Inherited human RelB deficiency impairs innate and adaptive immunity to infection

• 成果类型: Article
• 署名作者: Le Voyer, Tom; Renkilaraj, Majistor Raj Luxman Maglorius; Moriya, Kunihiko; Lorenzo, Malena Perez; Nguyen, Tina; Gao, Liwei; Rubin, Tamar; Cederholm, Axel; Ogishi, Masato; Franco, Carlos A. Arango-; Beziat, Vivien; Levy, Romain; Migaud, Melanie; Rapaport, Franck; Itan, Yuval; Deenick, Elissa K.; Cortese, Irene; Lisco, Andrea; Boztug, Kaan; Abel, Laurent; Boisson-Dupuis, Stephanie; Boisson, Bertrand; Frosk, Patrick; Ma, Cindy S.; Landegren, Nils; Celmeli, Fatih; Casanova, Jean- Laurent; Tangye, Stuart G.; Puel, Anne
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Garvan Institute of Medical Research; University of New South Wales Sydney; University of Manitoba; Uppsala University; Rockefeller University; Universidad de Antioquia; Icahn School of Medicine at Mount Sinai; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Saint Anna Children's Hospital; St. Anna Children's Cancer Research Institute (CCRI); Medical University of Vienna; Austrian Academy of Sciences; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences; University of Manitoba; Antalya Training & Research Hospital; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11585
• DOI: 10.1073/pnas.2321794121
• 发表日期: 2024-09-10
• 关键词: nf-kappa-b; chronic mucocutaneous candidiasis; stem-cell transplantation; multiorgan inflammation; i ifns; PATHWAY; autoantibodies; mutations; expression; responses

摘要

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-kappa B2 (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- 1 beta via the canonical NF-kappa B pathway remains intact. P1 and P2 have low proportions of na & iuml;ve CD4+ and CD8+ T cells and of memory B cells. Moreover, their na & iuml;ve 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-kappa B 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.