From Interferon Signature to the Clinical Landscape: Type I Interferonopathies

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Type I interferonopathies (IFN-I) are complex genetic disorders characterized by dysregulated IFN-I signaling.
• Diagnosis is challenging due to significant clinical and molecular variability, necessitating reliable IFN-I quantification methods.

Purpose of the Study:

• To comprehensively characterize the clinical, immunological, genetic, and molecular profiles of patients with suspected enhanced IFN-I signaling.
• To evaluate the diagnostic utility of interferon (IFN) signature, CXCL10 levels, and antiviral activity assays.

Main Methods:

• Whole exome sequencing (WES) for molecular diagnosis in 46 patients.
• RT-qPCR to assess IFN signature, CXCL9, and IFNG expression.
• ELISA to measure serum CXCL10 and CXCL9 levels.
• Functional antiviral activity assays were performed in a subset of patients.

Main Results:

• Molecular diagnosis was achieved in 80% of patients, identifying genetically confirmed and undifferentiated interferonopathies.
• A significant elevation in IFN signature and serum CXCL10 levels was observed in patients, with strong correlation between them.
• IFN signature and CXCL10 demonstrated high diagnostic discriminative capacity; 67% of patients had autoantibodies.

Conclusions:

• The study highlights the heterogeneity of interferonopathies and the diagnostic potential of serum CXCL10 levels.
• A distinct group of undifferentiated interferonopathies with clear IFN signatures was defined.
• Integrating molecular and functional IFN profiling is crucial for accurate diagnosis, monitoring, and advancing precision medicine in interferonopathies.