TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma
TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma
复制标题
DOI：
10.4049/jimmunol.172.2.812
复制
发表时间：
2004-01-15
影响因子：
4.4
通讯作者：
Mackay, F
中科院分区：
文献类型：
--
作者：
Batten, M;Fletcher, C;Mackay, F
肿瘤坏死因子被认为是炎症反应的中介物。肿瘤坏死因子还促进次级淋巴器官的组织，特别是B细胞滤泡和生发中心，这是T依赖抗体反应的标志。肿瘤坏死因子还调节对肿瘤的防御。我们通过建立缺乏肿瘤坏死因子的转基因(TG)小鼠，研究了肿瘤坏死因子在肿瘤坏死因子家族过量B细胞激活因子(BAFF)诱导的类似系统性红斑狼疮和干燥综合征的炎症性自身免疫性疾病的发生发展中的作用。在缺乏B细胞滤泡、滤泡树突状细胞和生发中心的情况下，TNF-/-BAFF-TG小鼠与TNF-/-小鼠相似，并且对T依赖的AGS的反应减弱。然而，TNF-/-BAFF-TG小鼠出现了与BAFF-TG小鼠相似的自身免疫性疾病。TNF-/-BAFF-TG小鼠的疾病与过渡型2型和边缘区B细胞群的扩张和T非依赖性免疫反应增强有关。BAFF-TG小鼠的肿瘤坏死因子缺乏也导致了令人惊讶的高B细胞淋巴瘤发生率(>；35%)，这很可能是由于BAFF促进肿瘤B细胞存活，以及缺乏肿瘤坏死因子的保护性抗肿瘤防御的综合作用。因此，对于BAFF介导的自身免疫性疾病，肿瘤坏死因子似乎是必不可少的，事实上，可以对抗高水平的BAFF在干燥综合征、系统性红斑狼疮和类风湿性关节炎等疾病中的任何原癌效应。免疫学杂志，2004,172：812-822。
TNF is well characterized as a mediator of inflammatory responses. TNF also facilitates organization of secondary lymphoid organs, particularly B cell follicles and germinal centers, a hallmark of T-dependent Ab responses. TNF also mediates defense against tumors. We examined the role of TNF in the development of inflammatory autoimmune disorders resembling systemic lupus erythematosus and Sjogren's syndrome induced by excess B cell-activating factor belonging to the TNF family (BAFF), by generating BAFF-transgenic (Tg) mice lacking TNF. TNF-/- BAFF-Tg mice resembled TNF-/- mice, in that they lacked B cell follicles, follicular dendritic cells, and germinal centers, and have impaired responses to T-dependent Ags. Nevertheless, TNF-/- BAFF-Tg mice developed autoimmune disorders similar to that of BAFF-Tg mice. Disease in TNF-/- BAFF-Tg mice correlates with the expansion of transitional type 2 and marginal zone B cell populations and enhanced T-independent immune responses. TNF deficiency in BAFF-Tg mice also led to a surprisingly high incidence of B cell lymphomas ( > 35%), which most likely resulted from the combined effects of BAFF promotion of neoplastic B cell survival, coupled with lack of protective antitumor defense by TNF. Thus, TNF appears to be dispensable for BAFF-mediated autoimmune disorders and may, in fact, counter any proneoplastic effects of high levels of BAFF in diseases such as Sjogren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. The Journal of Immunology, 2004, 172: 812-822.