DNASE1L3 is an extracellular nuclease that digests chromatin released from apoptotic cells. DNASE1L3 variants impair the enzyme function, enhance autoantibody production and type I interferon (IFN-I) responses, and cause different autosomal recessive phenotypes ranging from hypocomplementemic urticarial vasculitis syndrome to full-blown systemic lupus erythematosus (SLE). Kidney involvement in patients with DNASE1L3 variants is poorly characterized. Herein, we describe the clinical course of 3 children with monogenic SLE due to DNASE1L3 variants who developed refractory glomerulonephritis leading to kidney failure. They had different renal histopathological patterns (ie, membranous, endocapillary, and extracapillary glomerulonephritis and thrombotic microangiopathy), all belonging to the lupus nephritis (LN) spectrum. One patient had a mixed phenotype, showing an overlap between SLE and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Using immunofluorescence, we detected glomerular expression of the IFN-I–induced human myxovirus resistance protein 1 (MXA), which was particularly evident in glomerular endothelial cells. Two of the patients had increased expression of interferon-stimulated genes in the peripheral blood, and all 3 patients had reduced serum DNAse activity. Our findings suggest that DNASE1L3-related glomerulonephritis can be included in the spectrum of IFN-I–mediated kidney disorders and provide the rationale for IFN-I–directed therapies in order to improve the poor outcome of this rare condition.

中文翻译：

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狼疮肾炎模式和DNASE1L3 型患者对 I 型干扰素的反应：3 例报告


DNASE1L3 是一种细胞外核酸酶，可消化凋亡细胞释放的染色质。DNASE1L3 变体会损害酶功能，增强自身抗体产生和 I 型干扰素 （IFN-I） 反应，并导致不同的常染色体隐性表型，从低补体血症性荨麻疹血管炎综合征到全面的系统性红斑狼疮 （SLE）。DNASE1L3 变异型患者的肾脏受累特征不佳。在此，我们描述了 3 例因 DNASE1L3 变异导致的单基因 SLE 儿童的临床病程，这些儿童发展为难治性肾小球肾炎导致肾功能衰竭。他们具有不同的肾脏组织病理学模式（即膜性、毛细血管内和毛细血管外肾小球肾炎和血栓性微血管病），都属于狼疮性肾炎 （LN） 谱系。1 例患者具有混合表型，显示 SLE 和抗中性粒细胞胞浆抗体 （ANCA） 相关血管炎之间存在重叠。使用免疫荧光，我们检测到 IFN-I 诱导的人粘液病毒抗性蛋白 1 （MXA） 的肾小球表达，这在肾小球内皮细胞中尤为明显。其中 2 例患者外周血干扰素刺激基因表达增加，所有 3 例患者血清 DNAse 活性降低。我们的研究结果表明，DNASE1L3 相关的肾小球肾炎可以包含在 IFN-I 介导的肾脏疾病谱中，并为 IFN-I 定向疗法提供基本原理，以改善这种罕见病症的不良预后。