Lewis Y (Ley) orchestrates leukocyte trafficking and inflammatory remodeling in leprosy patients from the Brazilian Amazon

Leprosy is characterized by a complex inflammatory microenvironment in which host-related factors play a decisive role in disease progression. However, the contribution of tissue glycans to inflammatory remodeling remains poorly understood. In this study, we investigated the expression of Lewis blood group antigens in skin biopsies from patients with different clinical forms of leprosy in the Brazilian Amazon, a region marked by persistent hyperendemic transmission. Using immunohistochemistry, we demonstrate that the difucosylated epitope Lewis Y (Le^y) is preferentially expressed in inflamed lesions, particularly in endothelial cells, histiocytes, lymphocytes, and neural structures, while being absent in healthy skin. Quantitative and spatial analyses revealed that Le^y displays the broadest and most intense expression pattern among the investigated Lewis antigens, whereas Lewis X (Le^x) and sialyl-Lewis x (sLe^x) exhibited restricted, tissue-dependent expression profiles. Statistical analyses showed that Le^y expression varies significantly according to the clinical spectrum of leprosy, while Lewis X and sialyl-Lewis X are primarily dependent on tissue compartment rather than clinical classification. Mechanistically, our findings support a model in which endothelial Le^y functions as a central glycan regulator of the inflammatory microenvironment, promoting leukocyte recruitment, endothelial activation, angiogenesis, and immune–vascular interactions. We propose a Le^y-driven glyco-immune axis, involving DC-SIGN–mediated interactions with dendritic cells and macrophages, as a unifying mechanism linking glycan remodeling, immune cell trafficking, vascular remodeling, and tissue reorganization in leprosy lesions. Together, these results identify Le^y as a tissue-specific glycan signature of inflammatory remodeling and highlight glycan remodeling as a previously underexplored organizing principle in leprosy immunopathology, with translational implications for biomarker discovery, risk stratification, and therapeutic targeting in endemic settings.