Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 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-1ß 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: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.

OBJECTIVES: To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA). METHODS: Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline. RESULTS: Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10-5), myeloid cell development (p=8.13 x10-5), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021). CONCLUSIONS: Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.