Zapata Juan M, Llobet David, Krajewska Maryla, Lefebvre Sophie, Kress Christina L, Reed John C
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Blood. 2009 May 7;113(19):4595-603. doi: 10.1182/blood-2008-07-165456. Epub 2008 Dec 12.
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 ( approximately 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.
肿瘤坏死因子（TNF）受体相关因子3（TRAF3）通过调节Toll样受体（TLR）和TNF受体的信号传导来调控先天性免疫和适应性免疫。TRAF3最近被鉴定为人类多发性骨髓瘤中的一种肿瘤抑制因子，这表明它在浆细胞稳态中起着重要作用。我们已经培育出在淋巴细胞中表达人类TRAF3的转基因小鼠。这些小鼠出生时正常，但随着时间的推移会出现浆细胞增多症、高球蛋白血症，以及全身炎症和三级淋巴器官形成。对TRAF3小鼠体液反应的分析表明，与野生型小鼠相比，它们对T细胞依赖性和T细胞非依赖性抗原的反应增强，抗原特异性免疫球蛋白G（IgG）的产生增加。此外，TRAF3 B细胞中TLR介导的IgG产生也增加。另外，TRAF3小鼠会发生自身免疫并易患癌症，尤其是舌鳞状细胞癌（发病率约为50%）和唾液腺肿瘤。总之，TRAF3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原发性致癌作用提供了一个新模型。
