Monogenic autoinflammatory diseases: Cytokinopathies.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Monogenic autoinflammatory diseases are increasingly understood through genetic mutations affecting innate immune system function.
• Cytokine antagonism, particularly targeting interleukin-1 (IL-1), is effective for inflammasomopathies caused by mutations in sensors (e.g., NLRP3) or signaling molecules (e.g., IL-1Ra).
• Interferonopathies result from mutations in interferon (IFN) pathway components, including sensors (e.g., STING, MDA5) and signaling regulators (e.g., ISG15).

Purpose of the Study:

• To propose an extended nosology for autoinflammatory diseases based on cytokine pathway involvement.
• To identify potential autoinflammatory disease candidates associated with IL-36 and IL-10 pathways.
• To introduce the term 'Relopathies' for diseases involving NF-κB/Rel activation.

Main Methods:

• Review and analysis of genetic mutations causing monogenic autoinflammatory diseases.
• Classification of diseases based on affected cytokine pathways and their components (sensors, signaling molecules, inhibitors).
• Comparative analysis of known and potential cytokine pathway involvement in autoinflammation.

Main Results:

• Identified mutations in IL-1 and IFN pathways leading to inflammasomopathies and interferonopathies, respectively.
• Proposed extension of this framework to IL-36 and IL-10 pathways, despite current lack of sensor/upstream mutation data.
• Suggested 'Relopathies' for autoinflammatory conditions driven by NF-κB/Rel activation.

Conclusions:

• The proposed nosology provides insight into likely autoinflammatory disease candidates.
• Newly identified mutations can be associated with specific cytokine pathways for targeted therapies.
• Understanding cytokine involvement is crucial for diagnosing and treating a spectrum of autoinflammatory disorders.