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


NF-kappaB2/p100 (p100) is an inhibitor of kappaB (IkappaB) protein that is partially degraded to produce the NF-kappaB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IkappaB 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 IkappaB function of degradation-resistant p100.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Wirasinha, R. C.; Davies, A. R.; Srivastava, M.; Sheridan, J. M.; Sng, X. Y. X.; Delmonte, O. M.; Dobbs, K.; Loh, K. L.; Miosge, L. A.; Lee, C. E.; Chand, R.; Chan, A.; Yap, J. Y.; Keller, M. D.; Chen, K.; Rossjohn, J.; La Gruta, N. L.; Vinuesa, C. G.; Reid, H. H.; Lionakis, M. S.; Notarangelo, L. D.; Gray, D. H. D.; Goodnow, C. C.; Cook, M. C.; Daley, S. R.
Responsible Garvan Author Prof Christopher Goodnow
Published Date 2021-02-28
Published Volume 218
Published Issue 2
Published Pages e20200476
Status Published in-print
DOI 10.1084/jem.20200476
URL link to publisher's version