Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like disorder caused by loss-of-function mutations in LRBA

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 1; pp. 217 - 227.e9
• Main Authors: Charbonnier, Louis-Marie, Janssen, Erin, Chou, Janet, Ohsumi, Toshiro K., Keles, Sevgi, Hsu, Joyce T., Massaad, Michel J., Garcia-Lloret, Maria, Hanna-Wakim, Rima, Dbaibo, Ghassan, Alangari, Abdullah A., Alsultan, Abdulrahman, Al-Zahrani, Daifulah, Geha, Raif S., Chatila, Talal A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adolescent; Allergy and Immunology; Autoantibodies; Autoantibodies - immunology; autoimmunity; Child, Preschool; Diabetes Mellitus, Type 1 - congenital; Diarrhea; enteropathy; Female; forkhead box P3; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Humans; immune dysregulation; Immune System Diseases - congenital; Interleukin-10 - immunology; LPS-responsive beige-like anchor; Male; mammalian target of rapamycin complex; Mutation; polyendocrinopathy; regulatory T cells; T follicular helper cells; T follicular regulatory cells; T-Lymphocytes, Regulatory - immunology; X-linked syndrome; CD40L; BEACH; WES; polyendocrinopathy; iTreg; Tconv; SLE; CVID; LPS-responsive beige-like anchor; enteropathy; TFH; X-linked syndrome; mammalian target of rapamycin complex; CTLA-4; ICOS; forkhead box P3; TFR; Autoantibodies; LRBA; Treg; IVIG; T follicular helper cells; FOXP3; immune dysregulation; regulatory T cells; CT; autoimmunity; BCL6; Teff; IPEX; 4E-BP1; PD-1; mTORC; T follicular regulatory cells; Follicular regulatory T; Common variable immunodeficiency; Programmed death 1; Systemic lupus erythematosus; Computed tomography; Regulatory T; Induced regulatory T; Beige and Chediak-Higashi syndrome; Inducible costimulator; Conventional T; T FH; Effector T; T FR; Follicular helper T; Cytotoxic T lymphocyte–associated antigen 4; B-cell lymphoma 6; 4E binding protein 1; Whole-exome sequencing; Intravenous immunoglobulin; Immune dysregulation, polyendocrinopathy, enteropathy, X-linked; CD40 ligand
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.10.019

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. We sought to identify the genetic abnormalities in patients with idiopathic IPEX-like disorders. We performed whole-exome and targeted gene sequencing and phenotypic and functional analyses of Treg cells. 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. LRBA deficiency is a novel cause of IPEX-like syndrome and Treg cell deficiency associated with metabolic dysfunction and increased apoptosis of Treg cells.