Deciphering Central Nervous System Autoimmunity in Down Syndrome

Down syndrome (DS), caused by the triplication of chromosome 21, is associated with an increased prevalence of autoimmune diseases and neurological dysfunction, potentially driven by chronic inflammation resulting from the overexpression of four interferon receptors (IFNRs). Human chromosome 21 carries four of the six IFNR genes, and their triplication in DS results in significant immune dysregulation and chronic inflammation, characterized by elevated levels of various pro-inflammatory cytokines. This persistent systemic inflammation leads to an autoimmune-prone state, with over 60% of adults with DS experiencing one or more autoimmune diseases. Systemic inflammation and increased cytokine levels may also compromise the integrity of central nervous system (CNS) tight junctions (TJs) — essential structures that form seals between cells in the brain’s protective barriers, preventing harmful substances and immune cells from infiltrating the brain. When these TJs are disrupted, autoantibodies and immune cells can penetrate the CNS, contributing to neurological phenotypes. Despite substantial evidence of CNS TJ dysfunction in DS, including significant correlations between peripheral autoantibodies and neurological phenotypes, as well as elevated levels of a TJ-degrading protein, this critical aspect of neurological health remains underexplored in individuals with DS. This study seeks to uncover the mechanisms by which IFNR triplication induces CNS autoimmunity in DS through a cross-species investigation. By utilizing human samples and mouse models, this project will examine how IFNR triplication contributes to an autoimmune-prone state, CNS TJ dysfunction, and ultimately, CNS autoimmunity. In Aim 1, autoimmune processes affecting the CNS in DS will be identified. Aim 2 will complete a cross-species investigation of CNS TJ integrity in DS. Finally, in Aim 3, mechanisms of CNS autoimmunity will be investigated using a mouse model of DS. The overall hypothesis of this proposal is that systemic inflammation caused by IFNR triplication in DS leads to an autoimmune-prone state and CNS tight junction dysfunction, ultimately resulting in CNS autoimmunity. By elucidating these mechanisms, this study aims to guide therapeutic strategies that stabilize CNS barriers, mitigate immune cell infiltration, and improve neurological outcomes for individuals with DS. Additionally, this research has broader implications, as it sheds light on CNS TJ dysfunction and the effects of dysregulated inflammatory pathways, offering valuable insights into other inflammatory and autoimmune-driven neurological conditions beyond DS. Project Number: 1F31AI194862-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Cristina Lau | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $37,336 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F01A-S (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19486201