Distinct natural killer cell signature in still's disease: Insights from a multinational immunome project consortium for autoinflammatory disorders

Abstract

Objective Still's disease (SD) is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. While natural killer (NK) cells have been implicated in SD pathogenesis, their precise role remains elusive. Methods Within the framework of the ImmunAID consortium, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 SD, 23 chronic recurrent multifocal osteomyelitis, 23 Familial Mediterranean fever, and 22 inflammation of unknown origin) and 32 healthy controls. Results Our analysis revealed a unique NK cell signature in SD, characterized by a reduction in NK cell frequency and elevated Fas expression, rendering them more susceptible to in vitro Fas ligand‐induced apoptosis. Fas ligand was expressed by SD monocytes and CD38 + HLA‐DR + cycling lymphocytes. SD NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile normalized during clinical remission. Exposure of healthy NK cells to IL‐12, IL‐15 and IL‐18 recapitulates the SD‐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 immunological features of SD, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in SD and highlights inflammatory cytokines and miR‐146a as promising therapeutic targets to mitigate disease severity and prevent life‐threatening complications. image

Affiliated Institutions

• KU Leuven BE
• University of Geneva CH
• Pitié-Salpêtrière Hospital FR
• Inserm FR
• Hospices Civils de Lyon FR
• Rega Institute for Medical Research BE
• Sorbonne Université FR
• Erasmus MC NL

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