Immune Dysregulation in Down Syndrome: Implications for Infectious Susceptibility and Vaccine Response

Down syndrome (DS), caused by trisomy 21, is characterized by complex immune dysregulation that increases susceptibility to infections and alters vaccine responsiveness. Gene dosage effects involving interferon receptor loci on chromosome 21 contribute to chronic type I interferon hyperactivation, sustained JAK-STAT signaling, and persistent expression of interferon-stimulated genes. This baseline inflammatory state is accompanied by quantitative and functional defects in both innate and adaptive immunity, including impaired neutrophil chemotaxis, pro-inflammatory monocyte polarization, reduced naïve T- and B-cell compartments, restricted antigen receptor diversity, diminished class-switched memory B cells, and features of accelerated immunosenescence. Clinically, these immune alterations are associated with an increased risk of severe respiratory viral infections, such as respiratory syncytial virus, influenza, and SARS-CoV-2, as well as reduced magnitude and durability of vaccine-induced immunity. Cohort studies in both pediatric and adult populations have reported higher rates of hospitalization and mortality, along with lower peak antibody titers and more rapid waning of immunity following vaccination. This review integrates molecular, cellular, and clinical evidence to define the interferon-driven immune phenotype in DS and its implications for susceptibility to infection and vaccination response. A mechanistic understanding of this immune landscape provides a framework for developing tailored preventive strategies and optimizing vaccination approaches in this vulnerable population.