P29 Hidden immune memory niches in inflammatory skin diseases
Lloyd Steele, April Foster, Kenny Roberts, Chloe Admane, Sebastian Birk, Pavel Mazin, Amir Akbarnejad, Katy Tudor, Benjamin Rumney, Hon Man Chan, Bayanne Olabi, Treasa Jiang, Victoria Rowe, David Baudry, Christine Hale, Elena Winheim, Elias Farr, Joe McWilliam, Laura Gambardella, Keerthi Priya Chakala, Nusayhah Gopee, Amirhossein Vahidi, Edel A O’Toole, Daniela Basurto-Lozada, David Horsfall, Emily Stephenson, Vijaya Baskar Mahalingam Shanmugiah, Catherine Smith, Satveer Mahil, Mohammad Lotfollahi, Muzlifah HaniffaAbstract
Introduction and aims
Disease-associated histopathological features are widely used to identify tissue microenvironments or niches for diagnostics and treatment response in clinical practice. However, despite its widespread use, histopathology does not reveal the full cellular and molecular composition of known pathological niches. Furthermore, the existence of pathological niches that may not be histologically discernible remains unknown.
Methods
In this study, we generated a spatially resolved multimodal molecular atlas of ∼5 million human skin cells (including 113 skin sections profiled using Xenium-5k) and applied deep learning to unbiasedly decode 26 skin niches in health and disease.
Results
Several disease-associated niches corresponded to known histopathological features, and we defined their cellular and molecular features, colocalizations and interactions. Additionally, we discovered an immunologically active role for skin appendageal structures in disease mechanisms, potentially contributing to inflammatory memory, that was not identifiable using standard histopathological analysis. These include a resident memory T-cell-rich niche in the sebaceous gland and a plasma cell-rich niche in the sweat gland, analogous to the gland-associated immune niche in lung. Finally, we illustrate how our atlas can be used to generate high-resolution representations using transfer learning, resolving rare T-cell and sebocyte subsets not possible in the original studies, validating niche identification, and the spatial enrichment of candidate genes linked to disease-associated genetic variants.
Conclusions
Overall, our study links histopathology and atlas-scale genomics to reveal novel insights into inflammatory disease pathogenesis, chronicity and potentially curative therapeutic avenues, using skin as an exemplar tissue for this approach.