Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Next generation sequencing has led to the discovery of new diseases and molecules regulating immune function. Hypomorphic mutations in the TRNT1 gene cause a syndrome of sideroblastic anemia, immunodeficiency, periodic fevers and developmental delay, also known as SIFD. The TRNT1 enzyme catalyzes an essential step for tRNA maturation and protein synthesis, however, the underlying disease mechanisms are largely unknown. We aim to characterize the mechanisms of inflammation in this disease.
Methods: Whole exome sequencing or candidate gene screening was performed in two families, each with two affected siblings, and in three sporadic patients. Patient cells and tissue were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping through multicolor flow cytometry, H&E, immunohistochemistry and electron microscopy.
We identified seven patients with biallelic missense homozygous or compound heterozygous mutations in TRNT1. Four out of six mutations have not been reported. Three patients died of multiorgan failure. Two apparently unrelated patients shared the same genotype and had similar clinical presentation. Deep sequencing of tRNAs isolated from patients’ fibroblasts showed a significant down-regulation of mature tRNAs when compared to healthy controls. RNA-sequencing of patients’ whole blood revealed up-regulation of neutrophil-related genes. Consistent with these data, lesional biopsies from two patients’ colon showed cryptitis with neutrophilic infiltration. Cultured patients’ macrophages showed increased expression of proinflammatory cytokines IL-6, TNF-a, IL-1b, and accordingly, monocytes displayed increased phosphorylation of STAT3 ex vivo, possibly IL-6 induced, compared to monocytes isolated from healthy donors. Patients had variable degrees of B cell immunodeficiency with an increased population of immature B cells in the peripheral blood. Four patients had a bone marrow examination that revealed a markedly increased number of immature CD10+ CD20–B cells, and at the same time a decreased mature B cell population. Electron microscopy of BM smears showed evidence for abnormal morphology of blood vessels and endothelial cells, serum leakage and cellular debris in the stroma. Lymphocytes and monocytes displayed abnormal shape and degenerated mitochondria. Three patients have been on treatment with a TNF-a inhibitor that has shown promising results in attenuating the systemic inflammation and stabilizing the anemia.
Conclusion: Hypomorphic mutations in TRNT1 are associated with a new, often severe, autoinflammatory disease manifesting a pleiotropic clinical phenotype. Given the essential function and ubiquitous expression of TRNT1, multiple cell types are affected. Myeloid cells, macrophages and neutrophils, might play an important role in mediating inflammation. Further studies may lead to the discovery of a new pathway regulating immune function.
To cite this abstract in AMA style:Giannelou A, Zhou Q, Sun HW, Yang D, Moir S, Edwan JH, Tsai WL, Serti E, Stoffels M, Stone DL, Ombrello AK, Barron K, Su HC, Al Sonbul A, Joshi S, Risma K, Sramkova L, Quezado MM, Calvo K, Mones AA, Gutierrez-Cruz G, Gadina MG, Hafner M, Aksentijevich I, Kastner D. Immune Dysregulation in Patients with TRNT1 Deficiency [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/immune-dysregulation-in-patients-with-trnt1-deficiency/. Accessed December 5, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-dysregulation-in-patients-with-trnt1-deficiency/