Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), London, United Kingdom.
Front Immunol. 2023 Dec 5;14:1287258. doi: 10.3389/fimmu.2023.1287258. eCollection 2023.
ISG15 deficiency is a rare disease caused by autosomal recessive variants in the gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/β signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.
ISG15 缺乏症是一种由基因（编码 ISG15 蛋白）的常染色体隐性变异引起的罕见疾病。ISG15 蛋白在 I 型和 II 型干扰素（IFN）免疫途径中发挥双重作用。在细胞外，ISG15 蛋白对于 IFN-γ 依赖性抗分枝杆菌免疫至关重要，而在细胞内，ISG15 对于 USP18 介导的 IFN-α/β信号转导下调是必需的。由于这种双重作用，ISG15 缺乏症可表现出多种临床表型，从易感染分枝杆菌到以坏死性皮肤损伤、脑内钙化和肺部受累为特征的自身炎症。在本报告中，我们描述了在两个不同家庭中发现的导致完全 ISG15 缺乏和严重皮肤溃疡的新型变异。全外显子组测序在第一家族的先证者中发现了杂合错义 p.Q16X 变异和杂合多基因 1p36.33 缺失。在第二家族中，两个同胞均检测到基因完全缺失。我们还进行了进一步的分析，包括细胞因子失调、干扰素刺激基因表达和淋巴细胞及病变组织中 p-STAT1 激活的特征分析。最后，我们证明了第二家族中的一个同胞在接受 Janus 激酶（JAK）抑制剂巴瑞替尼治疗后，与 ISG15 缺乏相关的临床症状完全且迅速缓解。
