Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. Here we introduce MANTIS (Multiplexed Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically designed for spatially-resolved immune phenotyping of the skin in experimental or clinical samples. Based on phenotype attribution matrices coupled to alpha-shape algorithms, MANTIS projects a representative digital immune landscape, while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome, or COVID-19-associated skin manifestations share common quantitative immune features, while displaying a non-random distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.