{"doi":"10.1073/pnas.2321794121","title":"Inherited human RelB deficiency impairs innate and adaptive immunity to infection","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.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":437205,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":274472,"name":"Majistor Raj Luxman Maglorius Renkilaraj","orcid":"0000-0002-8385-2860","position":1,"is_corresponding":false},{"id":670958,"name":"Kunihiko Moriya","orcid":"0000-0002-0418-5132","position":2,"is_corresponding":false},{"id":1018725,"name":"Malena Pérez Lorenzo","orcid":"0000-0002-7933-5211","position":3,"is_corresponding":false},{"id":726108,"name":"Tina Nguyen","orcid":"0000-0003-0709-3636","position":4,"is_corresponding":false},{"id":1246051,"name":"Liwei Gao","orcid":"0000-0001-7652-7456","position":5,"is_corresponding":false},{"id":643373,"name":"Tamar Rubin","orcid":null,"position":6,"is_corresponding":false},{"id":1019802,"name":"Axel Cederholm","orcid":"0009-0006-5973-9637","position":7,"is_corresponding":false},{"id":104463,"name":"Masato Ogishi","orcid":"0000-0003-2421-7389","position":8,"is_corresponding":false},{"id":409917,"name":"Carlos A. 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