Tusseau Maud, Lovšin Ema, Samaille Charlotte, Pescarmona Rémi, Mathieu Anne-Laure, Maggio Maria-Cristina, Selmanović Velma, Debeljak Marusa, Dachy Angelique, Novljan Gregor, Janin Alexandre, Januel Louis, Gibier Jean-Baptiste, Chopin Emilie, Rouvet Isabelle, Goncalves David, Fabien Nicole, Rice Gillian I, Lesca Gaétan, Labalme Audrey, Romagnani Paola, Walzer Thierry, Viel Sebastien, Perret Magali, Crow Yanick J, Avčin Tadej, Cimaz Rolando, Belot Alexandre
The International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.
Genetics Department, Lyon University Hospital, Lyon, France.
J Clin Immunol. 2022 Aug;42(6):1310-1320. doi: 10.1007/s10875-022-01287-5. Epub 2022 Jun 7.
Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans.
To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human.
We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24 2022.
We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients.
DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).
脱氧核糖核酸酶1样3（DNASE1L3）是一种分泌酶，已被证明可消化源自凋亡小体的细胞外染色质，且DNASE1L3致病变体与狼疮表型相关。目前尚不清楚在人类DNASE1L3缺乏症中干扰素信号是否持续存在。
探索DNASE1L3缺乏症患者的干扰素信号。描述人类DNASE1L3缺乏症的特征。
我们鉴定、表征并分析了五名携带双等位基因DNASE1L3变异的新患者。对五名青少年系统性红斑狼疮（jSLE）患者进行了全外显子组或靶向外显子组和/或桑格测序，以检测致病变异。我们测量了所有患者中干扰素刺激基因（ISG）的表达。我们对2011年首次描述至2022年3月24日期间所有已发表的病例进行了系统综述。
我们鉴定出五名携带双等位基因DNASE1L3致病变异的新患者，包括三个先前未报告的突变。与典型的I型干扰素病相反，我们注意到血液中ISG出现短暂增加，随着疾病缓解恢复正常。一名患者的疾病以狼疮性肾炎和皮肤病变为特征，而其他四名患者表现为低补体血症性荨麻疹性血管炎综合征。第四名患者还患有早发性炎症性肠病。回顾先前的报告，我们确定了另外35名DNASE1L3缺乏症患者，其与狼疮性肾炎的显著风险和不良预后以及抗中性粒细胞胞浆抗体（ANCA）的存在相关。6/35的患者报告有肺部病变。
DNASE1L3缺乏症与广泛的表型相关，包括频繁出现的狼疮性肾炎和伴有ANCA阳性的低补体血症性荨麻疹性血管炎，以及罕见的肺泡出血和炎症性肠病。本报告表明，与艾卡迪-古铁雷斯综合征或婴儿期STING相关血管炎（SAVI）中观察到的细胞内DNA传感和信号异常相反，干扰素产生是短暂的。
