MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells
MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells
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DOI：
10.1084/jem.189.11.1799
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发表时间：
1999-06-07
影响因子：
15.3
通讯作者：
Erikson, J
中科院分区：
文献类型：
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作者：
Mandik-Nayak, L;Seo, SJ;Erikson, J
系统性红斑狼疮和MRL小鼠狼疮模型的一个特征是存在抗双链(DS)DNA抗体(Abs)。为了确定在自身免疫小鼠中产生这些抗体的步骤，我们比较了自身免疫(MRL+/+和LPR/LPR)小鼠和非自身免疫(BALB/c)小鼠抗dsDNA B细胞的表型和定位。在BALB/c小鼠体内，抗dsDNA B细胞的发育停滞和在脾毛囊T-B交界处的聚集表明，抗dsDNA B细胞受到活跃的调节。在MRL遗传背景下，抗dsDNA B细胞不再发育停滞，提示MRL背景基因导致了固有的B细胞缺陷。有了完整的Fas，它们继续表现出卵泡排斥；然而，在LPR/LPR突变的存在下，抗dsDNA B细胞现在存在于卵泡中。与抗dsDNA B细胞定位改变一致的是滤泡内的CD4T细胞。总之，这些数据表明，MRL小鼠在维持自身反应性B细胞的发育停滞方面存在缺陷，并表明Fas在限制进入卵泡方面发挥了作用。
A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is the presence of anti-double-stranded (ds)DNA antibodies (Abs). To identify the steps leading to the production of these Abs in autoimmune mice, we have compared the phenotype and localization of anti-dsDNA B cells in autoimmune (MRL+/+ and lpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNA B cells are actively regulated in BALB/c mice as indicated by their developmental arrest and accumulation at the T-B interface of the splenic follicle. In the MRL genetic background, anti-dsDNA B cells are no longer developmentally arrested, suggesting an intrinsic B cell defect conferred by MRL background genes. With intact Fas, they continue to exhibit follicular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident with the altered localization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells. Together, these data suggest that MRL mice are defective in maintaining the developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.