From Interferon Signature to the Clinical Landscape: Type I Interferonopathies

Background

Type I interferonopathies are heterogeneous diseases driven by dysregulated IFN‐I signaling. Diagnosis is challenging due to clinical/molecular variability and the need for IFN‐I quantification.

Objective

To characterize the clinical, immunological, genetic, molecular profiles of patients with suspected enhanced IFN‐I signaling, and assess diagnostic utility of IFN signature, CXCL10 levels, antiviral activity.

Methods

Forty‐six patients with clinical or genetic findings consistent with type I interferonopathies were included. The IFN signature, CXCL9 and IFNG were assessed using RT‐qPCR (n=34 each). Serum CXCL10 and CXCL9 were measured by ELISA (n=37 each). WES was performed for molecular diagnosis (n=46). Antiviral activity was evaluated using rVSV‐GFP (n=5).

Results

Two groups were defined: genetically confirmed and undifferentiated interferonopathies. Molecular diagnosis was established in 37/46 (80%) of the patients. IFN signature was evaluable in 34/46 and positive in 31/34 (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.

Conclusion

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 interferon 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.

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