Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
复制标题
DOI：
10.1038/nm.3746
复制
发表时间：
2014-12
期刊：
影响因子：
82.9
通讯作者：
Grimbacher B
中科院分区：
文献类型：
--
作者：
Schubert D;Bode C;Kenefeck R;Hou TZ;Wing JB;Kennedy A;Bulashevska A;Petersen BS;Schäffer AA;Grüning BA;Unger S;Frede N;Baumann U;Witte T;Schmidt RE;Dueckers G;Niehues T;Seneviratne S;Kanariou M;Speckmann C;Ehl S;Rensing-Ehl A;Warnatz K;Rakhmanov M;Thimme R;Hasselblatt P;Emmerich F;Cathomen T;Backofen R;Fisch P;Seidl M;May A;Schmitt-Graeff A;Ikemizu S;Salzer U;Franke A;Sakaguchi S;Walker LSK;Sansom DM;Grimbacher B
蛋白质细胞毒性T淋巴细胞抗原-4（CTLA-4）是免疫应答的重要负性调节剂，并且其缺失在小鼠中引起致命的自身免疫。我们调查了一个大型常染色体显性遗传家族，其中5名患者表现为复杂的免疫失调综合征，其特征为低丙种球蛋白血症、复发性感染和多种自身免疫特征。我们在CTLA 4的外显子1中发现了一个杂合性无义突变。筛选71名具有可比临床表型的无关患者，发现另外5个家族（9名个体）在CTLA 4中具有新的剪接位点和错义突变。虽然临床表现不完全（总共19名CTLA 4突变携带者中有8名成年人被认为未受影响），但CTLA 4突变患者和携带者的调节性T细胞（Treg细胞）中CTLA-4蛋白表达降低。虽然Treg细胞通常以升高的数量存在，但它们的抑制功能、CTLA-4配体结合和CD 80的转内吞作用受损。CTLA 4的突变也与循环B细胞数量和抗体水平降低有关。总之，导致CTLA-4单倍不足或配体结合受损的CTLA-4突变导致具有自身免疫和免疫缺陷特征的复杂综合征。
The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses and its loss causes fatal autoimmunity in mice. We investigated a large autosomal-dominant family with five individuals presenting with a complex immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with novel splice site and missense mutations in CTLA4. While clinical penetrance was incomplete (eight adults of a total of 19 CTLA4 mutation carriers were considered unaffected), CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in patients and carriers with CTLA4 mutations. Whilst Treg cells were generally present at elevated numbers, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers and antibody levels. Taken together, mutations in CTLA-4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding results in a complex syndrome with features of both autoimmunity and immunodeficiency.