Conley M E, Rohrer J, Rapalus L, Boylin E C, Minegishi Y
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38101-0318, USA.
Immunol Rev. 2000 Dec;178:75-90. doi: 10.1034/j.1600-065x.2000.17809.x.
Patients with genetic defects in B-cell development provide an unusual opportunity to dissect the requirements for normal B-cell maturation. It is striking that all of the known genetic defects that result in a failure of B-cell development involve signaling through the pre-B-cell receptor (pre-BCR). Approximately 85% of affected patients are males with mutations in the X chromosome-encoded cytoplasmic tyrosine kinase Btk. Preliminary experiments using stem cell transplants and retroviral-mediated gene therapy in Btk-deficient mice suggest that it may be relatively easy to correct serum immunoglobulins but harder to correct antibody production to T-cell-independent antigens in this disorder. About 3-6% of patients with defects in B-cell development have deletions or critical base pair substitutions in the mu constant region gene. Patients with defects in Igalpha, lambda5 and B-cell linker protein (BLNK) have also been described. All of these patients have a block at the pro-B to pre-B-cell transition. Defects in Btk, lambda5 and BLNK result in a more severe phenotype in the human compared to the mouse. These findings suggest that requirements for signaling through the pre-BCR are more stringent in the human compared to the mouse. Possible explanations for this observation are discussed.
B细胞发育存在基因缺陷的患者为剖析正常B细胞成熟的必要条件提供了一个特殊机会。引人注目的是，所有已知的导致B细胞发育失败的基因缺陷都涉及前B细胞受体（pre-BCR）信号传导。大约85%的受影响患者是男性，其X染色体编码的细胞质酪氨酸激酶Btk发生突变。在Btk缺陷小鼠中使用干细胞移植和逆转录病毒介导的基因治疗的初步实验表明，在这种疾病中纠正血清免疫球蛋白可能相对容易，但纠正对T细胞非依赖性抗原的抗体产生则较为困难。约3% - 6%的B细胞发育缺陷患者在μ恒定区基因存在缺失或关键碱基对替换。也有关于Igalpha、lambda5和B细胞连接蛋白（BLNK）缺陷患者的描述。所有这些患者在pro-B细胞向pre-B细胞转变阶段出现阻滞。与小鼠相比，Btk、lambda5和BLNK缺陷在人类中导致更严重的表型。这些发现表明，与小鼠相比，人类中通过pre-BCR进行信号传导的要求更为严格。本文讨论了对此观察结果的可能解释。
