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

Lucas N, Weidler S, Eicher AA, Keller B, Satirer Ö, Desrochers A, Ramnarine TJ, Mokhtari M, Elstner S, Strauss T, Mages SW, Kendirli A, Buzoianu OC, Haack TB, Igel L, Niehues T, von Hardenberg S, Fasshauer M, Abou Jamra R, Ott H, Hüffmeier U, Schütz C, Bijwaard M, Wagner S, Switala P, Koss S, Schultz J, Kretschmer S, Kümmerle-Deschner J, Wolf C, Klughammer J, Lee-Kirsch MA (2026)

Publication Type: Journal article

Publication year: 2026

Journal

JCI Insight American Society for Clinical Investigation

Book Volume: 11

Journal Issue: 18

DOI: 10.1172/jci.insight.200002

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 6 patients from 5 unrelated families carrying heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced proinflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA-KI 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 IFN and NF-κB activation, B cells retained partial compensatory signaling, and T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA-KI 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 with CRIS profile

Ulrike Hüffmeier Institute of Human Genetics

Involved external institutions

Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Klinikum der Universität München (LMU Klinikum) DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) HELIOS Kliniken DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universität Leipzig DE Germany (DE)

How to cite

APA:

Lucas, N., Weidler, S., Eicher, A.A., Keller, B., Satirer, Ö., Desrochers, A.,... Lee-Kirsch, M.A. (2026). Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-κB. JCI Insight, 11(18). https://doi.org/10.1172/jci.insight.200002

MLA:

Lucas, Nadja, et al. "Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-κB." JCI Insight 11.18 (2026).

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