DiSanto J P, Bonnefoy J Y, Gauchat J F, Fischer A, de Saint Basile G
INSERM U 132, Hôpital Necker-Enfants Malades, Paris, France.
Nature. 1993 Feb 11;361(6412):541-3. doi: 10.1038/361541a0.
Signalling for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T-B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein with homology to tumour necrosis factor-alpha and -beta, and has important functions in B-cell activation and differentiation. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.
B细胞免疫球蛋白同种型转换的信号传导需要T细胞衍生的细胞因子以及T-B细胞相互作用，这种相互作用主要通过B细胞上的CD40分子及其与活化T细胞上的配体（CD40L）来实现（参考文献1中有综述）。CD40L是一种II型膜蛋白，与肿瘤坏死因子-α和-β具有同源性，在B细胞活化和分化中具有重要功能。人类CD40L基因定位于Xq26.3 - 27.1（参考文献3），该区域是一种以免疫球蛋白同种型转换缺陷为特征的原发性免疫缺陷（高IgM免疫缺陷综合征，HIGM1）的定位区域。HIGM1涉及CD40L异常的假说已得到验证。我们在此报告，四名患有高IgM综合征的无亲缘关系男性儿童中缺乏CD40L表达。这些患者的CD40L转录本显示在CD40L细胞外结构域的有限区域内存在缺失或点突变。这些伴有异常CD40L表达的基因改变为在这种免疫缺陷中观察到的免疫球蛋白同种型转换缺陷提供了分子基础。
