Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease

Vincent van Unen, Laura F. Ouboter, Na Li, Mette Schreurs, Tamim Abdelaal, Yvonne Kooy-Winkelaar, Guillaume Beyrend, Thomas Höllt, P. W.Jeroen Maljaars, M. Luisa Mearin, Ahmed Mahfouz, Anne M.C. Witte, Cornelis H.M. Clemens, Sunje Abraham, Johanna C. Escher, Boudewijn P.F. Lelieveldt, M. Fernanda Pascutti, Andrea E. van der Meulen – de Jong, Frits Koning*

*Corresponding author for this work

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Abstract

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR+CD38+ EM CD4+ T cells, T regulatory-like cells, PD1+ EM CD8+ T cells, neutrophils, CD27+ TCRγδ cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4+ T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4+ T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD.

Original languageEnglish
Article number893803
JournalFrontiers in Immunology
Volume13
DOIs
Publication statusPublished - 23 Jun 2022

Bibliographical note

Funding Information:
This work was supported by the Leiden University Medical Center, the Netherlands Organization for Scientific Research [ZonMW 91112008, Rubicon 452181214 to VU], the Crohn’s & Colitis Foundation of America [grant CCFA Ref. 481437], and the collaboration project TIMID [LSHM18057-SGF] financed by the PPP allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public-private partnerships and co-financing by health foundations that are part of the SGF.

Publisher Copyright:
Copyright © 2022 van Unen, Ouboter, Li, Schreurs, Abdelaal, Kooy-Winkelaar, Beyrend, Höllt, Maljaars, Mearin, Mahfouz, Witte, Clemens, Abraham, Escher, Lelieveldt, Pascutti, van der Meulen – de Jong and Koning.

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