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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:135

Article

Charbonnier, Louis-Marie^1,2  Janssen, Erin^1,2  Chou, Janet^1,2  Ohsumi, Toshiro K.³  Keles, Sevgi^1,2  Hsu, Joyce T.^1,2  Massaad, Michel J.^1,2  Garcia-Lloret, Maria⁴  Hanna-Wakim, Rima⁵  Dbaibo, Ghassan⁵  Alangari, Abdullah A.⁶  Alsultan, Abdulrahman⁶  Al-Zahrani, Daifulah⁷  Geha, Raif S.^1,2  Chatila, Talal A.^1,2 

[1] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[4] Univ Calif Los Angeles, Dept Pediat, Div Immunol, Los Angeles, CA 90024 USA

[5] Amer Univ Beirut, Div Pediat Infect Dis, Beirut, Lebanon

[6] King Saud Univ, Coll Med, Dept Pediat, Riyadh 11461, Saudi Arabia

[7] King Abdul Aziz Med City, Immunol & Allergy Pediat Dept, Jeddah, Saudi Arabia

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

DOI  :  10.1016/j.jaci.2014.10.019

来源: Elsevier

【 摘 要 】

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 a (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 cellmediated 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.

【 授权许可】

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