Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)
Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)
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DOI：
10.1016/j.jaci.2017.06.047
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发表时间：
2018-05-01
影响因子：
14.2
通讯作者：
Roifman, Chaim M.
中科院分区：
文献类型：
--
作者：
Dadi, Harjit;Jones, Tyler A.;Roifman, Chaim M.
背景：联合免疫缺陷（CID）是一种t细胞缺陷，经常表现为复发性感染，以及相关的免疫失调，表现为自身免疫或过敏性炎症。目的：研究4例CID、早发性哮喘、湿疹、食物过敏及自身免疫相关患者的遗传畸变。方法：我们进行了全外显子组测序，随后进行Sanger确认，评估遗传变异对细胞信号传导的影响，并评估由此产生的免疫功能。结果：通过全外显子组测序，鉴定出caspase激活和募集结构域家族成员11 （CARD11）中导致R30W氨基酸变化的一种新的杂合c88t 1-bp取代，仅在严重特应性家族成员中分离得到，而在健康人群中未发现。我们证明R30W突变导致功能丧失，同时也对野生型CARD11产生主要的负面影响。CARD11缺陷改变了经典的核因子κ B通路，导致体外t细胞对有丝分裂原和抗原的反应较差，导致ifn - γ和IL-2分泌减少。结论：与CARD11双等位基因突变导致严重CID的患者不同，R30W缺陷导致对感染的易感性不那么深刻而突出，以及多器官特应性和自身免疫。
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 kappa B pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-gamma and IL-2.Conclusion: Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound et prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.