Schwaber J
Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115.
J Clin Invest. 1992 Jun;89(6):2053-9. doi: 10.1172/JCI115817.
X-linked agammaglobulinemia (XLA) results from a failure of B lymphoid development. We have previously examined pre-B cell hybrids from three patients with XLA and found them to be limited to production of a novel germ line transcript of the Ig H chain locus composed of a leader sequence (LS) spliced to the constant region of mu chain (C mu) as mRNA and polypeptide. These transcripts result from transcriptional activation of the germ line heavy chain locus from an LS exon upstream of the embryonic JH locus. Germ line LS-C mu transcripts are produced by pre-B cells from normal bone marrow and fetal liver, indicating that they are products of normal pre-B cell development, as part of the process of transcriptional activation to provide access for the recombinase. Bone marrow from three patients with XLA has been examined directly by polymerase chain reaction amplification to determine whether the exclusive production of LS-C mu by XLA pre-B cell hybrids is representative of XLA pre-B cells. I report that LS-C mu is the predominant Ig molecule produced by XLA pre-B cells, with limited production of the D mu product of DJH intermediate stage of V(D)J recombination. Mature VHDJH recombinations were not detected with a variety of primers that amplify VH sequences. I conclude that XLA is associated with a limitation in V(D)J recombination that may cause the failure of pre-B cell development.
X连锁无丙种球蛋白血症（XLA）是由B淋巴细胞发育失败引起的。我们之前检查了三名XLA患者的前B细胞杂交体，发现它们仅限于产生一种新的Ig H链基因座种系转录本，该转录本由一个与μ链恒定区（Cμ）拼接的前导序列（LS）作为mRNA和多肽组成。这些转录本是由胚胎JH基因座上游的LS外显子对种系重链基因座进行转录激活产生的。种系LS-Cμ转录本由正常骨髓和胎儿肝脏中的前B细胞产生，这表明它们是正常前B细胞发育的产物，是转录激活过程的一部分，为重组酶提供作用途径。我们通过聚合酶链反应扩增直接检测了三名XLA患者的骨髓，以确定XLA前B细胞杂交体独家产生LS-Cμ是否代表XLA前B细胞。我报告称，LS-Cμ是XLA前B细胞产生的主要Ig分子，V（D）J重组DJH中间阶段的Dμ产物产量有限。使用多种扩增VH序列的引物未检测到成熟的VHDJH重组。我的结论是，XLA与V（D）J重组受限有关，这可能导致前B细胞发育失败。
