Context-dependent regulation of epithelial and innate immune responses in inflammatory disease

Abstract

Innate immune responses are essential for host defense and tissue homeostasis, but they are shaped by tissue environment, prior inflammatory exposure, cellular composition, and pathway-specific signaling. This thesis investigates how these contextual factors regulate epithelial and innate immune function across inflammatory disease, autoimmunity, infection, and aging, asking whether immune dysfunction is selective rather than global across these settings. In ulcerative colitis, I identify anti-αvβ6 autoantibodies as functional inhibitors of epithelial αvβ6-dependent TGFβ activation that alter mucosal homeostasis and increase susceptibility to colitis. Motivated by the recurrent type I interferon exposure characteristic of systemic lupus erythematosus, I show that IFN-I can induce trained immunity-like, pathway-biased reprogramming of human monocyte-derived macrophages. Building on this concept, I demonstrate that severe COVID-19 is associated with a specific defect in IRF3-dependent interferon induction, impairing responses to poly-IC and LPS while sparing TLR7/8-dependent responses, despite preserved inflammatory cytokine production. In healthy aging, I identify a subset of older individuals with a stable, TLR3-selective defect in poly-IC-induced interferon responses that converges on this same signaling axis but is more narrowly restricted and dependent on whole-blood context. Together, these studies show that innate immune dysfunction is not uniform but instead reflects context-dependent, pathway-specific changes, providing a unifying framework for understanding inflammatory disease susceptibility and immune heterogeneity.