Pediatric bronchiolitis disease severity is associated with immune checkpoint dysregulation

Abstract

Background: Immune dysregulation plays a pivotal role in the pathogenesis of bronchiolitis. This study aimed to investigate the role of immune checkpoint molecules and regulatory cytokines in relation to disease severity. Methods: A prospective cohort of 151 pediatric patients aged 1 month to 2 years was enrolled and classified into control, mild, moderate, and severe bronchiolitis groups. Immune checkpoint molecules (CTLA-4, TIM-3, TIGIT, GARP) and cytokines (IL-2Rα, 4-1BB, TGF-β1, LAG-3, galectin-9) were evaluated in CD4 + FOXP3+ (Treg) and CD4 + FOXP3−T cells, and in plasma using flow cytometry and ELISA. Results: CD4+ T cell levels decreased with increasing disease severity. Treg frequencies were elevated in mild cases but decreased in moderate and severe cases. CTLA-4 and TIM-3 expression increased on both Treg and non-Treg CD4+ T cells in moderate and severe groups. Soluble PD-1, TIM-3, LAG-3, TGF-β1, and 4-1BB levels were significantly elevated in severe bronchiolitis. Conclusion: Disease severity in bronchiolitis is associated with immune checkpoint dysregulation and an immunosuppressive environment. The observed alterations in T cell subsets and increased expression of CTLA-4 and TIM-3 highlight the potential of these molecules as biomarkers of disease progression. Impact: This study demonstrates that the severity of pediatric bronchiolitis is associated with the dysregulation of immune checkpoint molecules. It adds novel insight into the immunopathogenesis of bronchiolitis by focusing on early immune biomarkers beyond conventional inflammatory parameters. These findings may support risk stratification and contribute to the development of targeted therapies in future pediatric bronchiolitis management.