Longitudinal Dynamics of NK-Cell Regulatory Signaling and IVIG Response in Kawasaki Disease

Background and Objectives: Kawasaki disease (KD) is an acute systemic vasculitis in children, and approximately 10-20% of patients develop resistance to intravenous immunoglobulin (IVIG), which is associated with an increased risk of coronary artery complications. Natural killer (NK) cells play an important role in innate immune regulation, but the temporal dynamics of NK-cell regulatory receptors during KD and their relationship with IVIG response remain unclear. Materials and Methods: In this prospective observational study, we performed longitudinal immunophenotyping in children with KD treated at a tertiary referral center. Peripheral blood samples were obtained before IVIG administration (D0) and at three follow-up timepoints after treatment (D2, D14, and D56). NK-cell subsets and receptor expression-including the activating receptor NKG2D and inhibitory receptor NKG2A-were analyzed using multiparameter flow cytometry. Associations with IVIG response were evaluated using Firth penalized logistic regression for baseline predictors and linear mixed-effects models to assess longitudinal immune trajectories. Results: A total of 69 patients with KD were included, of whom 17 (24.6%) were classified as IVIG resistant. Baseline NK-cell subsets and receptor expression did not differ significantly between IVIG-sensitive and IVIG-resistant patients, although the NKG2D/NKG2A ratio tended to be lower in resistant patients (median 2.51 vs. 3.34, p = 0.054). Longitudinal mixed-effects analysis demonstrated significant temporal changes in NK-cell regulatory signaling following IVIG therapy. Both NKG2A (P(time) = 0.019) and NKG2D (P(time) < 0.001) expression showed significant time effects across the disease course. Importantly, the NKG2D/NKG2A ratio demonstrated a significant time-by-group interaction (P(interaction) = 0.030), indicating divergent trajectories of activating and inhibitory NK-cell signaling according to IVIG response. At the convalescent phase (D56), IVIG-resistant patients showed significantly higher NKG2A expression (p = 0.038) and a lower NKG2D/NKG2A ratio (p = 0.023) than IVIG-sensitive patients. Conclusions: While baseline NK-cell immunophenotypes were not associated with IVIG response, longitudinal analysis revealed that IVIG-resistant patients exhibited a distinct immune trajectory, characterized by increased NKG2A expression and a lower NKG2D/NKG2A ratio during the convalescent phase. These findings suggest that differences in IVIG responsiveness may be related to alterations in immune regulatory processes during the resolution phase of inflammation. However, the clinical implications of these findings remain to be established and require validation in larger, multicenter studies with longitudinal outcome data.