NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.
Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility
S.R. Daley’s present address is Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
Disclosures: M.D. Keller reported "other" from Gilead outside the submitted work. D.H.D. Gray reported grants from Servier Pharmacetuicals outside the submitted work and is an employee of The Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax (BCL-2 inhibitor). No other disclosures were reported.
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Rushika C. Wirasinha, Ainsley R. Davies, Monika Srivastava, Julie M. Sheridan, Xavier Y.X. Sng, Ottavia M. Delmonte, Kerry Dobbs, Khai L. Loh, Lisa A. Miosge, Cindy Eunhee Lee, Rochna Chand, Anna Chan, Jin Yan Yap, Michael D. Keller, Karin Chen, Jamie Rossjohn, Nicole L. La Gruta, Carola G. Vinuesa, Hugh H. Reid, Michail S. Lionakis, Luigi D. Notarangelo, Daniel H.D. Gray, Christopher C. Goodnow, Matthew C. Cook, Stephen R. Daley; Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility. J Exp Med 1 February 2021; 218 (2): e20200476. doi: https://doi.org/10.1084/jem.20200476
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