Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases
Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases
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DOI：
10.1073/pnas.1813582116
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发表时间：
2019-01-15
影响因子：
11.1
通讯作者：
Kotlarz, Daniel
中科院分区：
文献类型：
--
作者：
Li, Yue;Fuehrer, Marita;Kotlarz, Daniel
受体相互作用丝氨酸/苏氨酸蛋白激酶1 （RIPK1）是细胞死亡和炎症的关键调节因子，但其与人类疾病发病机制的相关性尚不明确。单基因疾病的研究可能为了解疾病机制和RIPK1对常见疾病的治疗靶点提供重要见解。在这里，我们报告了来自6个不相关的家系的8例患者，他们的RIPK1双等位基因功能丧失突变表现为原发性免疫缺陷和/或肠道炎症。RIPK1突变与NF-kappa B活性降低、T细胞和B细胞分化缺陷、炎性体活性增加以及肠上皮细胞对tnfr1介导的细胞死亡的反应受损有关。RIPK1缺陷患者的特征突出了RIPK1在控制人类免疫和肠道稳态中的重要作用，并可能对靶向RIPK1的治疗具有重要意义。
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-kappa B activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.