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Le Voyer T, Maglorius Renkilaraj MRL, Moriya K, Pérez Lorenzo M, Nguyen T, Gao L, Rubin T, Cederholm A, Ogishi M, Arango-Franco CA, Béziat V, Lévy R, Migaud M, Rapaport F, Itan Y, Deenick EK, Cortese I, Lisco A, Boztug K, Abel L, Boisson-Dupuis S, Boisson B, Frosk P, Ma CS, Landegren N, Celmeli F, Casanova JL, Tangye SG, Puel A
Proc. Natl. Acad. Sci. U.S.A. 121 (37) e2321794121 [2024-09-10; online 2024-09-04]
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.
Autoimmunity and Serology Profiling [Service]
PubMed 39231201
DOI 10.1073/pnas.2321794121
Crossref 10.1073/pnas.2321794121