A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation
A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation
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一种人类免疫失调综合征，其特征是伴有纯合无义 Roquin-1 突变的严重过度炎症
DOI：
10.1038/s41467-019-12704-6
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发表时间：
2019-10-21
影响因子：
16.6
通讯作者：
Haerynck, F.
中科院分区：
文献类型：
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作者：
Tavernier, S. J.;Athanasopoulos, V.;Haerynck, F.
过度炎症综合征是由过度活跃的免疫细胞激活和细胞因子释放引起的危及生命的疾病，通常由负反馈机制的缺陷引起。在典型的高炎症综合征家族性噬血细胞性淋巴组织细胞增生症（HLH）中，细胞毒性的先天性错误导致效应细胞积累、免疫失调，如果不治疗，则导致组织损伤和死亡。在这里，我们描述了一个纯合无义R688* RC 3 H1突变的人类病例，患有炎症过度，表现为复发性HLH。RC 3 H1编码免疫调节蛋白如ICOS、OX 40和TNF的转录后抑制因子Roquin-1。将R688* 变体与鼠M199 R变体进行比较，揭示了在免疫细胞活化、高细胞因子血症和疾病发展方面的表型相似性。在机制上，R688* Roquin-1不能定位于P体并与CCR 4-NOT去腺苷化复合物相互作用，阻碍mRNA衰变和失调细胞因子产生。这一独特病例的结果表明，Roquin-1功能受损通过未能淬灭免疫激活而引起炎症过度。
Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immuneregulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.