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. Epub 2014 Nov 17.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Autoantibodies / immunology
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / congenital
  • Diarrhea
  • Female
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / immunology
  • Humans
  • Immune System Diseases / congenital
  • Interleukin-10 / immunology
  • Male
  • Mutation
  • T-Lymphocytes, Regulatory / immunology*


  • Adaptor Proteins, Signal Transducing
  • Autoantibodies
  • Interleukin-10
  • LRBA protein, human

Supplementary concepts

  • Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome