Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Area of Science:

• Immunology
• Genetics
• Rheumatology

Background:

• Undifferentiated systemic autoinflammatory diseases (USAIDs) pose diagnostic and therapeutic challenges.
• Chronic interferon (IFN) signaling and cytokine dysregulation may indicate treatable conditions.

Purpose of the Study:

• To screen USAID patients for an interferon signature (IRG-S) and identify associated clinical features and genetic underpinnings.
• To expand diagnostic capabilities for USAIDs through molecular and genetic profiling.

Main Methods:

• Sixty-six USAID patients were evaluated using a type-I IFN-response-gene score (IRG-S), cytokine profiling, and next-generation sequencing.
• Clinical features and genetic mutations were correlated with IRG-S levels.

Main Results:

• 55% of patients exhibited an elevated IRG-S, associated with increased prevalence of neutrophilic panniculitis, basal ganglia calcifications, interstitial lung disease, and myositis.
• Identified novel autoinflammatory disease subtypes: IL-18-mediated pulmonary alveolar proteinosis and recurrent macrophage activation syndrome (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD).
• Discovered mutations in LRBA, IKBKG, and SAMD9L, suggesting distinct NF-κB activation pathways in some patients.

Conclusions:

• Elevated IRG-S is a valuable biomarker in USAIDs, aiding in diagnosis and identifying distinct disease entities.
• The IRG-S expands the diagnostic toolkit for USAIDs, pointing to diverse regulatory pathways of interferon response.
• This research facilitates the identification of patients eligible for targeted treatments based on their molecular and clinical profiles.