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

NF-kappa B2/p100 (p100) is an inhibitor of kappa B (I kappa B) protein that is partially degraded to produce the NF-kappa B2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or I kappa B 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 I kappa B function of degradation-resistant p100.

Automated summary

Mutations in the p100 degron domain increase degradation resistance and lead to autoimmune diseases in mice. Both affected humans and mice show a hydrophobic signature of increased self-reactivity in their T cell receptor repertoires.