Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility

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. LionakisLuigi D. Notarangelo, Daniel H.D. Gray, Christopher C. Goodnow, Matthew C. Cook, Stephen R. Daley

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15 Citations (Scopus)


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.

Original languageEnglish
Article numbere20200476
Number of pages19
JournalJournal of Experimental Medicine
Issue number2
Publication statusPublished - 27 Oct 2020


  • autoimmunity

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