Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada; Canadian Centre for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Md.
J Allergy Clin Immunol. 2018 May;141(5):1818-1830.e2. doi: 10.1016/j.jaci.2017.06.047. Epub 2017 Aug 19.
Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation.
We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity.
We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function.
A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2.
Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.
联合免疫缺陷（CID）是一种 T 细胞缺陷，常表现为反复感染，以及相关的免疫失调，表现为自身免疫或过敏炎症。
我们试图确定 4 名具有 CID、早发性哮喘、湿疹和食物过敏以及自身免疫的相关患者的遗传异常。
我们进行了全外显子组测序，随后进行了 Sanger 确认、遗传变异对细胞信号转导的影响评估以及由此产生的免疫功能评估。
通过全外显子组测序发现了一种杂合的新型 c.C88T 1 碱基替换，导致半胱氨酸天冬氨酸蛋白酶激活和募集结构域家族成员 11（CARD11）的氨基酸改变 R30W，该突变完全与严重过敏的家族成员分离，但在健康受试者中未发现。我们证明 R30W 突变导致功能丧失，同时对野生型 CARD11 产生显性负效应。CARD11 缺陷改变了经典的核因子 κB 途径，导致体外 T 细胞对有丝分裂原和抗原的反应减弱，原因是 IFN-γ 和 IL-2 的分泌减少。
与 CARD11 双等位基因突变导致严重 CID 的患者不同，R30W 缺陷导致感染、多器官过敏和自身免疫的易感性较低，但更为显著。
