AUTHOR=van Unen Vincent , Ouboter Laura F. , Li Na , Schreurs Mette , Abdelaal Tamim , Kooy-Winkelaar Yvonne , Beyrend Guillaume , Höllt Thomas , Maljaars P. W. Jeroen , Mearin M. Luisa , Mahfouz Ahmed , Witte Anne M. C. , Clemens Cornelis H. M. , Abraham Sunje , Escher Johanna C. , Lelieveldt Boudewijn P. F. , Pascutti M. Fernanda , van der Meulen – de Jong Andrea E. , Koning Frits TITLE=Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.893803 DOI=10.3389/fimmu.2022.893803 ISSN=1664-3224 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.