Nat Immunol. 2024 Nov;25(11):2152-2165. doi: 10.1038/s41590-024-01994-8.Epub 2024 Oct 22.

Tom Thomas ^1 2 3, Matthias Friedrich ^# 1 3, Charlotte Rich-Griffin ^# 2, Mathilde Pohin ^# 1, Devika Agarwal ^# 1, Julia Pakpoor ^1 2 3, Carl Lee ¹, Ruchi Tandon ⁴, Aniko Rendek ⁵, Dominik Aschenbrenner ³, Ashwin Jainarayanan ¹, Alexandru Voda ¹, Jacqueline H Y Siu ¹, Raphael Sanches-Peres ¹, Eloise Nee ¹, Dharshan Sathananthan ^6 7, Dylan Kotliar ^8 9, Peter Todd ², Maria Kiourlappou ², Lisa Gartner ³, Nicholas Ilott ¹, Fadi Issa ¹⁰, Joanna Hester ¹⁰, Jason Turner ¹¹, Saba Nayar ^11 12 13, Jonas Mackerodt ¹, Fan Zhang ^8 9 14, Anna Jonsson ^8 9, Michael Brenner ^8 9, Soumya Raychaudhuri ^8 9, Ruth Kulicke ¹⁵, Danielle Ramsdell ¹⁵, Nicolas Stransky ¹⁵, Ray Pagliarini ¹⁵, Piotr Bielecki ¹⁵, Noah Spies ¹⁵, Brian Marsden ², Stephen Taylor ², Allon Wagner ^16 17, Paul Klenerman ³, Alissa Walsh ³, Mark Coles ¹, Luke Jostins-Dean ¹, Fiona M Powrie ¹, Andrew Filer ^11 12 13, Simon Travis ^18 19 20, Holm H Uhlig ^21 22 23, Calliope A Dendrou ^24 25 26, Christopher D Buckley ^{27 28 29 30}

Author information

¹Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

²Centre for Human Genetics, University of Oxford, Oxford, UK.

³Translational Gastroenterology & Liver Unit, John Radcliffe Hospital, Headington, Oxford, UK.

⁴University College London Hospitals NHS Foundation Trust, London, UK.

⁵Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

⁶University of Adelaide, Adelaide, Australia.

⁷Lyell McEwin Hospital, Adelaide, Australia.

⁸Broad Institute of MIT and Harvard, Cambridge, MA, USA.

⁹Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

¹⁰Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

¹¹Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

¹²National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and NIHR Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

¹³Birmingham Tissue Analytics, Institute of Translational Medicine, University of Birmingham, Birmingham, UK.

¹⁴Center for Health AI, University of Colorado Anschutz, Anschutz, CO, USA.

¹⁵Celsius Therapeutics, Cambridge, MA, USA.

¹⁶Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA, USA.

¹⁷The Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.

¹⁸Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. simon.travis@kennedy.ox.ac.uk.

¹⁹Translational Gastroenterology & Liver Unit, John Radcliffe Hospital, Headington, Oxford, UK. simon.travis@kennedy.ox.ac.uk.

²⁰NIHR Oxford Biomedical Research Centre, Oxford, UK. simon.travis@kennedy.ox.ac.uk.

²¹Translational Gastroenterology & Liver Unit, John Radcliffe Hospital, Headington, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

²²NIHR Oxford Biomedical Research Centre, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

²³Department of Paediatrics, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

²⁴Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. calliope.dendrou@kennedy.ox.ac.uk.

²⁵Centre for Human Genetics, University of Oxford, Oxford, UK. calliope.dendrou@kennedy.ox.ac.uk.

²⁶NIHR Oxford Biomedical Research Centre, Oxford, UK. calliope.dendrou@kennedy.ox.ac.uk.

²⁷Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. christopher.buckley@kennedy.ox.ac.uk.

²⁸Translational Gastroenterology & Liver Unit, John Radcliffe Hospital, Headington, Oxford, UK. christopher.buckley@kennedy.ox.ac.uk.

²⁹Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. christopher.buckley@kennedy.ox.ac.uk.

³⁰NIHR Oxford Biomedical Research Centre, Oxford, UK. christopher.buckley@kennedy.ox.ac.uk.

^#Contributed equally.

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.