Neutralizing autoantibodies against IFN-α2 and IFN-ω in a boy with a heterozygous variant in the FOXN1 gene
Abstract
Background: 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.
Methods: 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.
Results: 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%.
Conclutions: These findings suggest that heterozygous FOXN1 variants can impair thymic development in…
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Evidence Hub reads this as a case report, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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