Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

作者：Angeliki Giannelou, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones Abu‐Asab, Kris Ylaya, Deborah L. Stone, Anna Šedivá, Rola Sleiman, Lucie Šrámková, Deepika Bhatla, Elisavet Serti, Wanxia Li Tsai, Dan Yang, Kevin Bishop, Blake Carrington, Wuhong Pei, Natalie Deuitch, Stephen R. Brooks, Jehad H. Edwan, Sarita Joshi, Seraina Prader, Daniela Kaiser, William Owen, Abdullah Al Sonbul, Yu Zhang, Julie E. Niemela, Shawn M. Burgess, Manfred Boehm, Barbara Rehermann, JaeJin Chae, Martha Quezado, Amanda K. Ombrello, Rebecca H. Buckley, Alexi Grom, Elaine F. Remmers, Jana Pachlopnik Schmid, Helen C. Su, Gustavo Gutierrez-Cruz, Stephen M. Hewitt, Raman Sood, Kimberly Risma, Katherine R. Calvo, Sergio D. Rosenzweig, Massimo Gadina, Markus Hafner, Hong‐Wei Sun, Daniel L. Kastner, Ivona Aksentijevich · 发表于：Annals of the Rheumatic Diseases · 年份：2018 · DOI：10.1136/annrheumdis-2017-212401 · 被引用次数：59 · 研究领域：Porphyrin Metabolism and Disorders、RNA modifications and cancer、Folate and B Vitamins Research

OBJECTIVES: , a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular d...