Defective B-cell-negative selection and terminal differentiation in the ICF syndrome
Defective B-cell-negative selection and terminal differentiation in the ICF syndrome
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DOI：
10.1182/blood-2003-08-2632
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发表时间：
2004-04-01
期刊：
影响因子：
20.3
通讯作者：
Schiff, C
中科院分区：
文献类型：
--
作者：
Blanco-Betancourt, CE;Moncla, A;Schiff, C
免疫缺陷、着丝粒区不稳定和面部异常（ICF）综合征是一种罕见的常染色体隐性遗传病。DNA甲基转移酶3B（DNMT3B）基因突变是大多数ICF病例报告的原因。我们通过分析4例ICF患者的原代B细胞，研究了该综合征中与无丙种球蛋白血症相关的B细胞缺陷。ICF外周血（PB）仅含有幼稚B细胞;不存在记忆细胞和肠浆细胞。与正常PB过渡和成熟B细胞相反，幼稚ICF B细胞携带富含带正电荷残基的潜在自身反应性长重链可变区互补决定区3（V（H）CDR 3），表明患者中的负选择受损。与转基因模型中的无反应性B细胞一样，新生成的未成熟B细胞在PB中积聚。此外，这些细胞分泌免疫球蛋白并在体外活化后表现出增加的凋亡。然而，它们能够上调CD 86，表明能量以外的机制参与ICF B细胞的沉默。1例无DNMT3B突变的患者显示免疫球蛋白E（IgE）转换诱导的差异，表明免疫缺陷可能随综合征的遗传起源而变化。在这项研究中，我们确定了阴性选择破坏和外周B细胞成熟障碍有助于ICF综合征中的无丙种球蛋白血症。(C)2004年，美国血液学会。
immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (V(H)CDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than energy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin E (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome. (C) 2004 by The American Society of Hematology.