Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes
Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes
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DOI：
10.1016/j.jaci.2007.10.001
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发表时间：
2007-11-01
影响因子：
14.2
通讯作者：
Cunningham-Rundles, Charlotte
中科院分区：
文献类型：
--
作者：
Zhang, Li;Radigan, Lin;Cunningham-Rundles, Charlotte
背景资料：在常见变异型免疫缺陷（CVID）中，已发现编码跨膜激活因子和钙调节亲环蛋白配体相互作用因子（TACI）的基因突变。目的：由于大多数CVID患者无免疫缺陷家族成员，杂合突变占优势，TACI突变在散发性CVID中的作用尚不清楚。检查具有或不具有突变的受试者的B细胞与配体（增殖诱导配体（APRIL））的结合，以及配体刺激后的增殖和免疫球蛋白产生。结果：在13例（7.3%）受试者中发现杂合子TACI突变。6例突变患者（46%）发生自身免疫性血小板减少症，而163例无突变患者中有12%发生自身免疫性血小板减少症;脾肿大和脾切除显著增加（P = 0.012; P = 0.001）。一些受试者的B细胞与APRIL的结合受损，在与该配体一起培养时，其增殖和免疫球蛋白产生缺陷;然而，这与无突变受试者的B细胞没有差异。来自5个家族的8名一级亲属具有相同的突变，但没有免疫缺陷，其B细胞在APRIL刺激后产生正常量的IgG和伊加。结论：TACI突变显著地倾向于CVID的自身免疫和淋巴增生，但需要额外的遗传或环境因素来诱导免疫缺陷。这种常见的免疫缺陷综合征的其他原因仍有待确定。
Background: Mutations in the gene coding for transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) have been identified in common variable immunodeficiency (CVID). Mutations coincided with immunodeficiency in families, suggesting dominant inheritance.Objective: Because most subjects with CVID have no immunodeficient family members and heterozygous mutations predominate, the role of TACI mutations in sporadic CVID is unclear.Methods: TACI was sequenced from the genomic DNA of 176 subjects with CVID and family members. B cells of subjects with or without mutations were examined for binding to the ligand, a proliferation inducing ligand (APRIL), and for proliferation and immunoglobulin production after ligand stimulation. Data analysis was performed to assess the clinical relevance of TACI mutations.Results: Heterozygous TACI mutations were found in 13 subjects (7.3%). Six with mutations (46%) had episodes of autoimmune thrombocytopenia, in contrast with 12% of 163 subjects without mutations; splenomegaly and splenectomy were significantly increased (P =.012; P =.001.) B cells of some had impaired binding of APRIL and on culture with this ligand were defective in proliferation and immunoglobulin production; however, this was not different from B cells of subjects without mutations. Eight first-degree relatives from 5 families had the same mutations but were not immune-deficient, and their B cells produced normal amounts of IgG and IgA after APRIL stimulation.Conclusion: Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in CVID, but additional genetic or environmental factors are required to induce immune deficiency.Clinical implications: Additional causes of this common immune deficiency syndrome remain to be determined.