B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice
B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice
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DOI：
10.1371/journal.pone.0011691
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发表时间：
2010-07-21
期刊：
影响因子：
3.7
通讯作者：
Wither, Joan
中科院分区：
文献类型：
--
作者：
Chang, Nan-Hua;Cheung, Yui-Ho;Wither, Joan
新西兰黑 (NZB) 小鼠中自身抗体的存在表明 B 细胞耐受缺陷，但这种缺陷的性质尚不清楚。为了确定 B 细胞无反应性缺陷是否会导致 NZB 小鼠的自身免疫表型，将可溶性鸡蛋溶菌酶 (sHEL) 和抗 HEL Ig 转基因培育到 NZB 背景上，以产生双转基因 (dTg) 小鼠。尽管体外 B 细胞功能无反应性明显正常，但 NZB dTg 小鼠的抗 HEL 抗体水平升高。 NZB dTg B 细胞在转移至 sHEL 小鼠后也表现出存活率增加和异常进入毛囊室的情况。由于该过程依赖于 BAFF，因此对 NZB dTg 小鼠中的 BAFF 血清和 mRNA 水平进行了评估，发现其水平显着升高。用 TACI-Ig 治疗 NZB sHEL 受体小鼠可降低过继转移后 NZB dTg B 细胞的存活率，证实了 BAFF 在此过程中的作用。尽管 NZB 小鼠的 BAFF 略有升高，但 NZB B 细胞存活反应的增强似乎是由于对 BAFF 的反应改变所致。相比之下，T 细胞阻断对 B 细胞存活的影响很小，但抑制了抗 HEL 抗体的产生。研究结果表明，NZB 小鼠中 BAFF 的适度升高足以扰乱 B 细胞耐受性，特别是在与 B 细胞功能异常和 T 细胞帮助协同作用时。
The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.