Downregulation of cytokine responses and STAT signaling in children with sickle cell disease

Abstract

Abstract Sickle cell disease (SCD) is characterized by chronic inflammation and immune dysfunction, yet the underlying signaling defects and their relationship with cellular and systemic immune profiles remain incompletely understood, particularly across different genotypes (HbSS vs HbSC) in pediatric populations. This study characterized the immune landscape in children with SCD. We conducted a case-control study with 53 children with SCD (HbSS and HbSC genotypes) and 27 healthy children with the HbAA genotype. The phenotypes of T helper cells and the phosphorylation status of their STAT proteins were characterised using flow cytometry. Cytokine levels in systemic circulation were quantified using Sandwich ELISA. Children with the HbSC genotype showed significant reductions in CD4 + Tbet + IFN-γ + (Th1) and CD4 + Foxp3 + IL-10 + (Treg) cell populations compared to healthy controls. SCD patients exhibited low activation of STAT1, STAT2, STAT4, STAT5, and STAT6 pathways, along with decreased circulating levels of IL-1β, IL-6, TNF-α, IFN-γ, and IL-10. In contrast, IL-17A (Th17) and IL-5 (Th2) levels did not differ between groups. In untreated pediatric SCD, we observed STAT downregulation, Th1/Treg deficits, and decreased IL-1β, TNF-α, IL-6, IFN-γ, and IL-10, with preserved Th2/Th17 responses. HbSS and HbSC showed minimal differences, suggesting a shared impairment of the STAT-Th1-IFN-γ axis.