NK cell dysfunction and interferon-γ production underlie autoinflammation in mevalonate kinase deficiency

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Prenylopathies, like mevalonate kinase deficiency (MKD), are monogenic autoinflammatory diseases linked to defects in isoprenoid lipid synthesis and protein prenylation.
• The precise mechanisms connecting impaired protein prenylation to systemic inflammation are not fully understood.

Purpose of the Study:

• To investigate the immunological consequences of MKD, focusing on natural killer (NK) cell function and interferon-gamma (IFN-γ) production.
• To explore the therapeutic potential of Janus kinase (JAK) inhibitors in managing severe MKD.

Main Methods:

• Comparative analysis of NK cell frequency, cytotoxic activity, and cytokine profiles in MKD models (mice) and human patients.
• Assessment of MCMV infection clearance and inflammatory pathology in MKD mice.
• Clinical observation of an infant with severe MKD treated with a JAK inhibitor.

Main Results:

• MKD was associated with reduced mature NK cell frequency, impaired cytolytic granule trafficking, and diminished cytotoxic activity.
• MKD patients and mice exhibited increased IFN-γ production and elevated inflammatory pathology.
• MKD mice showed impaired clearance of murine cytomegalovirus (MCMV) infections.
• A JAK inhibitor demonstrated beneficial effects in an infant with severe MKD.

Conclusions:

• Dysregulated cytotoxic cells and elevated IFN-γ production play a critical role in the pathogenesis of MKD and potentially other prenylopathies.
• JAK inhibitors represent a promising therapeutic strategy for treating severe MKD due to their ability to block aberrant cytokine signaling.