Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer
Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer
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DOI：
10.1182/blood-2008-07-165456
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发表时间：
2009-05-07
期刊：
影响因子：
20.3
通讯作者：
Reed, John C.
中科院分区：
文献类型：
--
作者：
Zapata, Juan M.;Llobet, David;Reed, John C.
肿瘤坏死因子（TNF）受体相关因子3（TRAF 3）通过调节Toll样受体（TLR）和TNF受体的信号传导来调节先天性和获得性免疫。TRAF 3最近被鉴定为人类多发性骨髓瘤中的肿瘤抑制因子，表明在浆细胞稳态中起重要作用。我们已经产生了在淋巴细胞中表达人TRAF 3的转基因小鼠。这些小鼠在出生时是正常的，但随着时间的推移，它们会出现浆细胞增多症和高丙种球蛋白血症，以及全身炎症和三级淋巴器官形成。TRAF 3小鼠的体液应答分析表明，与野生型小鼠相比，对T依赖性和T非依赖性抗原的应答增加，抗原特异性免疫球蛋白G（IgG）的产生增加。此外，TLR介导的IgG产生在TRAF 3 B细胞中也增加。此外，TRAF 3小鼠产生自身免疫性并易患癌症，特别是舌鳞状细胞癌（发病率约为50%）和唾液腺肿瘤。总之，TRAF 3使B细胞对抗原和TLR激动剂反应过度，促进自身免疫、炎症和癌症，从而为研究由B细胞引发的慢性炎症促进的从头致癌提供了新的模型。（血。2009;113：4595-4603）
Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) regulates both innate and adaptive immunity by modulating signaling by Toll-like receptors (TLR) and TNF receptors. TRAF3 was recently identified as a tumor suppressor in human multiple myeloma, suggesting a prominent role in plasma cell homeostasis. We have generated transgenic mice expressing human TRAF3 in lymphocytes. These mice are normal at birth, but they develop over time plasmacytosis and hypergammaglobulinemia, as well as systemic inflammation and tertiary lymphoid organ formation. The analysis of the humoral responses of the TRAF3 mice demonstrated increased responses to T-dependent and T-independent antigens with increased production of antigen-specific immunoglobulin Gs (IgGs) compared with wild-type mice. Furthermore, TLR-mediated IgG production is also increased in TRAF3 B cells. In addition, TRAF3 mice develop autoimmunity and are predisposed to cancer, particularly squamous cell carcinomas of the tongue (approximate to 50% incidence) and salivary gland tumors. In summary, TRAF3 renders B cells hyperreactive to antigens and TLR agonists, promoting autoimmunity, inflammation, and cancer, hereby providing a new model for studying de novo carcinogenesis promoted by B cell-initiated chronic inflammation. (Blood. 2009;113:4595-4603)