Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Mendelian susceptibility to mycobacterial diseases (MSMD) causes susceptibility to mycobacteria in healthy individuals.
• Mutations in six genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1, NEMO) have been identified, leading to at least 13 distinct disorders.
• These genetically diverse conditions share a common immunological defect: impaired IL-12/23-IFN-gamma-mediated immunity.

Purpose of the Study:

• To review the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-gamma circuit.
• To consolidate current knowledge on Mendelian susceptibility to mycobacterial diseases.
• To highlight the expanding global diagnosis of these rare genetic immune deficiencies.

Main Methods:

• Literature review of genetic mutations and associated clinical phenotypes.
• Analysis of immunological pathways, specifically the IL-12/23-IFN-gamma axis.
• Compilation of patient data from global case reports and registries.

Main Results:

• Identification of disease-causing mutations in six genes, resulting in at least 13 MSMD disorders.
• Demonstration of a shared immunological defect in IL-12/23-IFN-gamma pathway function across these disorders.
• Diagnosis of MSMD in over 220 patients across 43 countries, indicating it is less rare than previously thought.

Conclusions:

• Inborn errors of the IL-12/23-IFN-gamma circuit represent a spectrum of Mendelian susceptibility to mycobacterial diseases.
• Understanding the molecular and cellular basis of these disorders is crucial for diagnosis and management.
• Global collaboration and awareness are increasing the identification of patients with these genetic immune deficiencies.