Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
J Allergy Clin Immunol. 2014 Jul;134(1):135-44. doi: 10.1016/j.jaci.2013.11.015. Epub 2014 Jan 11.
Individuals with genetic defects in CD40 ligand (CD40L) or B-cell antigen receptor coreceptor molecules CD19 and CD81 suffer from an antibody deficiency. Still, these patients carry low levels of memory B cells and serum antibodies.
We sought to assess why the remaining memory B cells and antibodies in the blood of these patients do not provide functional immunity.
We included CD19-deficient patients (n = 8), CD40L-deficient patients (n = 8), and healthy controls (n = 50) to perform detailed flow cytometry on blood B cells, molecular analysis of IgA and IgG transcripts, as well as functional analysis of B-cell activation.
CD19-deficient and CD40L-deficient patients carried reduced numbers of all memory B-cell subsets except CD27(-)IgA(+) B cells. Their immunoglobulin heavy chain class-switched transcripts contained less somatic mutations and reduced usage of IgM-distal IgG2 and IgA2 subclasses. The selection strength of mutations for antigen binding was significantly lower than in controls, whereas selection to maintain superantigen binding was normal. Furthermore, the patients showed impaired selection against inherently autoreactive properties of their immunoglobulins. Somatic hypermutation analysis revealed decreased activation-induced cytidine deaminase and uracil-DNA glycosylase 2 activity in CD40L deficiency and increased uracil-DNA glycosylase 2 but decreased mismatch repair in CD19 deficiency. B-cell activation studies revealed that this was at least in part due to transcriptional regulation of DNA repair genes.
This study on CD19 and CD40L deficiencies illustrates that both the B-cell antigen receptor and CD40 signaling pathways are required for the selection of immunoglobulin reactivity. Still, they differentially mediate DNA repair pathways during somatic hypermutation, thereby together shaping the human in vivo antigen-experienced B-cell repertoire.
患有 CD40 配体（CD40L）或 B 细胞抗原受体共受体分子 CD19 和 CD81 遗传缺陷的个体患有抗体缺陷。尽管如此，这些患者仍携带低水平的记忆 B 细胞和血清抗体。
我们试图评估为什么这些患者血液中的剩余记忆 B 细胞和抗体不能提供功能性免疫。
我们纳入了 CD19 缺陷患者（n=8）、CD40L 缺陷患者（n=8）和健康对照者（n=50），对血液 B 细胞进行详细的流式细胞术分析、IgA 和 IgG 转录本的分子分析以及 B 细胞激活的功能分析。
CD19 缺陷和 CD40L 缺陷患者除 CD27(-)IgA(+)B 细胞外，所有记忆 B 细胞亚群的数量均减少。他们的免疫球蛋白重链类别转换转录本包含较少的体细胞突变和减少的 IgM 远端 IgG2 和 IgA2 亚类的使用。针对抗原结合的突变选择强度明显低于对照组，而维持超抗原结合的选择是正常的。此外，患者显示出对自身免疫球蛋白固有自身反应性的选择受损。体细胞超突变分析显示 CD40L 缺陷中激活诱导的胞嘧啶脱氨酶和尿嘧啶-DNA 糖基化酶 2 活性降低，而 CD19 缺陷中尿嘧啶-DNA 糖基化酶 2 增加但错配修复减少。B 细胞激活研究表明，这至少部分是由于 DNA 修复基因的转录调节。
这项关于 CD19 和 CD40L 缺陷的研究表明，B 细胞抗原受体和 CD40 信号通路都需要选择免疫球蛋白反应性。尽管如此，它们在体细胞超突变过程中差异调节 DNA 修复途径，从而共同塑造人类体内抗原经验性 B 细胞库。
