Innate Lymphoid Cell Phenotypic and Functional Alterations in Patients With Systemic Juvenile Idiopathic Arthritis

Area of Science:

• Immunology
• Pediatric Rheumatology

Background:

• Systemic juvenile idiopathic arthritis (sJIA) is a chronic childhood autoinflammatory disease.
• Innate immune cell dysregulation is a hallmark of sJIA.
• The role of innate lymphoid cells (ILCs) in sJIA during clinically inactive disease (CID) remains unclear.

Purpose of the Study:

• To investigate the phenotypic and functional characteristics of ILCs, including natural killer (NK) cells and helper-ILCs (hILCs), in children with sJIA during CID.
• To explore the association between ILCs and cytokine profiles, particularly Interleukin-18 (IL-18), in sJIA.

Main Methods:

• Flow cytometry analysis of peripheral blood ILCs from sJIA patients in CID (n=40) on IL-1 inhibitors, compared to healthy children (HC, n=23) and patients with other autoinflammatory diseases.
• Plasma proteomic profiling to assess cytokine levels.
• Functional assays to evaluate NK cell and hILC cytokine production (IFN-γ, IL-13).

Main Results:

• sJIA patients in CID exhibited reduced NK cell frequencies with a higher proportion of CD56^bright NK cells compared to HC.
• Increased ILC1s and reduced ILC precursors (ILCPs) were observed in sJIA patients.
• Impaired IFN-γ production by NK cells and hILCs was noted, inversely correlated with elevated plasma IL-18 levels and potentially linked to reduced IL-18 receptor α (IL-18RA) expression on ILC1s.

Conclusions:

• Children with sJIA in CID display significant innate immune abnormalities, including altered ILC subset distribution and impaired IFN-γ production.
• These immune alterations are strongly associated with elevated IL-18 levels, suggesting ongoing immune dysregulation.
• ILCs and their interaction with cytokines like IL-18 may play a crucial role in sJIA pathogenesis even during clinical remission.