Type I interferon-mediated autoinflammation due to DNase II deficiency

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Microbial nucleic acid recognition is crucial for antiviral responses.
• Misinterpreting self nucleic acids can trigger autoinflammation.
• Interferon-stimulated genes are key regulators of innate immunity.

Observation:

• Two families presented with severe neonatal anemia, glomerulonephritis, liver fibrosis, arthropathy, and anti-DNA antibodies.
• Systematic screening identified biallelic mutations in DNASE2, leading to loss of DNase II endonuclease activity.
• Patients exhibited elevated interferon-alpha protein levels and enhanced interferon signaling.

Findings:

• Mutations in DNASE2 cause a loss of DNase II activity.
• Increased interferon signaling (STAT1/STAT3 phosphorylation) was observed in patient immune cells.
• A distinct hematological disease transcriptomic signature and increased erythroblasts suggest interferon's impact on hematopoiesis.

Implications:

• This study defines a novel human type I interferonopathy linked to DNase II deficiency.
• Understanding DNase II's role is critical for managing autoimmune and inflammatory diseases.
• This discovery opens avenues for targeted therapies for interferonopathies.