Inherited human RelB deficiency impairs innate and adaptive immunity to infection.

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

pmc: PMC11406260


Publications 9.5.0