Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-κB

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Abstract

The NF-κB signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-κB subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying previously unreported heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-κB signaling was intact, but induction of inhibitory regulators such as IκBα and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-κB activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-κB feedback control to unchecked inflammation and inflammatory cell death.

Authors

Nadja Lucas, Sophia Weidler, Antonia A. Eicher, Baerbel Keller, Özlem Satirer, Adam Desrochers, Timothy J.S. Ramnarine, Mohammad Mokhtari, Sophie Elstner, Timmy Strauss, Simon W. Mages, Arek Kendirli, Oana Cristina Buzoianu, Tobias B. Haack, Lina Igel, Tim Niehues, Sandra von Hardenberg, Maria Fasshauer, Rami Abou Jamra, Hagen Ott, Ulrike Hüffmeier, Catharina Schütz, Marisa Bijwaard, Susan Wagner, Paulina Switala, Sarah Koss, Jurek Schultz, Stefanie Kretschmer, Jasmin Kümmerle-Deschner, Christine Wolf, Johanna Klughammer, Min Ae Lee-Kirsch