Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-kB pathway

Abstract

Patients with inborn errors of the alternative NF-κB pathway have low thymic AIRE expression, leading to the development of auto-Abs neutralizing type I IFNs, and severe viral diseases.

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

“…Defective AIRE therefore leads to loss of tolerance, and autoreactivity directed towards self-antigens, which includes a poorly understood dominance towards IFN-Is (particularly IFN-α/IFN-ω). Furthermore, genetic mutations in NFKB2, as well as other non-canonical NF-κB pathway genes (such as MAP3K14 (NIK) and RELB), have recently been identified in a number of patients who developed anti-IFN-I autoAbs [32][33][34][35][36][37]. Interestingly, NFKB2 is required for the correct expression of AIRE [38], and patients with defects in these non-canonical NF-κB pathway genes have a lower thymic expression of AIRE [37], again likely impacting the establishment of self-tolerance and promoting development of autoAbs, including those against IFN-Is.…”

“…Furthermore, genetic mutations in NFKB2, as well as other non-canonical NF-κB pathway genes (such as MAP3K14 (NIK) and RELB), have recently been identified in a number of patients who developed anti-IFN-I autoAbs [32][33][34][35][36][37]. Interestingly, NFKB2 is required for the correct expression of AIRE [38], and patients with defects in these non-canonical NF-κB pathway genes have a lower thymic expression of AIRE [37], again likely impacting the establishment of self-tolerance and promoting development of autoAbs, including those against IFN-Is. A similar picture is noted in patients with mutations in RAG1/RAG2, who have a high prevalence of anti-IFN-I autoAbs [25], and who exhibit a disorganized thymus lacking AIRE expression in medullary thymic epithelial cells [39,40].…”