Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus
Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus
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DOI：
10.1002/eji.200425267
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发表时间：
2004-10-01
影响因子：
5.4
通讯作者：
Hirose, S
中科院分区：
文献类型：
--
作者：
Wen, XS;Zhang, DQ;Hirose, S
IL-5 优先激活 B1 细胞产生与自身抗原发生交叉反应的天然抗体。为了确定 IL-5 在抗体介导的自身免疫性疾病中的作用，我们生成了 IL-5 转基因同源的系统性红斑狼疮 (SLE) 倾向 (NZBxNZW)F1 小鼠 (TG-F1)。转基因出人意料地降低了狼疮性肾炎的发病率。 TG-F1 小鼠血清中的抗 DNA 抗体和体外脾 B 细胞产生的抗 DNA 抗体显着降低，而总多克隆 Ig 水平与 IL-5 转基因阴性 (NZBxNZW)F1（非 TG-F1）同窝小鼠的水平相当。流式细胞仪分选的脾 B1 细胞显示，针对 IL-5 的抗 DNA 抗体合成显着减少，而 TG-F1 和非 TG-F1 小鼠之间对 IL-5 的增殖反应没有显着差异。随着TG-F1小鼠年龄的增长，外周B1细胞的频率逐渐增加，并且小鼠经常患上B细胞慢性淋巴细胞白血病（B-CLL）。我们的研究结果表明，SLE易感小鼠中IL-5的失调、持续高表达可能直接或间接介导自身抗原激活的B1细胞增殖/分化的倾斜信号传导，导致自身免疫性疾病的抑制，但反而导致B1细胞的异常扩增，导致B-CLL。因此，该模型可能为 SLE 和 B-CLL 的发病机制提供线索。
IL-5 preferentially activates B1 cells to produce natural antibodies cross-reactive to self antigens. To determine the role of IL-5 in antibody-mediated autoimmune disease, we generated systemic lupus erythematosus (SLE)-prone (NZBxNZW)F1 mice congenic for IL-5 transgene (TG-F1). The transgene unexpectedly reduced the incidence of lupus nephritis. Anti-DNA antibodies in sera and those produced by splenic B cells in vitro were markedly decreased in TG-F1 mice, while total polyclonal Ig levels were comparable to those in IL-5 transgene-negative (NZBxNZW)F1 (non-TG-F1) littermates. Flow cytometry-sorted splenic B1 cells showed a significant reduction of anti-DNA antibody synthesis in response to IL-5, while proliferative responses to IL-5 did not significantly differ between TG-F1 and non-TG-F1 mice. As TG-F1 mice aged, frequencies of peripheral B1 cells progressively increased, and the mice frequently developed B cell chronic lymphocytic leukemia (B-CLL). Our results suggest that dysregulated, continuous high expression of IL-5 in SLE-prone mice may directly or indirectly mediate a skewed signaling of proliferation/differentiation of self-antigen-activated B1 cells, leading to suppression of autoimmune disease, but instead to aberrant expansion of B1 cells, giving rise to B-CLL. Thus, this model may provide a clue to the pathogenesis of both SLE and B-CLL.