达Ｆａｓ的淋巴细胞浸润肿瘤组织后不仅未能杀伤肿瘤细胞,反被诱导凋亡。ＦａｓＬ在诱导Ｆａｓ免疫细胞凋亡,保护机体免疫赦免部位及异源移植物免于排斥方面起着积极作用。     

白血病中Fas/FasL系统诱导的细胞凋亡作用

Fas FasL系统是研究最深入的介导细胞凋亡的途径 ,当Fas与FasL结合时 ,可直接引起Fas+ 细胞的凋亡。但是在白血病的发病过程中 ,尽管高表达Fas,似乎仍存在着血细胞的凋亡不足。许多研究表明 ,白血病细胞对Fas FasL途径介导的凋亡不敏感或存在抵抗也是导致白血病耐药的原因之一 ,白血病的Fas抗性与多种因素有关 ,对它们的研究可为白血病的治疗提供新的方法     

027 Fas/FasL系统与肿瘤的免疫逃逸

最近的研究揭示肿瘤细胞通过表达FasL反击免疫系统,消除体内抗肿瘤T细胞,并且抵抗Fas/FasL系统介导的凋亡,从而使肿瘤成为机体的免疫豁免部位而逃逸免疫系统的攻击.Fas反击作为肿瘤免疫逃逸新机制的阐明为临床工作及肿瘤的免疫治疗提供了新策略.     

The role of Fas/FasL system in induction of hepatocyte apoptosis in chronic viral hepatitides

The aim of the study was assessment of hepatocyte apoptosis depending on expression of Fas and FasL proteins by various liver cells in patients with chronic viral hepatitis B (CVHB) or chronic viral hepatitis C (CVHC). The symptoms of hepatocyte apoptosis were observed in 3 of 12 patients with CVHB and in 9 of 14 patients with CVHC, the proportion of apoptotic cells being 12-65%. Hepatocytes of healthy people and patients with hepatitis B or C express Fas protein in the cytoplasm diffusely, as granules or on cell membrane. In health, hepatocytes do not express FasL, but in CVH they do. The highest apoptosis was observed in Fas protein location as granules in cytoplasm or in their preferable location on the cell membrane. The severity of hepatocyte apoptosis in CVH directly correlated with FasL expression by the cells of the lymphoid-histiocytic infiltrate in the liver and inversely correlated with FasL expression by hepatocytes. Thus, a great part of hepatocytes in CVH are killed by the virus; Fas/FasL interaction is leading in damage to hepatocytes in CVH.     

Fas/FasL信号在免疫系统中的作用

Fas/FasL通路是介导细胞凋亡的一条重要途径.近年来研究发现,它可以促进分泌炎症细胞因子,激发炎性反应,参与免疫豁免、免疫逃逸、肿瘤形成及转移等过程.此外,FasL还可以作为受体传递反向信号,促进细胞增殖,并参与一些自身免疫性疾病的发生.     

Relationship of acute lung inflammatory injury to Fas/FasL system

There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters ((125)I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.     

Fas/FasL系统参与的几种生物学效应

Fas／FasL通路是介导细胞凋亡的一条重要途径。近年来的研究表明,它参与了胸腺选择、免疫赦免以及协调了免疫反应的平衡,同时它亦与一些肿瘤的发生发展、移植排斥、自身免疫性疾病的产生以及诸多的生理病理反应密切相关。     

Immature B cells in bone marrow express Fas/FasL

Negative selection is a process by which autoreactive lymphocytes are eliminated from the developing antigen receptor repertoire. The mechanisms regulating negative selection of immature B lymphocytes in the bone marrow are poorly elucidated. Human bone marrow cells were examined in order to investigate the presence of the members of the Fas (APO-1/CD95) system. Here we demonstrate the expression of Fas in immature B lymphocytes (CD10/CD19+/CD40+/sIg+), and the presence of Fas natural ligand (FasL) in CD19+ bone marrow cells. The observed expression of apoptosis-related molecules might indicate how negative selection of autoreactive B cells can occur in human bone marrow.     

支气管哮喘大鼠淋巴液中淋巴细胞线粒体跨膜电位以及Fas/FasL变化

目的探讨哮喘大鼠淋巴液中淋巴细胞跨膜电位（mitochondrial membrane potential,△.ψm）和淋巴细胞表面Fas、FasL表达水平,并与其血液、支气管肺泡灌洗液（bronchoalveolar lavage fluid,BALF）水平比较。方法流式细胞仪、免疫组化方法检测对照组和哮喘组激发后2、6、12、24、48h各时间点淋巴液、血液、BALF中淋巴细胞线粒体的跨膜电位、淋巴细胞表面Fas、FasL蛋白表达。结果哮喘组淋巴液、血液和BALF中淋巴细胞△.ψm峰值在各时间点均较对照组明显升高（P〈0.01）,Fas、FasL蛋白表达水平低于对照组水平（P〈0.01）;哮喘组淋巴液中淋巴细胞△.ψm在不同时间点均较血液水平明显升高（P〈0.05）,血液中淋巴细胞△.ψm与BALF水平间无显著性差异（P〉0.05）。结论哮喘大鼠淋巴液、血液、BALF中均存在明显的淋巴细胞早期凋亡障碍和Fas/FasL表达降低,尤其是哮喘淋巴液中淋巴细胞凋亡障碍和Fas/FasL降低程度较其血液、BALF更为明显。     

Involvement of Fas/FasL system in the pathogenesis of autoimmune diseases and Wilson's disease.

The interaction of Fas with FasL has been demonstrated to be implicated in the pathogenesis of several autoimmune and liver diseases. Recently, attention has been focused on the hypothesis that thyrocytes and beta cells undergo massive Fas/FasL-mediated apoptosis during autoimmune response. Similarly, hepatocyte cell death occurring following copper accumulation points towards the same mechanism.     

Fas/FasL mediated apoptosis of thyrocytes in Graves' disease.

We examined in the present study the possible involvement of Fas and its ligand (FasL) in the process of Graves' disease. Immunohistochemical analysis showed that few normal thyrocytes expressed Fas but many thyrocytes in Graves' disease expressed this molecule. The percentage of FasL-positive thyrocytes in Graves' thyroids was, however, less than in normal thyroids. Several apoptotic thyrocytes and infiltrating mononuclear cells (MNCs) were detected scattered throughout Graves' thyroid tissues and abundant proliferating cell nuclear antigen (PCNA)-positive thyrocytes were present. Apoptotic cells, as well as PCNA-positive cells, were scarcely detectable in normal thyroid glands, however. In vitro treatment of thyrocytes by IL-1beta a cytokine found to be expressed in Graves' thyroid glands, increased Fas but reduced FasL expression. IL-1beta-stimulated thyrocytes became sensitive to apoptosis by anti-Fas IgM monoclonal antibody (mAb). Activated T cells, which strongly expressed FasL, showed cytotoxic activity toward IL-1beta-stimulated thyrocytes but not toward unstimulated thyrocytes. This cytotoxic activity involved the Fas/FasL pathway. Importantly, unstimulated thyrocytes could kill activated, but not resting, T cells. IL-1beta-stimulated thyrocytes, with down-regulated FasL expression, could not efficiently kill activated T cells. The cytotoxic activity of unstimulated thyrocytes toward activated T cells was inhibited by anti-FasL mAb. Interestingly, unstimulated thyrocytes induced apoptosis in IL-1beta-stimulated thyrocytes but not in unstimulated thyrocytes. These interactions were also blocked by anti-FasL mAb. Our results suggest that the apoptotic cell death of both thyrocytes and infiltrating MNCs found in Graves' thyroid glands is regulated by IL-1beta through Fas/FasL interactions.     

C-reactive protein in acute viral infections

A sensitive solid-phase enzyme immunoassay procedure was used to determine the concentrations of C-reactive protein (CPR) in the acute and convalescent phase sera of patients with verified rubella, herpes simplex, cytomegalo, influenza A or B, enterovirus, or mycoplasma infection. In all infection groups about 90% (80% for influenza) elevated CRP values were observed in the acute phase sera (mean values in the different groups 16-57 micrograms/ml), the highest values exceeding or approaching 100 micrograms/ml. The serum CRP values were highest in all groups before the specific serum antibodies were detectable and decreased approaching the upper limit or normal controls (2 microgram/ml) within 2 weeks. Notable individual variation in the CRP production was seen. We conclude tha serum CRP determination should not be used as a reliable criterion to distinguish bacterial and viral infections.