Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.
Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.
复制标题
早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
复制
发表时间：
2015-06-18
期刊：
影响因子：
--
通讯作者：
Notarangelo LD
中科院分区：
文献类型：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
联合免疫缺陷（CID）是指先天性T细胞免疫缺陷，T细胞存在但数量或功能缺陷。由于原发性B细胞缺陷或继发于T细胞缺陷而导致的体液免疫受损也是常见的。因此，CID患者表现出严重的感染和/或自身免疫。许多类型的CID的特定分子、细胞和临床特征仍然未知。我们对5名无血缘关系的儿童进行了遗传和细胞免疫学研究，这些儿童都有早发性侵入性细菌和病毒感染史，伴有淋巴细胞减少症和T、B和NK细胞反应缺陷。两名患者在儿童早期死亡，而其他三名接受异基因造血干细胞移植，T细胞功能正常化和临床改善。我们在这5名患者中鉴定了胞质分裂贡献因子2（DOCK 2）基因的双等位基因突变。T细胞中的RAC 1活化受损。趋化因子诱导的迁移和肌动蛋白聚合在T、B和NK细胞中是缺陷的。NK细胞脱粒也受到影响。病毒感染后，外周血单个核细胞（PBMC）产生干扰素（IFN）-α和-λ减少。此外，在DOCK 2缺陷型成纤维细胞中，病毒复制增加，病毒诱导的细胞死亡增强，这可以通过IFN-α2β处理或野生型DOCK 2表达来正常化。常染色体隐性DOCK 2缺陷是一种孟德尔遗传疾病，具有造血和非造血免疫的多效性缺陷。具有CID临床特征的儿童，特别是在存在早发性侵入性感染的情况下，可能具有这种情况。
Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-α and -λ by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-α2β or upon expression of wild-type DOCK2. Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition.