胞质溶胶中的线粒体RNA(mtRNA)可触发固有免疫传感器MDA5,并因I型IFN而引发自身炎性疾病。这里,我们表明,编码线粒体外切核酸酶REXO2的基因中的显性阴性突变可能通过触发MDA5途径引起干扰素病.以这种杂合从头突变为特征的患者(p。T132A)表现为持续性皮疹,以角化过度为特征,角化不全和棘皮病,小血管周围有淋巴细胞和嗜酸性粒细胞浸润。此外,循环IgE水平和炎症细胞因子,包括IFNα,被发现持续升高。转录分析突出PBMC中的I型IFN基因特征。机械上,REXO2(T132A)缺乏切割RNA的能力并抑制野生型REXO2的活性。这导致线粒体dsRNA在细胞质中的积累,MDA5识别,导致相关的I型IFN基因签名。这些结果表明,在缺乏REXO2适当调节的情况下,异常的细胞核酸可能会积累并持续触发先天传感器,导致天生的豁免权错误。
Mitochondrial RNA (mtRNA) in the cytosol can trigger the innate immune sensor MDA5, and autoinflammatory disease due to type I IFN. Here, we show that a dominant negative mutation in the gene encoding the mitochondrial exonuclease REXO2 may cause interferonopathy by triggering the MDA5 pathway. A patient characterized by this heterozygous de novo mutation (p.T132A) presented with persistent skin rash featuring hyperkeratosis, parakeratosis and acanthosis, with infiltration of lymphocytes and eosinophils around small blood vessels. In addition, circulating IgE levels and inflammatory cytokines, including IFNα, are found consistently elevated. Transcriptional analysis highlights a type I IFN gene signature in PBMC. Mechanistically, REXO2 (T132A) lacks the ability to cleave RNA and inhibits the activity of wild-type REXO2. This leads to an accumulation of mitochondrial dsRNA in the cytosol, which is recognized by MDA5, leading to the associated type I IFN gene signature. These results demonstrate that in the absence of appropriate regulation by REXO2, aberrant cellular nucleic acids may accumulate and continuously trigger innate sensors, resulting in an inborn error of immunity.