Hein K, Lorenz M G, Siebenkotten G, Petry K, Christine R, Radbruch A
Deutsches Rheuma-Forschungszentrum Berlin, 10115 Berlin, Germany.
J Exp Med. 1998 Dec 21;188(12):2369-74. doi: 10.1084/jem.188.12.2369.
Antibody class switching is mediated by somatic recombination between switch regions of the immunoglobulin heavy chain gene locus. Targeting of recombination to particular switch regions is strictly regulated by cytokines through the induction of switch transcripts starting 5' of the repetitive switch regions. However, switch transcription as such is not sufficient to target switch recombination. This has been shown in mutant mice, in which the I-exon and its promoter upstream of the switch region were replaced with heterologous promoters. Here we show that, in the murine germline targeted replacement of the endogenous gamma1 promoter, I-exon, and I-exon splice donor site by heterologous promoter and splice donor sites directs switch recombination in activated B lymphocytes constitutively to the gamma1 switch region. In contrast, switch recombination to IgG1 is inhibited in mutant mice, in which the replacement does not include the heterologous splice donor site. Our data unequivocally demonstrate that targeting of switch recombination to IgG1 in vivo requires processing of the Igamma1 switch transcripts. Either the processing machinery or the processed transcripts are involved in class switch recombination.
抗体类别转换由免疫球蛋白重链基因座的转换区之间的体细胞重组介导。通过诱导从重复转换区5'端起始的转换转录本，细胞因子严格调控重组靶向特定的转换区。然而，仅转换转录本身不足以靶向转换重组。这已在突变小鼠中得到证实，其中转换区上游的I外显子及其启动子被异源启动子取代。在此我们表明，在小鼠种系中，用异源启动子和剪接供体位点定向取代内源性γ1启动子、I外显子和I外显子剪接供体位点，可使活化B淋巴细胞中的转换重组持续定向至γ1转换区。相比之下，在不包括异源剪接供体位点的突变小鼠中，向IgG1的转换重组受到抑制。我们的数据明确表明，体内向IgG1的转换重组靶向需要对Igγ1转换转录本进行加工。加工机制或加工后的转录本参与类别转换重组。
