Human IFNAR2 deficiency: Lessons for antiviral immunity.

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Type I interferons (IFN-α/β) are crucial for antiviral defense.
• Mouse models inform our understanding, but human validation is limited.

Observation:

• A previously healthy child developed fatal encephalitis post-measles, mumps, and rubella (MMR) vaccination.
• Genetic analysis revealed a homozygous mutation in the IFN-α/β receptor (IFNAR2) gene in the child and sibling.

Findings:

• The IFNAR2 mutation rendered the patient's cells unresponsive to IFN-α/β.
• Restoring wild-type IFNAR2 in cells re-established IFN-α/β responsiveness and viral control.
• The patient showed no prior susceptibility to common respiratory viruses.

Implications:

• This IFNAR2 deficiency highlights a narrow but essential role for IFN-α/β in human antiviral immunity.
• Findings align with STAT2-deficient patient phenotypes, reinforcing IFNAR2's importance.
• Understanding genetic defects in interferon pathways is vital for managing vaccine responses and infectious diseases.