A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease
Tom Thomas, Matthias Friedrich, Charlotte Rich‐Griffin, Mathilde Pohin, Devika Agarwal, Julia Pakpoor, Carl Lee, Ruchi Tandon, Aniko Rendek, Dominik Aschenbrenner, Ashwin Jainarayanan, Alexandru-Ioan Voda, Jacqueline H. Y. Siu, Raphael Sanches Peres, Eloise Nee, Dharshan Sathananthan, Dylan Kotliar, Peter Todd, Maria Kiourlappou, Lisa Gartner, Nicholas E. Ilott, Fadi Issa, Joanna Hester, Jason D. Turner, Saba Nayar, Jonas Mackerodt, Fan Zhang, Anna Jonsson, Michael B. Brenner, Soumya Raychaudhuri, Ruth Kulicke, Danielle Ramsdell, Nicolas Stransky, Ray Pagliarini, Piotr Bielecki, Noah Spies, Brian D. Marsden, Stephen Taylor, Allon Wagner, Paul Klenerman, Alissa Walsh, Mark Coles, Luke Jostins-Dean, Fiona Powrie, Andrew Filer, Simon Travis, Holm H. Uhlig, Calliope A. Dendrou, Christopher D. Buckley
Abstract
Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.