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

Systemic juvenile idiopathic arthritis (sJIA) is a chronic childhood disease classically attributed to innate immune cell dysregulation. This study aimed to elucidate the role of innate lymphoid cells (ILCs), including natural killer (NK) cells and helper-ILCs (hILCs), in sJIA during clinically inactive disease (CID) through phenotypic and functional analysis.

Peripheral ILCs from children with sJIA during CID receiving interleukin-1 (IL-1) inhibitors (n = 40) were analyzed by flow cytometry and compared to 23 healthy children (HC) and 22 patients with unrelated autoinflammatory diseases taking IL-1 inhibitors. Plasma proteomic profiling was also performed.

Patients with sJIA showed a significant reduction in circulating NK cell frequencies compared to HC, with an increased proportion of CD56^bright NK cells. Although overall hILC frequencies were comparable to HC, ILC1s were increased, whereas ILC precursors were reduced. ILC1 frequency correlated positively with IL-18 plasma levels, whereas ILC2 frequency correlated negatively. Functional assessments revealed that NK cells from patients with sJIA had variable interferon γ (IFNγ) production upon IL-18/IL-12 stimulation, inversely correlating with IL-18 levels. Additionally, hILCs from these patients showed a specific impairment in IFNγ production despite normal IL-13 production, potentially linked to decreased IL-18 receptor α expression in ILC1s. Proteomic analysis confirmed IL-18 as the most up-regulated cytokine in sJIA plasma.

Patients with sJIA in CID exhibit significant innate immune abnormalities, including altered ILC subset distribution and impaired IFNγ production, strongly associated with IL-18 levels. These findings suggest ongoing immune dysregulation despite clinical remission, underscoring a potential role for ILCs and cytokine interaction in sJIA pathogenesis.