From Interferon Signature to the Clinical Landscape: Type I Interferonopathies

TypeI interferonopathies are heterogeneous diseases driven by dysregulated type I interferon (IFN-I) signaling. Diagnosis is challenging due to clinical/molecular variability and the need for IFN-I quantification. The aim of this study was to characterize the clinical, immunologic, genetic, molecular profiles of patients with suspected enhanced IFN-I signaling and assess diagnostic utility of IFN signature, CXCL10 levels, and antiviral activity.

A total of 46 patients with clinical or genetic findings consistent with type I interferonopathies were included. The IFN signature, CXCL9, and IFNG were assessed using quantitative reverse transcription polymerase chain reaction (n = 34 each). Serum CXCL10 and CXCL9 were measured by enzyme-linked immunosorbent assay (n = 37 each). Whole exome sequencing was performed for molecular diagnosis (n = 46). Antiviral activity was evaluated using recombinant vesicular stomatitis virus expressing green fluorescent protein (n = 5).

Two groups were defined: genetically confirmed and undifferentiated interferonopathies. Molecular diagnosis was established in 37 of 46 of the patients (80%). IFN signature was evaluable in 34 of 46 patients and positive in 31 of 34 (91%); median IFN score was higher in patients (P < 0.0001). CXCL10 levels were higher in patients and correlated with IFN scores (r_s = 0.4994, P = 0.0026). Both IFN score and CXCL10 showed strong discriminative capacity. Autoantibodies were detected in 67%. Antiviral activity varied across phenotype.

Our findings highlight the clinical and molecular diversity of interferonopathies and underscore the possible diagnostic utility of CXCL10 levels. We define a group of patients with consistent clinical features and clear IFN signatures as undifferentiated interferonopathies. Variable antiviral responses indicate differential IFN pathway modulation. These results support the integration of molecular and functional IFN profiling into the diagnostic workup and monitoring of suspected interferonopathies, which may aid in precision medicine.