Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
| Title: | Inherited human RelB deficiency impairs innate and adaptive immunity to infection. |
|---|---|
| Authors: | Le Voyer T; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Clinical Immunology Department, Assistance Publique Hôpitaux de Paris, Saint-Louis Hospital, Paris 75010, France.; Maglorius Renkilaraj MRL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Moriya K; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Pérez Lorenzo M; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Nguyen T; Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2052, Australia.; Gao L; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Rubin T; Division of Pediatric Clinical Immunology and Allergy, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.; Cederholm A; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala SE-751 05, Sweden.; Ogishi M; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Arango-Franco CA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Group of Inborn Errors of Immunity, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín 050010, Colombia.; Béziat V; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Lévy R; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Migaud M; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; Rapaport F; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Itan Y; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Deenick EK; Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2052, Australia.; Cortese I; Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892.; Lisco A; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.; Boztug K; St. Anna Children's Cancer Research Institute, Vienna 1090, Austria.; Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Vienna 1090, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.; Abel L; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Boisson-Dupuis S; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Boisson B; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Frosk P; Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, Canada.; Ma CS; Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2052, Australia.; Landegren N; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala SE-751 05, Sweden.; Celmeli F; Department of Allergy and Immunology, University of Medical Science, Antalya Education and Research Hospital, Antalya 07100, Türkiye.; Casanova JL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris 75015, France.; HHMI, New York, NY 10065.; Tangye SG; Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2052, Australia.; Puel A; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.; Imagine Institute, Paris Cité University, Paris 75015, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065. |
| Source: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Sep 10; Vol. 121 (37), pp. e2321794121. Date of Electronic Publication: 2024 Sep 04. |
| Publication Type: | Journal Article; Case Reports |
| Language: | English |
| Journal Info: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : National Academy of Sciences |
| MeSH Terms: | Transcription Factor RelB*/genetics ; Transcription Factor RelB*/metabolism ; Adaptive Immunity*/genetics ; Immunity, Innate*; B-Lymphocytes/immunology ; NF-kappa B p52 Subunit/genetics ; NF-kappa B p52 Subunit/metabolism ; Fibroblasts/metabolism ; Fibroblasts/immunology ; Interferon Type I/immunology ; Interferon Type I/metabolism ; Humans ; Female ; Male ; Adult |
| Abstract: | We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB). The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact. P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells. Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro. Finally, the patients produce neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens. Thus, inherited human RelB deficiency disrupts the alternative NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections. |
| Competing Interests: | Competing interests statement:Tim Niehues was a co-author on publications with the following co-authors within the last 4 y: K.B., C.S.M., and S.G.T. (https://doi.org/10.1182/blood.2020006738) and K.B. (https://doi.org/10.1016/j.jaci.2019.11.051; https://doi.org/10.1002/eji.202048713). Andrew R. Gennery was a co-author with S.G.T. (https://doi.org/10.1016/j.jaci.2020.09.010; https://doi.org/10.1016/j.jaci.2022.09.002) within the last 4 y. |
| References: | J Leukoc Biol. 2013 Nov;94(5):941-51. (PMID: 23922380); J Exp Med. 2024 Sep 2;221(9):. (PMID: 39017930); Pediatr Infect Dis J. 2018 Apr;37(4):373-375. (PMID: 29189676); Science. 2020 Oct 23;370(6515):. (PMID: 32972996); J Immunol. 2013 Apr 15;190(8):3959-66. (PMID: 23509356); Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):. (PMID: 33408250); J Exp Med. 1997 Apr 7;185(7):1359-70. (PMID: 9104822); Cell Res. 2011 Feb;21(2):223-44. (PMID: 21243012); Eur J Immunol. 2023 Jun;53(6):e2250164. (PMID: 37027328); Immunol Rev. 2024 Mar;322(1):98-112. (PMID: 38193358); J Allergy Clin Immunol. 2017 Oct;140(4):1199-1201.e3. (PMID: 28552761); Nat Methods. 2016 Feb;13(2):109-10. (PMID: 26820543); Am J Hum Genet. 2013 Nov 7;93(5):812-24. (PMID: 24140114); Nat Immunol. 2024 May;25(5):743-754. (PMID: 38698239); J Autoimmun. 2017 Jul;81:56-67. (PMID: 28385374); J Clin Immunol. 2019 Jan;39(1):55-64. (PMID: 30552536); BMC Med Genet. 2018 Mar 9;19(1):41. (PMID: 29523099); Nat Rev Dis Primers. 2019 Mar 7;5(1):16. (PMID: 30846703); PLoS Genet. 2013;9(8):e1003709. (PMID: 23990802); Curr Opin Immunol. 2021 Oct;72:277-285. (PMID: 34364035); J Autoimmun. 2015 Dec;65:90-100. (PMID: 26385063); J Exp Med. 2010 Feb 15;207(2):291-7. (PMID: 20123958); Nature. 2020 May;581(7809):434-443. (PMID: 32461654); J Exp Med. 2011 Aug 1;208(8):1635-48. (PMID: 21727188); Nature. 2023 Nov;623(7988):803-813. (PMID: 37938781); Front Immunol. 2016 Nov 17;7:507. (PMID: 27909435); Oncogene. 2006 Oct 30;25(51):6781-99. (PMID: 17072328); J Clin Invest. 2015 Nov 2;125(11):4135-48. (PMID: 26457731); J Immunol. 1997 Jun 1;158(11):5211-8. (PMID: 9164938); Sci Signal. 2016 Sep 27;9(447):ra96. (PMID: 27678221); N Engl J Med. 2010 Oct 21;363(17):1631-7. (PMID: 20961246); Sci Immunol. 2021 Sep 17;6(63):eabf6723. (PMID: 34533979); Am J Hum Genet. 2016 Jan 7;98(1):5-21. (PMID: 26748513); Blood. 2017 Sep 28;130(13):1553-1564. (PMID: 28778864); Hum Genet. 2020 Jun;139(6-7):1011-1022. (PMID: 32124012); Front Cell Infect Microbiol. 2021 Mar 15;11:605589. (PMID: 33791233); J Autoimmun. 2023 May;137:102946. (PMID: 36402602); Am J Med Genet A. 2015 Mar;167A(3):545-52. (PMID: 25691407); J Allergy Clin Immunol. 2019 Mar;143(3):1240-1243.e4. (PMID: 30445060); Mol Cell Biol. 1990 Mar;10(3):1281-6. (PMID: 2406568); J Clin Immunol. 2020 Nov;40(8):1093-1101. (PMID: 32813180); Cell. 1995 Jan 27;80(2):331-40. (PMID: 7834753); J Exp Med. 2010 Jan 18;207(1):155-71. (PMID: 20048285); J Biol Chem. 2011 Jan 14;286(2):1093-102. (PMID: 21071440); Biol Blood Marrow Transplant. 2017 Sep;23(9):1437-1446. (PMID: 28495643); J Immunol. 1996 Nov 1;157(9):3974-9. (PMID: 8892630); Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276); Nature. 1995 Feb 9;373(6514):531-6. (PMID: 7845467); Clin Immunol. 2021 Oct;231:108851. (PMID: 34508889); Front Immunol. 2019 Mar 19;10:297. (PMID: 30941118); J Exp Med. 2022 Apr 4;219(4):. (PMID: 35319722); J Clin Invest. 2023 Feb 1;133(3):. (PMID: 36719370); J Exp Med. 2018 Sep 3;215(9):2289-2310. (PMID: 30068544); Blood. 2010 Jan 21;115(3):519-29. (PMID: 19965666); BMC Med Genet. 2014 Dec 19;15:139. (PMID: 25524009); Dev Cell. 2023 Nov 20;58(22):2428-2446.e9. (PMID: 37652013); J Allergy Clin Immunol. 2019 May;143(5):1688-1701. (PMID: 30940520); Science. 2003 Mar 28;299(5615):2076-9. (PMID: 12637671); Front Immunol. 2015 Apr 28;6:159. (PMID: 25972864); Front Immunol. 2017 Nov 27;8:1624. (PMID: 29230214); PLoS Biol. 2022 Jul 5;20(7):e3001709. (PMID: 35788562); Immunity. 2012 Oct 19;37(4):721-34. (PMID: 22940098); Sci Immunol. 2021 Aug 19;6(62):. (PMID: 34413139); Nat Commun. 2014 Nov 19;5:5360. (PMID: 25406581); Biol Blood Marrow Transplant. 2016 Feb;22(2):195-206. (PMID: 26341398); Nat Rev Immunol. 2017 Sep;17(9):545-558. (PMID: 28580957); Sci Rep. 2021 Oct 4;11(1):19674. (PMID: 34608221); Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13615-20. (PMID: 26483451); Cell Res. 2011 Jan;21(1):86-102. (PMID: 21102550); J Exp Med. 2010 Feb 15;207(2):299-308. (PMID: 20123959) |
| Grant Information: | N/A Department of Health of the New South Wales Government of Australia; N/A Bettencourt-Schueller Foundation; ANR-20-CO11-0001 Agence Nationale de la Recherche (ANR); N/A Imagine Institute; N/A HHMI (HHMI); N/A Stavros Niarchos Foundation (SNF); UL1TR001866 HHS | NIH | National Center for Advancing Translational Sciences (NCATS); N/A HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS); 1042925 DHAC | National Health and Medical Research Council (NHMRC); F99 CA274708 United States CA NCI NIH HHS; N/A Fondation du Souffle (FdS); EQU201903007798 Fondation pour la Recherche Médicale (FRM); N/A apanese Foundation for Pediatric Research; 1176665 DHAC | National Health and Medical Research Council (NHMRC); N/A William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director and Head of business in EMEA, General Atlantic Foundation; R01 AI127564 United States AI NIAID NIH HHS; ANR-21-RHUS-08-COVIFERON Agence Nationale de la Recherche (ANR); R01AI127564 HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID); N/A Grandir - Fonds de solidarité pour l'enfance; N/A European Society for Immunodeficiencies (ESID); N/A Rockefeller University (The Rockefeller Institute); ANR-22-CE15-0046 Agence Nationale de la Recherche (ANR); 01057100 (UNDINE) EC | HORIZON EUROPE Framework Programme (Horizon Europe); F99CA274708 HHS | NIH | National Cancer Institute (NCI); N/A New York Hideyo Noguchi Memorial Society; UL1 TR001866 United States TR NCATS NIH HHS; 1113904 DHAC | National Health and Medical Research Council (NHMRC); ANR-18-CE93-0008 Agence Nationale de la Recherche (ANR); N/A Honjo International Scholarship Foundation (HISF); N/A FULBRIGHT | Fulbright U.S. Scholar Program; N/A Paris Cite University; ANR-10-LABX-62-IBEID Agence Nationale de la Recherche (ANR); N/A Philipp Foundation; ANR-10-IAHU-01 Agence Nationale de la Recherche (ANR); N/A HHS | NIH | NIAID | Division of Intramural Research (DIR, NIAID); N/A Institut National de la Santé et de la Recherche Médicale (Inserm); N/A Square Foundation; N/A Funai Foundation for Information Technology |
| Contributed Indexing: | Keywords: NF-κB pathway; RelB deficiency; autoantibodies; immunodeficiency; type I IFNs |
| Substance Nomenclature: | 147337-75-5 (Transcription Factor RelB); 0 (RELB protein, human); 0 (NF-kappa B p52 Subunit); 0 (NFKB2 protein, human); 0 (Interferon Type I) |
| Entry Date(s): | Date Created: 20240904 Date Completed: 20240904 Latest Revision: 20241025 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11406260 |
| DOI: | 10.1073/pnas.2321794121 |
| PMID: | 39231201 |
| Database: | MEDLINE |
Journal Article; Case Reports