ABSTRACT
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.
Subject(s)
Anemia, Sideroblastic/genetics , Anti-Inflammatory Agents/therapeutic use , Genetic Diseases, X-Linked/genetics , Immunologic Deficiency Syndromes/genetics , Mutation , Nucleotidyltransferases/genetics , RNA, Transfer/genetics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Anemia, Sideroblastic/blood , Child , Child, Preschool , Cytokines/blood , Cytokines/genetics , Developmental Disabilities/genetics , Female , Genetic Diseases, X-Linked/blood , Humans , Immunophenotyping , Male , Pedigree , Phenotype , Tumor Necrosis Factor-alpha/analysis , Exome SequencingABSTRACT
IgG autoantibodies against the alpha-chain of the high affinity IgE receptor are claimed to play a pathogenetic role in autoimmune urticaria. The best methods for detection of functional autoantibodies are currently the autologous serum skin test and the basophil histamine release assay. A simplified and feasible screening test would facilitate the diagnosis of autoimmune urticaria. Here we offer an explanation for the difficulties in establishing a screening test for autoantibodies directed against the alpha-chain of the high affinity IgE receptor in autoimmune urticaria. Identical autoantibodies in chronic urticaria patients and healthy donors belonging to the natural autoantibody repertoire were found by sequence analysis of anti-alpha-chain autoantibodies isolated by repertoire cloning from antibody libraries. These natural autoantibodies bound to the receptor and triggered histamine release but only if IgE was previously removed from the receptor. Diagnostic assays used for detection of antibodies directed against the IgE receptor may require signal comparison with and without the artificial removal of IgE, immune complexes, and complement in order to avoid false positive or negative results. After IgE removal diagnostic tests will detect natural autoantibodies against the high affinity IgE receptor regardless of whether they are pathogenic or not.
Subject(s)
Autoantibodies/immunology , Autoimmune Diseases/diagnosis , Diagnostic Errors , Immunoglobulin Fc Fragments/immunology , Receptors, IgE/immunology , Urticaria/diagnosis , Amino Acid Sequence , Animals , Antibody Affinity , Autoantibodies/blood , Autoimmune Diseases/immunology , Histamine/blood , Humans , Immunoglobulin E/immunology , Mice , Molecular Sequence Data , Recombinant Proteins/immunology , Urticaria/immunologyABSTRACT
A child with a history of diarrhea presented with transient anemia, reticolucytosis, and red blood cell fragmentation. Blood pressure and levels of blood platelets, creatinine, and urea were normal, as were results of urinalysis. Escherichia coli harboring genes for Shiga toxin were detected in stool specimens. It is concluded that extraintestinal diseases caused by Shiga toxin-producing bacteria sometimes present without any renal involvement.
Subject(s)
Anemia, Hemolytic/etiology , Diarrhea/microbiology , Escherichia coli Infections/complications , Escherichia coli , Shiga Toxin/toxicity , Anemia, Hemolytic/chemically induced , Anemia, Hemolytic/microbiology , Child , Diarrhea/etiology , Erythrocytes/metabolism , Escherichia coli/chemistry , Hemolysis , Humans , Infant , Kidney Diseases/etiology , Male , Shiga Toxin/chemistry , Thrombocytopenia/etiologyABSTRACT
A 12-month-old boy developed a mild hemolytic uremic syndrome with no acute diarrheal prodrome. The typical clinical, hematological, and serological features of infectious mononucleosis were also noted. The clinical course of both hemolytic uremic syndrome and infectious mononucleosis was uneventful. A review of the literature disclosed that hemolytic uremic syndrome has been noted in two adolescents with infectious mononucleosis.
