Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency
Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency
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DOI：
10.1182/blood-2009-02-207423
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发表时间：
2009-11-05
期刊：
影响因子：
20.3
通讯作者：
Hammarstrom, Lennart
中科院分区：
文献类型：
--
作者：
Borte, Stephan;Pan-Hammarstrom, Qiang;Hammarstrom, Lennart
白细胞介素-21 （IL-21）是人B细胞向免疫球蛋白（Ig）分泌细胞分化的重要启动子。本研究的目的是评估一种基于il -21的方法诱导常见变异性免疫缺陷（CVID）或选择性IgA缺乏（IgAD）患者B细胞产生免疫球蛋白。我们发现，在CVID或IgAD患者中，IL-21、IL-4和抗cd40刺激的组合诱导了IgG和IgA的类转换重组和IgG分泌细胞的分化，包括表面IgG(+) （sIgG(+)）和sIgA(+) B细胞和CD138（+）浆细胞。IL-21刺激远比IL-4或IL-10刺激有效。此外，IL-21、IL-4和抗cd40联合刺激可阻止CVID或IgAD患者CD19(+) B细胞的自发凋亡。然而，分析抗cd3刺激T细胞后IL-21和IL-21受体（IL-21R） mRNA的表达，未发现CVID患者IL-21表达缺陷的证据，IL-21基因编码区测序未发现任何突变，提示存在调节缺陷。因此，我们的工作为IL-21在CVID和IgAD中重建免疫球蛋白产生的潜在治疗作用提供了初步基础。[血液。2009;114:4089-4098]
Interleukin-21 (IL-21) is an important promoter for differentiation of human B cells into immunoglobulin (Ig)-secreting cells. The objective of this study was to evaluate an IL-21-based approach to induce immunoglobulin production in B cells from patients with common variable immunodeficiency (CVID) or selective IgA deficiency (IgAD). We show that a combination of IL-21, IL-4, and anti-CD40 stimulation induces class-switch recombination to IgG and IgA and differentiation of Ig-secreting cells, consisting of both surface IgG(+) (sIgG(+)) and sIgA(+) B cells and CD138(+) plasma cells, in patients with CVID or IgAD. Stimulation with IL-21 was far more effective than stimulation with IL-4 or IL-10. Moreover, spontaneous apoptosis of CD19(+) B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4, and anti-CD40 stimulation. Analysis of IL-21 and IL-21 receptor (IL-21R) mRNA expression upon anti-CD3 stimulation of T cells, however, showed no evidence for defective IL-21 expression in CVID patients and sequencing of the coding regions of the IL21 gene did not reveal any mutations, suggesting a regulatory defect. Thus, our work provides an initial basis for a potential therapeutic role of IL-21 to reconstitute immunoglobulin production in CVID and IgAD. (Blood. 2009; 114: 4089-4098)