Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells
Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells
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DOI：
10.1073/pnas.040577497
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发表时间：
2000-03-14
影响因子：
11.1
通讯作者：
Diamond, B
中科院分区：
文献类型：
--
作者：
Bynoe, MS;Grimaldi, CM;Diamond, B
性激素被认为在免疫系统的性别二态性中起作用。特别是雌激素，被认为使女性易患系统性红斑狼疮。我们在此报道，雌二醇（E - 2）可打破B细胞耐受性，并在转染了致病性抗DNA抗体重链的非自身免疫小鼠中诱导狼疮样表型。E - 2处理导致抗DNA血清滴度升高以及免疫球蛋白在肾小球沉积，酶联免疫斑点分析证实，E - 2处理小鼠脾脏中分泌高亲和力抗DNA抗体的细胞数量显著增加。从E - 2处理小鼠产生的杂交瘤表达高亲和力、未突变的抗DNA抗体，这表明通常被清除或失能的初始B细胞从耐受诱导中被挽救。最后，免疫组织化学研究显示，E - 2处理小鼠脾脏B细胞中Bcl - 2表达增加。这些数据表明，雌激素干扰初始自身反应性B细胞的耐受诱导，并且这些外周B细胞的存在与Bcl - 2的上调有关。
Sex hormones are presumed to contribute to sexual dimorphism in the immune system. Estrogen, in particular, has been suggested to predispose women to systemic lupus erythematosus. We report here that estradiol (E-2) can break B cell tolerance and induce a lupus-like phenotype in nonautoimmune mice transgenic for the heavy chain of a pathogenic anti-DNA antibody. E-2 treatment resulted in a rise in anti-DNA serum titers and in Ig deposition in renal glomeruli, ELISPOT analysis confirmed a significant increase in the number of high-affinity anti-DNA antibody-secreting a cells in the spleens of E-2-treated mice. Hybridomas generated from E2-treated mice express high-affinity, unmutated anti-DNA antibodies, indicating that naive B cells that are normally deleted or anergized are rescued from tolerance induction. Finally, immunohistochemical studies revealed increased Bcl-2 expression in splenic B cells of E-2-treated mice. These data demonstrate that estrogen interferes with tolerance induction of naive autoreactive B cells and that the presence of these B cells in the periphery is associated with up-regulation of Bcl-2.