Impact of environment and genetics on the pathogenesis of non-communicable inflammatory skin diseases

Abstract

Chronic non-communicable inflammatory skin diseases (CNISDs), including psoriasis, hidradenitis suppurativa, and autoimmune blistering diseases, represent a major and increasing global health burden. These disorders arise from complex interactions between genetic susceptibility, environmental exposures, and dysregulated immune responses. Although targeted biologic therapies have transformed clinical management, the upstream mechanisms that initiate and sustain chronic cutaneous inflammation remain incompletely understood. This cumulative dissertation aimed to elucidate key determinants of CNISD pathogenesis by integrating epidemiological analysis, genetic discovery, and mechanistic immunological studies. First, a large-scale real-world data analysis using electronic health records from the TriNetX network examined the relationship between obesity and the risk of chronic inflammatory diseases. In a cohort comprising more than three million individuals, obesity was associated with a significantly increased risk for a broad spectrum of inflammatory conditions, including several dermatological diseases. These findings highlight obesity as a systemic and potentially modifiable driver of immune dysregulation and chronic inflammation. Second, a forward genetics approach in a murine model of Aldara-induced psoriasiform dermatitis identified Itga11, encoding integrin α11, as a previously unrecognized genetic modulator of inflammatory skin disease. Functional studies demonstrated that Itga11 deficiency attenuates skin inflammation, reduces immune cell infiltration, and alters extracellular matrix remodeling, implicating fibroblast-mediated tissue architecture as a critical regulator of immune responses in the skin. Third, the functional role of interferon-γ (IFN-γ) in epidermolysis bullosa acquisita (EBA) was investigated using an antibody-transfer mouse model. Pharmacological inhibition of IFN-γ significantly reduced disease severity and neutrophil recruitment, demonstrating that IFN-γ promotes autoantibody-mediated cutaneous inflammation. Together, these studies demonstrate that CNISDs are driven by the interplay of systemic metabolic factors, genetic modifiers, and local immune mechanisms. By combining population-scale analyses with experimental models, this work provides new insights into disease pathogenesis and identifies potential avenues for therapeutic intervention targeting metabolic, stromal, and immunological pathways.