Background

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.

Objective

We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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caspase激活和募集域家族成员11（CARD11）的显性负突变引起的联合免疫缺陷和特应性

背景

合并免疫缺陷症（CID）是一种T细胞缺陷，经常表现为反复感染以及表现为自身免疫或过敏性炎症的相关免疫失调。

客观的

我们试图确定4名CID，早发性哮喘，湿疹和食物过敏以及自身免疫性疾病相关患者的遗传畸变。

方法

我们执行了全外显子组测序，然后进行Sanger确认，评估遗传变异对细胞信号传导的作用以及评估所得的免疫功能。

结果

通过使用全外显子组测序鉴定了一种杂合的新型c.C88T 1-bp取代导致caspase激活和募集结构域家族成员11（CARD11）中的氨基酸变化R30W，并且仅与严重特应性的家族成员完美隔离，但未发现在健康受试者中。我们证明，R30W突变导致功能丧失，同时对野生型CARD11发挥显性负作用。CARD11缺陷改变了经典的核因子κB通路，导致体外T细胞对有丝分裂原和抗原的不良反应，这是由于IFN-γ和IL-2分泌减少所致。

结论

与导致严重CID的CARD11中具有双等位基因突变的患者不同，R30W缺陷导致对感染以及多器官异位症和自身免疫的敏感性降低，但不那么突出。