Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions.
Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions.
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FAS FAS配体相互作用有缺陷的小鼠中静脉瘤肿瘤的自发发展。
DOI：
10.1084/jem.187.11.1825
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发表时间：
1998-06-01
影响因子：
15.3
通讯作者：
Fredrickson, T N
中科院分区：
文献类型：
--
作者：
Davidson, W F;Giese, T;Fredrickson, T N
B细胞恶性肿瘤在老年人和遗传或获得性免疫缺陷（如艾滋病）或自身免疫性疾病患者中出现的频率增加。这些个体的淋巴瘤形成机制尚不清楚。在本报告中，我们研究了Fas （lpr）和Fasl （gld）位点突变的可能性，Fas （lpr）和Fasl （gld）位点可以阻止Fas介导的细胞凋亡，导致早期良性淋巴样增生和自身免疫，也使小鼠在以后的生活中易患恶性淋巴瘤。直到6个月大，lpr和gold小鼠的增生是由于多克隆T细胞亚群的主要积累和较少数量的多克隆B细胞和浆细胞。在这里，我们检查了6-15月龄的C3H-lpr、C3H-gld和BALB-gld小鼠克隆T细胞和B细胞群的出现，发现相当大比例的衰老小鼠只发展为B细胞恶性肿瘤，具有许多免疫缺陷相关B淋巴瘤的特征。到1岁时，约60%的balb - gold和30%的c3h - gold小鼠具有单克隆B细胞群，在scid受体中生长和转移，但在大多数情况下被免疫能力强的小鼠排斥。肿瘤在浆细胞、CD23−B细胞和免疫缺陷记忆T细胞大量富集的环境中发展，而B220+ DN T细胞则不同程度地减少。从5个肿瘤中建立了不依赖生长因子的细胞系。大多数肿瘤为CD23−和IgH同型转换，CD5+和暗Mac-1+占高比例。考虑到其体内的Ig分泌和形态，大多数肿瘤被归类为恶性浆细胞样淋巴瘤。gld肿瘤的延迟发展表明，除了Fas/Fasl突变外，遗传缺陷也是恶性转化所必需的。有趣的是，没有肿瘤显示出c-Myc基因组组织的变化，但许多肿瘤具有一个或多个体获得性的MuLV前病毒整合，这些整合在scid传代和细胞系中传播。因此，插入突变可能是金B细胞转化的一种机制。我们的体内传代和体外适应金淋巴瘤小组将成为未来识别衰老和自身免疫小鼠中与B细胞转化相关的遗传异常的有价值的工具。
B cell malignancies arise with increased frequency in aging individuals and in patients with genetic or acquired immunodeficiency (e.g., AIDS) or autoimmune diseases. The mechanisms of lymphomagenesis in these individuals are poorly understood. In this report we investigated the possibility that mutations at the Fas (lpr) and Fasl (gld) loci, which prevent Fas-mediated apoptosis and cause an early onset benign lymphoid hyperplasia and autoimmunity, also predispose mice to malignant lymphomas later in life. Up to 6 mo of age, hyperplasia in lpr and gld mice results from the predominant accumulation of polyclonal T cell subsets and smaller numbers of polyclonal B cells and plasma cells. Here, we examined C3H-lpr, C3H-gld, and BALB-gld mice 6–15 mo of age for the emergence of clonal T and B cell populations and found that a significant proportion of aging mice exclusively developed B cell malignancies with many of the hallmarks of immunodeficiency-associated B lymphomas. By 1 yr of age, ∼60% of BALB-gld and 30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice. The tumors developed in a milieu greatly enriched for plasma cells, CD23− B cells and immunodeficient memory T cells and variably depleted of B220+ DN T cells. Growth factor–independent cell lines were established from five of the tumors. The majority of the tumors were CD23− and IgH isotype switched and a high proportion was CD5+ and dull Mac-1+. Considering their Ig secretion and morphology in vivo, most tumors were classified as malignant plasmacytoid lymphomas. The delayed development of the gld tumors indicated that genetic defects in addition to the Fas/Fasl mutations were necessary for malignant transformation. Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one or more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines. Therefore, insertional mutagenesis may be a mechanism for transformation in gld B cells. Our panel of in vivo passaged and in vitro adapted gld lymphomas will be a valuable tool for the future identification of genetic abnormalities associated with B cell transformation in aging and autoimmune mice.