Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA
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Mosby Inc.
Abstract
Background A number of heritable immune dysregulatory diseases result from defects affecting regulatory T (Treg) cell development, function, or both. They include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is caused by mutations in forkhead box P3 (FOXP3), and IPEX-like disorders caused by mutations in IL-2 receptor α (IL2RA), signal transducer and activator of transcription 5b (STAT5b), and signal transducer and activator of transcription 1 (STAT1). However, the genetic defects underlying many cases of IPEX-like disorders remain unknown.; Objective We sought to identify the genetic abnormalities in patients with idiopathic IPEX-like disorders.; Methods We performed whole-exome and targeted gene sequencing and phenotypic and functional analyses of Treg cells.; Results A child who presented with an IPEX-like syndrome and severe Treg cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), which was previously implicated as a cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked Treg cell depletion; profoundly decreased expression of canonical Treg cell markers, including FOXP3, CD25, Helios, and cytotoxic T lymphocyte-associated antigen 4; and impaired Treg cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production, with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced Treg cells were normal, LRBA-deficient T cells exhibited increased apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin complexes 1 and 2.; Conclusion LRBA deficiency is a novel cause of IPEX-like syndrome and Treg cell deficiency associated with metabolic dysfunction and increased apoptosis of Treg cells. © 2014 American Academy of Allergy, Asthma & Immunology.
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Autoantibodies, Autoimmunity, Enteropathy, Forkhead box p3, Immune dysregulation, Lps-responsive beige-like anchor, Mammalian target of rapamycin complex, Polyendocrinopathy, Regulatory t cells, T follicular helper cells, T follicular regulatory cells, X-linked syndrome, Adaptor proteins, signal transducing, Adolescent, Child, preschool, Diabetes mellitus, type 1, Diarrhea, Female, Genetic diseases, x-linked, Humans, Immune system diseases, Interleukin-10, Male, Mutation, T-lymphocytes, regulatory, Autoantibody, Cytotoxic t lymphocyte antigen 4, Immunoglobulin, Insulin antibody, Interleukin 2 receptor alpha, Lrba protein, Mammalian target of rapamycin complex 1, Mammalian target of rapamycin complex 2, Protein, Protein hydrolysate, Thyroid antibody, Transcription factor foxp3, Unclassified drug, Interleukin 10, Lrba protein, human, Signal transducing adaptor protein, Antibody production, Apoptosis, Article, Autoimmune hemolytic anemia, Case report, Cd4+ t lymphocyte, Cd8+ t lymphocyte, Cell differentiation, Cell expansion, Cell selection, Chediak higashi syndrome, Child, Controlled study, Exome, Flow cytometry, Gene, Gene sequence, Heterozygote, Homozygosity, Human, Human cell, Hypothyroidism, Immune deficiency, Immunoblotting, Immunoglobulin blood level, In vitro study, Insulin dependent diabetes mellitus, Ipex syndrome, Loss of function mutation, Lrba gene, Lymphocyte function, Memory t lymphocyte, Nonsense mutation, Peripheral blood mononuclear cell, Phenotype, Pneumococcal infection, Preschool child, Protein expression, Pseudomonas infection, Regulatory t cell deficiency, Regulatory t lymphocyte, Septic shock, Septicemia, Stop codon, Deficiency, Genetics, Immunology, X chromosome linked disorder