Immunological and pathological consequences of mutations in both Fas and Fas ligand.
Immunological and pathological consequences of mutations in both Fas and Fas ligand.
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DOI：
10.1006/cimm.1998.1290
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发表时间：
1998-05
影响因子：
4.3
通讯作者：
J. Weintraub;V. Godfrey;P. A. Wolthusen;R. Cheek;R. Eisenberg;P. Cohen
中科院分区：
文献类型：
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作者：
J. Weintraub;V. Godfrey;P. A. Wolthusen;R. Cheek;R. Eisenberg;P. Cohen
小鼠的lpr突变导致编码凋亡信号受体Fas基因的转录过早终止。结果，lpr小鼠出现严重的淋巴增生和狼疮样自身抗体。越来越多的证据表明，lpr突变是“漏的”，低水平的Fas在lpr小鼠中表达。为了确定在lpr小鼠中表达的Fas是否有助于细胞凋亡，我们产生了一种新的小鼠菌株（B6/lprgld），该菌株对lpr突变和编码无功能Fas配体（FasL）蛋白的gld突变都是纯合的。如果B6/lpr小鼠中低水平的Fas有助于细胞凋亡并减轻疾病的严重程度，那么同样缺乏功能性FasL的B6/lprgld小鼠将比B6/lpr小鼠发展出更严重的疾病形式。我们的研究结果显示，与B6/lpr或B6/gld小鼠相比，B6/lprgld小鼠的淋巴细胞增殖或自身免疫没有显著增加。流式细胞术检测B6/lprgld淋巴细胞与B6/lpr淋巴细胞相比，Fas表面表达未见增加。然而，与B6/lpr和B6/gld小鼠相比，B6/lprgld小鼠肝脏的组织学检查显示淋巴细胞浸润明显增加。我们的研究结果表明，虽然lpr小鼠体内低水平的Fas可能不会改善淋巴细胞增殖或自身免疫，但它们可能在一定程度上保护肝脏免受Fas介导的细胞凋亡导致的异常。
The lpr mutation in mice results in premature termination of transcription of the gene encoding the apoptosis-signaling receptor Fas. As a result, lpr mice develop severe lymphoproliferation and lupus-like autoantibodies. Growing evidence suggests that the lpr mutation is "leaky" and that low levels of Fas are expressed in lpr mice. To determine if Fas expressed in lpr mice is contributing to apoptosis we generated a novel strain of mice (B6/lprgld) which is homozygous for both the lpr mutation and the gld mutation which encodes nonfunctional Fas ligand (FasL) protein. If low levels of Fas in B6/lpr mice contribute to apoptosis and lessen the severity of disease, the B6/lprgld mice, which also lack functional FasL, would be expected to develop a more severe form of disease than B6/lpr mice. Our results revealed no significant increase in either lymphoproliferation or autoimmunity in B6/lprgld mice compared to B6/lpr or B6/gld mice. Additionally, no increase in surface expression of Fas was detected by flow cytometry on B6/lprgld lymphocytes compared to B6/lpr lymphocytes. However, histological examination of B6/lprgld liver revealed a marked increase in lymphocytic infiltration, compared to livers of B6/lpr and B6/gld mice. Our results suggest that, while low levels of Fas in lpr mice may not be contributing to amelioration of lymphoproliferation or autoimmunity, they may be partially protecting the liver from abnormalities which arise in the absence of Fas-mediated apoptosis.