Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology · 2026
Neutralizing autoantibodies against IFN-α2 and IFN-ω in a boy with a heterozygous variant in the FOXN1 gene.
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Gutiérrez-Guerrero Arturo, García-Vargas Daniela, Cortés-Acevedo Paulina, Yamazaki-Nakashimada Marco Antonio, Scheffler-Mendoza Selma Cecilia, Berrón-Ruiz Laura, Blancas-Galicia Lizbeth, Barcenas-Morales Gabriela, Espinosa-Padilla Sara Elva
Аннотация
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 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.
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 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.