Louis-Marie Charbonnier1, Erin Janssen1, Janet Chou1, Toshiro K Ohsumi2, Sevgi Keles1, Joyce T Hsu1, Michel J Massaad1, Maria Garcia-Lloret3, Rima Hanna-Wakim4, Ghassan Dbaibo4, Abdullah A Alangari5, Abdulrahman Alsultan5, Daifulah Al-Zahrani6, Raif S Geha1, Talal A Chatila7. 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: talal.chatila@childrens.harvard.edu.
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.
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.
Authors: Wen Lin; Dipica Haribhai; Lance M Relland; Nga Truong; Marc R Carlson; Calvin B Williams; Talal A Chatila Journal: Nat Immunol Date: 2007-02-02 Impact factor: 25.606
Authors: Vanessa M Hubbard; Rut Valdor; Bindi Patel; Rajat Singh; Ana Maria Cuervo; Fernando Macian Journal: J Immunol Date: 2010-11-08 Impact factor: 5.422
Authors: Aileen C Cohen; Kari C Nadeau; Wenwei Tu; Vivian Hwa; Kira Dionis; Liliana Bezrodnik; Alejandro Teper; Maria Gaillard; Juan Heinrich; Alan M Krensky; Ron G Rosenfeld; David B Lewis Journal: J Immunol Date: 2006-09-01 Impact factor: 5.422
Authors: R S Wildin; F Ramsdell; J Peake; F Faravelli; J L Casanova; N Buist; E Levy-Lahad; M Mazzella; O Goulet; L Perroni; F D Bricarelli; G Byrne; M McEuen; S Proll; M Appleby; M E Brunkow Journal: Nat Genet Date: 2001-01 Impact factor: 38.330
Authors: F Barzaghi; L Passerini; E Gambineri; S Ciullini Mannurita; T Cornu; E S Kang; Y H Choe; C Cancrini; S Corrente; R Ciccocioppo; M Cecconi; G Zuin; V Discepolo; C Sartirana; J Schmidtko; A Ikinciogullari; A Ambrosi; M G Roncarolo; S Olek; R Bacchetta Journal: J Autoimmun Date: 2012-01-20 Impact factor: 7.094
Authors: Svetlana O Sharapova; Emma Haapaniemi; Inga S Sakovich; Jessica Rojas; Laura Gámez-Díaz; Yuliya E Mareika; Irina E Guryanova; Alexandr A Migas; Taisiya M Mikhaleuskaya; Bodo Grimbacher; Olga V Aleinikova Journal: J Clin Immunol Date: 2018-05-26 Impact factor: 8.317
Authors: Charlotte Schwab; Annemarie Gabrysch; Peter Olbrich; Virginia Patiño; Klaus Warnatz; Daniel Wolff; Akihiro Hoshino; Masao Kobayashi; Kohsuke Imai; Masatoshi Takagi; Ingunn Dybedal; Jamanda A Haddock; David M Sansom; Jose M Lucena; Maximilian Seidl; Annette Schmitt-Graeff; Veronika Reiser; Florian Emmerich; Natalie Frede; Alla Bulashevska; Ulrich Salzer; Desirée Schubert; Seiichi Hayakawa; Satoshi Okada; Maria Kanariou; Zeynep Yesim Kucuk; Hugo Chapdelaine; Lenka Petruzelkova; Zdenek Sumnik; Anna Sediva; Mary Slatter; Peter D Arkwright; Andrew Cant; Hanns-Martin Lorenz; Thomas Giese; Vassilios Lougaris; Alessandro Plebani; Christina Price; Kathleen E Sullivan; Michel Moutschen; Jiri Litzman; Tomas Freiberger; Frank L van de Veerdonk; Mike Recher; Michael H Albert; Fabian Hauck; Suranjith Seneviratne; Jana Pachlopnik Schmid; Antonios Kolios; Gary Unglik; Christian Klemann; Carsten Speckmann; Stephan Ehl; Alan Leichtner; Richard Blumberg; Andre Franke; Scott Snapper; Sebastian Zeissig; Charlotte Cunningham-Rundles; Lisa Giulino-Roth; Olivier Elemento; Gregor Dückers; Tim Niehues; Eva Fronkova; Veronika Kanderová; Craig D Platt; Janet Chou; Talal A Chatila; Raif Geha; Elizabeth McDermott; Su Bunn; Monika Kurzai; Ansgar Schulz; Laia Alsina; Ferran Casals; Angela Deyà-Martinez; Sophie Hambleton; Hirokazu Kanegane; Kjetil Taskén; Olaf Neth; Bodo Grimbacher Journal: J Allergy Clin Immunol Date: 2018-05-04 Impact factor: 10.793