Vanessa Mitsialis1, Sarah Wall2, Peng Liu3, Jose Ordovas-Montanes4, Tamar Parmet2, Marko Vukovic5, Dennis Spencer2, Michael Field2, Collin McCourt6, Jessica Toothaker7, Athos Bousvaros2, Alex K Shalek5, Leslie Kean8, Bruce Horwitz2, Jeffrey Goldsmith9, George Tseng3, Scott B Snapper10, Liza Konnikova11. 1. Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts. 2. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts. 3. Department of Biostatistics University of Pittsburgh, Pittsburgh, Pennsylvania. 4. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts. 5. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. 6. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. 7. Harvard Stem Cell Institute, Cambridge, Massachusetts. 8. Division of Hematology Oncology, Boston Children's Hospital, Boston, Massachusetts. 9. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. 10. Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts. Electronic address: scott.snapper@childrens.harvard.edu. 11. Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Developmental Biology University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut. Electronic address: Liza.konnikova@chp.edu.
Abstract
BACKGROUND & AIMS: Studies are needed to determine the mechanisms of mucosal dysregulation in patients with inflammatory bowel diseases (IBDs) and differences in inflammatory responses of patients with ulcerative colitis (UC) vs Crohn's disease (CD). We used mass cytometry (CyTOF) to characterize and compare immune cell populations in the mucosa and blood from patients with IBD and without IBD (controls) at single-cell resolution. METHODS: We performed CyTOF analysis of colonic mucosa samples (n = 87) and peripheral blood mononuclear cells (n = 85) from patients with active or inactive UC or CD and controls. We also performed single-cell RNA sequencing, flow cytometry, and RNA in situ hybridization analyses to validate key findings. We used random forest modeling to identify differences in signatures across subject groups. RESULTS: Compared with controls, colonic mucosa samples from patients with IBD had increased abundances of HLA-DR+CD38+ T cells, including T-regulatory cells that produce inflammatory cytokines; CXCR3+ plasmablasts; and IL1B+ macrophages and monocytes. Colonic mucosa samples from patients with UC were characterized by expansion of IL17A+ CD161+ effector memory T cells and IL17A+ T-regulatory cells; expansion of HLA-DR+CD56+ granulocytes; and reductions in type 3 innate lymphoid cells. Mucosal samples from patients with active CD were characterized by IL1B+HLA-DR+CD38+ T cells, IL1B+TNF+IFNG+ naïve B cells, IL1B+ dendritic cells (DCs), and IL1B+ plasmacytoid DCs. Peripheral blood mononuclear cells from patients with active CD differed from those of active UC in that the peripheral blood mononuclear cells from patients with CD had increased IL1B+ T-regulatory cells, IL1B+ DCs and IL1B+ plasmacytoid DCs, IL1B+ monocytes, and fewer group 1 innate lymphoid cells. Random forest modeling differentiated active UC from active CD in colonic mucosa and blood samples; top discriminating features included many of the cellular populations identified above. CONCLUSIONS: We used single-cell technologies to identify immune cell populations specific to mucosa and blood samples from patients with active or inactive CD and UC and controls. This information might be used to develop therapies that target specific cell populations in patients with different types of IBD.
BACKGROUND & AIMS: Studies are needed to determine the mechanisms of mucosal dysregulation in patients with inflammatory bowel diseases (IBDs) and differences in inflammatory responses of patients with ulcerative colitis (UC) vs Crohn's disease (CD). We used mass cytometry (CyTOF) to characterize and compare immune cell populations in the mucosa and blood from patients with IBD and without IBD (controls) at single-cell resolution. METHODS: We performed CyTOF analysis of colonic mucosa samples (n = 87) and peripheral blood mononuclear cells (n = 85) from patients with active or inactive UC or CD and controls. We also performed single-cell RNA sequencing, flow cytometry, and RNA in situ hybridization analyses to validate key findings. We used random forest modeling to identify differences in signatures across subject groups. RESULTS: Compared with controls, colonic mucosa samples from patients with IBD had increased abundances of HLA-DR+CD38+ T cells, including T-regulatory cells that produce inflammatory cytokines; CXCR3+ plasmablasts; and IL1B+ macrophages and monocytes. Colonic mucosa samples from patients with UC were characterized by expansion of IL17A+ CD161+ effector memory T cells and IL17A+ T-regulatory cells; expansion of HLA-DR+CD56+ granulocytes; and reductions in type 3 innate lymphoid cells. Mucosal samples from patients with active CD were characterized by IL1B+HLA-DR+CD38+ T cells, IL1B+TNF+IFNG+ naïve B cells, IL1B+ dendritic cells (DCs), and IL1B+ plasmacytoid DCs. Peripheral blood mononuclear cells from patients with active CD differed from those of active UC in that the peripheral blood mononuclear cells from patients with CD had increased IL1B+ T-regulatory cells, IL1B+ DCs and IL1B+ plasmacytoid DCs, IL1B+ monocytes, and fewer group 1 innate lymphoid cells. Random forest modeling differentiated active UC from active CD in colonic mucosa and blood samples; top discriminating features included many of the cellular populations identified above. CONCLUSIONS: We used single-cell technologies to identify immune cell populations specific to mucosa and blood samples from patients with active or inactive CD and UC and controls. This information might be used to develop therapies that target specific cell populations in patients with different types of IBD.
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