Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD, USA.
Allergy. 2021 Aug;76(8):2510-2523. doi: 10.1111/all.14762. Epub 2021 Mar 15.
Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+).
Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation.
Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR).
SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
疱疹性湿疹（EH）是特应性皮炎（AD）的一种罕见并发症，由单纯疱疹病毒（HSV）的播散性感染引起。在疾病病因中，稀有和/或有害的遗传变异的作用在很大程度上是未知的。本研究旨在鉴定与有复发性疱疹性湿疹（ADEH+）病史的 AD 中 HSV 感染相关的、携带破坏性遗传变异的基因。
对 49 例复发性 ADEH+（≥3 次 EH 发作）、491 例无疱疹性湿疹病史的 AD（ADEH-）和 237 例非特应性对照（NA）受试者进行全基因组测序（WGS）。对变异进行注释，并采用基于基因的方法（SKAT-O）鉴定与 ADEH+相关的、携带破坏性遗传变异的基因。对通过 WGS 鉴定的基因进行研究，以评估其对 HSV 反应和角质形成细胞分化的影响。
在复发性 ADEH+与 ADEH-和 NA 受试者的比较中，鉴定出了 8 个基因：SIDT2、CLEC7A、GSTZ1、TPSG1、SP110、RBBP8NL、TRIM15 和 FRMD3。在正常人原代角质形成细胞（NHPK）中沉默 SIDT2 和 RBBP8NL，导致 HSV-1 复制显著增加。在 SIDT2 沉默的 NHPK 中，HSV-1 感染后 IFNk 和 IL1b 的基因表达减少。在 RBBP8NL 沉默的 NHPK 中，IFNk 的基因表达减少，但 IL1b 的基因表达增加。此外，沉默 SIDT2 和 RBBP8NL 还抑制角质形成细胞分化标志物角蛋白 10（KRT10）和层粘连蛋白（LOR）的基因表达。
SIDT2 和 RBBP8NL 参与角质形成细胞对 HSV-1 感染的反应。SIDT2 和 RBBP8NL 还调节 KRT10 和 LOR 等角质形成细胞分化基因的表达。
