Binding of LBP-1a to specific immunoglobulin switch regions in vivo correlates with specific repression of class switch recombination.
Binding of LBP-1a to specific immunoglobulin switch regions in vivo correlates with specific repression of class switch recombination.
复制标题
LBP-1a 与体内特定免疫球蛋白转换区域的结合与类别转换重组的特异性抑制相关。
DOI：
10.1002/eji.200838226
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发表时间：
2009
影响因子：
5.4
通讯作者：
Hansen,Ulla
中科院分区：
文献类型：
--
作者：
Repetny,KarenJ;Zhong,Xuemei;Holodick,NicholE;Rothstein,ThomasL;Hansen,Ulla
在刺激成熟B细胞后，类别转换重组（CSR）可改变表达的特异性免疫球蛋白重链恒定区。在组织培养细胞系中，我们先前证明了晚期SV 40因子（LSF）家族成员的抑制增强IgM至伊加CSR。在此，在原代小鼠脾B细胞中解决了LSF家族成员对CSR调节的同种型特异性。首先，我们证明了前导结合蛋白-1a（LBP-1a）是B淋巴细胞中普遍存在的家族成员。其次，我们通过ChIP证明LBP-1a以同种型特异性方式结合小鼠开关（S）区域周围的基因组序列，与计算预测一致：观察到与Sμ和Sα结合，但未观察到与测试的Sγ1区域结合。重要的是，LBP-1a的结合受到严格调控，在LPS刺激后，基因组S区域的占用率急剧下降。最后，使用骨髓嵌合小鼠确定LBP-1a与DNA结合的结果，其中LSF/LBP-1活性在造血谱系中受到抑制。这种原代B细胞的尿钙蛋白体外刺激，CSR以更高的效率对伊加发生，但对IgG 1不发生。这些结果支持LBP-1a通过与重组中涉及的S区直接相互作用以同种型特异性方式抑制CSR的模型。
Upon stimulation of mature B cells, class switch recombination (CSR) can alter the specific immunoglobulin heavy chain constant region that is expressed. In a tissue culture cell line, we previously demonstrated that inhibition of late SV40 factor (LSF) family members enhanced IgM to IgA CSR. Here, isotype specificity of CSR regulation by LSF family members is addressed in primary mouse splenic B cells. First, we demonstrate that leader‐binding protein‐1a (LBP‐1a) is the prevalent family member in B lymphocytes. Second, we demonstrate by ChIP that LBP‐1a binds genomic sequences around mouse switch (S) regions in an isotype‐specific manner, in accordance with computational predictions: binding is observed to Sμ and Sα, but not to the tested Sγ1, regions. Importantly, binding of LBP‐1a is tightly regulated, with occupancy at genomic S regions dramatically decreasing following LPS stimulation. Finally, the consequence of DNA‐binding by LBP‐1a is determined using bone marrow chimeric mice in which LSF/LBP‐1 activity is inhibited in hematopoietic lineages. Uponin vitrostimulation of such primary B cells, CSR occurs with a higher efficiency to IgA, but not to IgG1. These results are supportive of a model whereby LBP‐1a represses CSR in an isotype‐specific mannerviadirect interaction with S regions involved in the recombination.