Previous studies have linked autoantibodies that target type I interferons (IFNs) to severe sequelae after SARS-CoV-2 virus infection. In a follow-up study published in Nature, Le Voyer and an international consortium of researchers identified a cohort of patients who had non-synonymous autosomal-dominant mutations in NFKB2 and presented with severe or recurrent viral disease. NFKB2 encodes p100, which functions as an inhibitor of the non-canonical NF-κB signaling pathway; upstream receptor signaling triggers phosphorylation and cleavage of p100 to p52 (a positive regulator), which then transmigrates to the nucleus to initiate target gene expression. The researchers found that specific NFKB2 mutations that caused simultaneous p52 loss-of-function (p52LOF) and p100 gain-of-function (that is, IκBδ activity) were associated with the presence of neutralizing autoantibodies to IFNα and IFNω, but curiously not to IFNβ; similar anti-type I IFN autoantibodies were found in patients with defective NIK or RelB expression (both active in the non-canonical NF-κB pathway). The authors link these NFKB2 mutations to defects in thymic stromal cells, in particular impaired maturation and reduced frequencies of AIRE-expressing medullary thymic epithelial cells. Analysis showed that the thymic volume of pediatric patients with NFKB2 variants (p52LOF/IκBδGOF) was reduced compared with age-matched controls. Importantly, however, the spectrum of autoimmunity in patients with NFKB2 deletions (p52LOF/IκBδGOF) differs from patients with AIRE deficiency who develop autoimmune polyendocrinopathy syndrome. How aberrant regulation of p100 and p52 activity specifically leads to the production of autoantibodies against type I interferons remains unclear.
Original reference: Nature https://doi.org/10.1038/s41586-023-06717-x (2023)
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