Neutralizing autoantibodies against IFN-α2 and IFN-ω in a boy with a heterozygous variant in the FOXN1 gene

Inborn errors of immunity (IEIs) affecting thymic cell development or function can result in thymic aplasia or hypoplasia, autoimmunity, and the generation of neutralizing autoantibodies (Auto-Abs) targeting type I interferons (IFNs) (AAN-I-IFNs). FOXN1 is a master transcriptional regulator of thymic epithelial cells and the impact of the FOXN1 variants spans a spectrum from pathogenic to benign. In pediatric patients with heterozygous FOXN1 variants the full spectrum of clinical and immunological determinants remains to be defined.

Using a luminex multiplex immunoassay, we assessed the presence of auto-Abs against 14 cytokines. We then employed two complementary in vitro cellular assays to test the neutralizing capacity of circulating auto-Abs against type I IFNs.

Here, we present the case of an 11-year-old child who presented at 20 days of age with multiple severe infections. Genetic analysis revealed a heterozygous FOXN1 variant: c.1448_1451del. The patient tested positive for auto-Abs against type I IFNs. Functional assays confirmed the presence of auto-Abs with neutralizing activity against IFN-α2 (at both low [10 ng/mL] and high [50 ng/mL] concentrations) and against IFN-ω (only at 0.1 ng/mL and 10 ng/mL), but not against IFN-β. Five months later, following four doses of rituximab, circulating autoantibodies levels decreased by about 60%.

These findings suggest that heterozygous FOXN1 variants can impair thymic development in a manner that promotes the selective emergence of neutralizing auto-Abs against type I IFNs, thereby predisposing affected individuals to severe viral infections. Monitoring these auto-Abs may support personalized therapeutic strategies for affected patients.