Work

Distinct Natural Killer Cell Signature in Still Disease: Insights From a Multinational Immunome Project Consortium for Autoinflammatory Disorders

Year: 2025

Type: article

Abstract: OBJECTIVE: Still disease is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. Although natural killer (NK) cells have been implicated in Still disease pathogenesis, their precise role remains elusive. METHODS: Within the framework of the Immunome Project Consortium for Autoinflammatory Disorders, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 with Still disease, 23 with chronic recurrent multifocal osteomyelitis, 23 with familial Mediterranean fever, and 22 with inflammation of unknown origin) and 32 healthy controls. RESULTS: cycling lymphocytes. Still disease NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile was normalized during clinical remission. Exposure of healthy NK cells to interleukin (IL)-12, IL-15, and IL-18 recapitulates the Still disease-associated phenotype, suggesting an inflammation-driven mechanism. Transcriptomic profiling identified microRNA miR-146a as a potential regulator of this NK cell dysfunction. CONCLUSION: Our findings establish NK cell apoptosis, exhaustion, and cytokine unresponsiveness as defining immunologic features of Still disease, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in Still disease and highlights inflammatory cytokines and miR-146a as promising therapeutic targets to mitigate disease severity and prevent life-threatening complications.

Source: Arthritis & Rheumatology

DOI: 10.1002/art.70008