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

  • J Allergy Clin Immunol. 2015 Jan;135(1):217-27. doi: 10.1016/j.jaci.2014.10.019.
Louis-Marie Charbonnier  1 ,  Erin Janssen  1 ,  Janet Chou  1 ,  Toshiro K Ohsumi  2 ,  Sevgi Keles  1 ,  Joyce T Hsu  1 ,  Michel J Massaad  1 ,  Maria Garcia-Lloret  3 ,  Rima Hanna-Wakim  4 ,  Ghassan Dbaibo  4 ,  Abdullah A Alangari  5 ,  Abdulrahman Alsultan  5 ,  Daifulah Al-Zahrani  6 ,  Raif S Geha  1 ,  Talal A Chatila  7
Affiliations
  • 1. Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
  • 2. Department of Molecular Biology, Massachusetts General Hospital, Boston, Mass.
  • 3. Division of Immunology, Department of Pediatrics, University of California at Los Angeles, Los Angeles, Calif.
  • 4. Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon.
  • 5. Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 6. Immunology and Allergy, Pediatric Department, King Abdulaziz Medical City-WR, Jeddah, Saudi Arabia.
  • 7. Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: [email protected].
PMID: 25468195 DOI: 10.1016/j.jaci.2014.10.019
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.

Keywords
Autoantibodies; LPS-responsive beige-like anchor; T follicular helper cells; T follicular regulatory cells; X-linked syndrome; autoimmunity; enteropathy; forkhead box P3; immune dysregulation; mammalian target of rapamycin complex; polyendocrinopathy; regulatory T cells.