Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris 75015, France.
Imagine Institute, Paris Cité University, Paris 75015, France.
Proc Natl Acad Sci U S A. 2024 Sep 10;121(37):e2321794121. doi: 10.1073/pnas.2321794121. Epub 2024 Sep 4.
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 ( The resulting deficiency of functional RelB impairs the induction of mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type 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.
我们报告了两名无关的成年人，他们分别携带 V-Rel 网状内皮组织增生病毒癌基因同源物 B（RelB）的纯合（P1）或复合杂合（P2）私有失活变异。患者成纤维细胞中，功能性 RelB 的缺失导致淋巴毒素诱导的 mRNA 和 NF-κB2（p100/p52）蛋白的产生受损。这些缺陷可以通过转导野生型 cDNA（cDNA）来挽救。相比之下，RelB 缺陷型成纤维细胞对肿瘤坏死因子（TNF）或白细胞介素 1β（IL-1β）通过经典 NF-κB 途径的反应仍然完整。P1 和 P2 的幼稚 CD4 和 CD8 T 细胞以及记忆 B 细胞比例较低。此外，他们的幼稚 B 细胞不能在 CD40L/IL-21 的作用下分化为分泌免疫球蛋白 G（IgG）或免疫球蛋白 A（IgA）的细胞，体外产生白细胞介素 17A/F 的 T 细胞的发育也受到严重损害。最后，即使在造血干细胞移植后，患者也会产生针对 I 型干扰素（IFN）的中和自身抗体，这证明了胸腺上皮细胞在 T 细胞选择和对某些自身抗原的中枢耐受方面持续存在功能障碍。因此，遗传性人类 RelB 缺乏会破坏替代 NF-κB 途径，导致 T 和 B 细胞免疫缺陷，加上针对 I 型 IFNs 的中和自身抗体，使患者易患病毒、细菌和真菌感染。
