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Ribeiro NV, Anwar S, Withoff S, Jonkers IH. Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells. Int J Mol Sci 2025; 26:2982. [PMID: 40243612 PMCID: PMC11988521 DOI: 10.3390/ijms26072982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/14/2025] [Accepted: 03/23/2025] [Indexed: 04/18/2025] Open
Abstract
The contribution of genetics to the development of gut-related autoimmune diseases such as celiac disease (CeD) and inflammatory bowel diseases (IBDs) is well-established, especially in immune cells, but pinpointing the significance of genetic variants to other cell types is more elusive. Increasing evidence indicates that intestinal epithelial cells are active players in modulating the immune response, suggesting that genetic variants affecting these cells could change cell behavior during disease. Moreover, fine-mapping genetic variants and causal genes to relevant cell types can help to identify drug targets and develop personalized targeted therapies. In this context, we reviewed the functions of genes in disease-associated loci shared by CeD and IBD that are expressed in epithelial cells and explored their potential impacts.
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Affiliation(s)
| | | | | | - Iris H. Jonkers
- Department of Genetics, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands; (N.V.R.); (S.A.); (S.W.)
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Fachi JL, de Oliveira S, Trsan T, Penati S, Gilfillan S, Cao S, Ribeiro Castro P, Fernandes MF, Hyrc KL, Liu X, Rodrigues PF, Bhattarai B, Layden BT, Vinolo MAR, Colonna M. Fiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection. Cell Host Microbe 2025; 33:235-251.e7. [PMID: 39826540 PMCID: PMC11974464 DOI: 10.1016/j.chom.2024.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/18/2024] [Accepted: 12/27/2024] [Indexed: 01/22/2025]
Abstract
Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4+ intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate-induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4+ IELs.
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Affiliation(s)
- José L Fachi
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA.
| | - Sarah de Oliveira
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
| | - Tihana Trsan
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Silvia Penati
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Susan Gilfillan
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Siyan Cao
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Pollyana Ribeiro Castro
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
| | - Mariane Font Fernandes
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
| | - Krzysztof L Hyrc
- Alafi Neuroimaging Laboratory, The Hope Center of Neurological Disorders, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Patrick Fernandes Rodrigues
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Bishan Bhattarai
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA
| | - Brian T Layden
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Marco Aurélio R Vinolo
- Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, Saint Louis, MO 63110, USA.
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Clements RL, Kennedy EA, Song D, Campbell A, An HH, Amses KR, Miller-Ensminger T, Addison MM, Eisenlohr LC, Chou ST, Jurado KA. Human erythroid progenitors express antigen presentation machinery. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.27.601047. [PMID: 39005276 PMCID: PMC11244935 DOI: 10.1101/2024.06.27.601047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.
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Heuberger CE, Janney A, Ilott N, Bertocchi A, Pott S, Gu Y, Pohin M, Friedrich M, Mann EH, Pearson C, Powrie FM, Pott J, Thornton E, Maloy KJ. MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T-cell responses. Mucosal Immunol 2024; 17:416-430. [PMID: 37209960 DOI: 10.1016/j.mucimm.2023.05.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/18/2023] [Accepted: 05/01/2023] [Indexed: 05/22/2023]
Abstract
Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favors pro- or anti-inflammatory CD4+ T-cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T-cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen-presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T-cell responses during intestinal inflammation.
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Affiliation(s)
- Cornelia E Heuberger
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Alina Janney
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Nicholas Ilott
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Alice Bertocchi
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Sebastian Pott
- Department of Human Genetics, University of Chicago, Chicago, United States
| | - Yisu Gu
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Mathilde Pohin
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Matthias Friedrich
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Elizabeth H Mann
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Claire Pearson
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Fiona M Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Johanna Pott
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Emily Thornton
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Kevin Joseph Maloy
- School of Infection and Immunity, University of Glasgow, Glasgow, United Kingdom.
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Jelinsky S, Lee I, Monetti M, Breitkopf S, Martz F, Kongala R, Culver J, Vo V, Xue L, Gieseck R, Dickinson C, Kasaian M, Lord JD. Proteomic Differences in Colonic Epithelial Cells in Ulcerative Colitis Have an Epigenetic Basis. GASTRO HEP ADVANCES 2024; 3:830-841. [PMID: 39280905 PMCID: PMC11401595 DOI: 10.1016/j.gastha.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 04/30/2024] [Indexed: 09/18/2024]
Abstract
Background and Aims The colonic epithelium serves as both a barrier to lumenal contents and a gatekeeper of inflammatory responses. In ulcerative colitis (UC), epithelial dysfunction is a core feature, but little is known about the cellular changes that may underlie disease pathology. We therefore evaluated how the chromatin epigenetics and proteome of epithelial cells differs between health and UC. Methods We sorted live CD326+ epithelial cells from colon biopsies of healthy control (HC) screening colonoscopy recipients and from inflamed or uninflamed colon segments of UC patients on no biologic nor immunomodulator therapy (n = 5-7 subjects per group). Cell lysates were analyzed by proteomic evaluation and nuclei were analyzed for open chromatin with assay for transposase-accessible chromatin using sequencing. Results Proteins most highly elevated in inflamed UC biopsies relative to HC were those encoded by the HLA-DRA (P = 3.1 × 10-33) and CD74 (P = 1.6 × 10-27), genes associated with antigen presentation, and the antimicrobial dual oxidase 2 (DUOX2) (P = 3.2 × 10-28) and lipocalin-2 (P = 2.2 × 10-26) genes. Conversely, the water channel aquaporin 8 was strikingly less common with inflammation (P = 1.9 × 10-18). Assay for transposase-accessible chromatin using sequencing revealed more open chromatin around the aquaporin 8 gene in HCs (P = 2.0 × 10-2) and more around the DUOX2/DUOXA2 locus in inflamed UC colon (P = 5.7 × 10-4), suggesting an epigenetic basis for differential protein expression by epithelial cells in health and disease. Conclusion Numerous differences exist between the proteome and chromatin of colonic epithelial cells in UC patients and HCs, some of which correlate to suggest specific epigenetic mechanisms regulating the epithelial proteome.
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Affiliation(s)
- Scott Jelinsky
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Isac Lee
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Mara Monetti
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | | | - Flora Martz
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
| | - Ramya Kongala
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
| | - Jeffrey Culver
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | - Vanessa Vo
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts
| | - Liang Xue
- Machine Learning and Computational Sciences, Early Clinical Development, Pfizer, Cambridge, Massachusetts
| | - Richard Gieseck
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Caitlyn Dickinson
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - Marion Kasaian
- Department of Inflammation and Immunology, Pfizer, Cambridge, Massachusetts
| | - James D Lord
- Translational Research Program, Benaroya Research Institute, Seattle, Washington
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Lucafò M, Muzzo A, Marcuzzi M, Giorio L, Decorti G, Stocco G. Patient-derived organoids for therapy personalization in inflammatory bowel diseases. World J Gastroenterol 2022; 28:2636-2653. [PMID: 35979165 PMCID: PMC9260862 DOI: 10.3748/wjg.v28.i24.2636] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/21/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries. Knowledge of IBD pathogenesis is still incomplete, and the most widely-accepted interpretation considers genetic factors, environmental stimuli, uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD, leading to dysfunction of the intestinal epithelial functions. In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture. An important innovation is represented by organoids, 3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures. Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile. These models are powerful pharmacological tools to better understand IBD pathogenesis, to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD, and to evaluate novel target-directed molecules which could improve therapeutic strategies. The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.
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Affiliation(s)
- Marianna Lucafò
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
| | - Antonella Muzzo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Martina Marcuzzi
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Lorenzo Giorio
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Giuliana Decorti
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Gabriele Stocco
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
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Sæterstad S, Østvik AE, Røyset ES, Bakke I, Sandvik AK, Granlund AVB. Profound gene expression changes in the epithelial monolayer of active ulcerative colitis and Crohn's disease. PLoS One 2022; 17:e0265189. [PMID: 35275975 PMCID: PMC8916644 DOI: 10.1371/journal.pone.0265189] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 02/25/2022] [Indexed: 12/21/2022] Open
Abstract
In recent years it has become apparent that the epithelium is highly involved in inflammatory bowel disease (IBD) pathophysiology. The majority of gene expression studies of IBD are generated from heterogeneous biopsies, providing no distinction between immune cells, the epithelium and other mucosal cells. By using laser capture microdissection (LCM) coupled with RNA sequencing, we aimed to characterize the expressional changes of the isolated colonic epithelial monolayer from ulcerative colitis (UC) and Crohn’s disease (CD) patients compared to healthy controls (HC). The analysis identified 3706 genes as differentially expressed between active IBD epithelium and HC. Weighted gene co-expression network analysis was used to stratify genes into modules, which were subsequently characterized using enrichment analysis. Our data show a distinct upregulation of the antigen presentation machinery during inflammation, including major histocompatibility complex class II molecules (e.g. HLA-DPA1, HLA-DPB1, HLA-DRA) and key transcription factors/activators (STAT1, IRF1, CIITA). We also see an epithelial downregulation of retinoic acid-responsive nuclear receptors (RARA, RARB, RXRA), but upregulation of retinoid-metabolizing enzymes (RDH11, ALDH1A2, ALDH1A3), which together suggest a perturbation of epithelial vitamin A signaling during active IBD. Lastly, we identified a cluster of stress-related genes, including activator protein 1 components JUNB and ATF3, as significantly upregulated in active UC but not in CD, revealing an interesting aspect of IBD heterogeneity. The results represent a unique resource for enhanced understanding of epithelial involvement in IBD inflammation and is a valuable tool for further studies on these processes.
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Affiliation(s)
- Siri Sæterstad
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Ann Elisabet Østvik
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav’s University Hospital, Trondheim, Norway
| | - Elin Synnøve Røyset
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Pathology, St. Olav’s University Hospital, Trondheim, Norway
| | - Ingunn Bakke
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway
| | - Arne Kristian Sandvik
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav’s University Hospital, Trondheim, Norway
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Atle van Beelen Granlund
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- * E-mail:
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Advances in Intestinal Barrier Preservation and Restoration in the Allogeneic Hematopoietic Cell Transplantation Setting. J Clin Med 2021; 10:jcm10112508. [PMID: 34204044 PMCID: PMC8201017 DOI: 10.3390/jcm10112508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 05/30/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023] Open
Abstract
The intestinal barrier consists of an epithelial lining covered with specialized mucus inhabited by intestinal microbiota. An intact gut barrier ensures a resistance to bacteria and toxins translocation. On the other hand, gut permeability allows the absorption of essential nutrients, fluids and ions. This balance is achieved only by the complex structure and functional characteristics of the intestinal barrier. Allogenic hematopoietic cell transplantation remains the only curative treatment for many hematological diseases, but its application is limited because of possible transplant-related mortality mainly due to graft-versus-host disease and infectious complications. The intestinal barrier has been extensively studied in recent years as the primary site of graft-versus-host disease initiation and propagation. In the present review, we focused on the physiological structure and function of the gut barrier and the evidence of how the disruption of the gut barrier and increased intestinal permeability affects transplant recipients. Finally, therapeutic strategies aiming at intestinal barrier protection with a special focus on microbiome preservation and restoration in the allogenic hematopoietic cell transplantation setting are discussed.
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Kelsen JR, Dawany N, Conrad MA, Karakasheva TA, Maurer K, Wei JM, Uman S, Dent MH, Behera R, Bryant LM, Ma X, Moreira L, Chatterji P, Shraim R, Merz A, Mizuno R, Simon LA, Muir AB, Giraudo C, Behrens EM, Whelan KA, Devoto M, Russo PA, Andres SF, Sullivan KE, Hamilton KE. Colonoids From Patients With Pediatric Inflammatory Bowel Disease Exhibit Decreased Growth Associated With Inflammation Severity and Durable Upregulation of Antigen Presentation Genes. Inflamm Bowel Dis 2021; 27:256-267. [PMID: 32556182 PMCID: PMC7813751 DOI: 10.1093/ibd/izaa145] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids. METHODS We measured growth efficiency relative to histopathological and clinical parameters in patient enteroid (ileum) and colonoid (colon) lines. We performed RNA-sequencing on patient colonoids and subsequent flow cytometry after multiple passages to evaluate changes that persisted in culture. RESULTS Enteroids and colonoids from pediatric patients with IBD exhibited decreased growth associated with histological inflammation compared with non-IBD controls. We observed increased LYZ expression in colonoids from pediatric IBD patients, which has been reported previously in adult patients with IBD. We also observed upregulation of antigen presentation genes HLA-DRB1 and HLA-DRA, which persisted after prolonged passaging in patients with pediatric IBD. CONCLUSIONS We present the first functional evaluation of enteroids and colonoids from patients with VEO-IBD and older onset pediatric IBD, a subset of which exhibits poor growth. Enhanced, persistent epithelial antigen presentation gene expression in patient colonoids supports the notion that epithelial cell-intrinsic differences may contribute to IBD pathogenesis.
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Affiliation(s)
- Judith R Kelsen
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Noor Dawany
- Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Maire A Conrad
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Tatiana A Karakasheva
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kelly Maurer
- Division of Allergy Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jane M Wei
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Selen Uman
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
| | - Maiah H Dent
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Rithika Behera
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Laura M Bryant
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Xianghui Ma
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Leticia Moreira
- Department of Gastroenterology, Hospital Clinic, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain
| | - Priya Chatterji
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
| | - Rawan Shraim
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Audrey Merz
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Rei Mizuno
- Department of Medicine, Gastroenterology Division, University of Pennsylvania, Philadelphia, PA, United States
| | - Lauren A Simon
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Amanda B Muir
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Claudio Giraudo
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Edward M Behrens
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kelly A Whelan
- Fels Institute for Cancer Research & Molecular Biology, Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Marcella Devoto
- Division of Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Division of Anatomic Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Pierre A Russo
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States
| | - Sarah F Andres
- Department of Translational and Precision Medicine, University of Rome Sapienza, Rome, Italy
| | - Kathleen E Sullivan
- Division of Allergy Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kathryn E Hamilton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
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10
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Beck A, Schulte L, Möller P. [Autoimmune enteropathy in adults : A rare and difficult but relevant differential diagnosis of chronic diarrhea]. DER PATHOLOGE 2020; 41:230-237. [PMID: 32239324 DOI: 10.1007/s00292-020-00769-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Autoimmune enteropathy (AIE) was originally believed to be a pediatric disease until there were increasing numbers of adult cases reported over the last 20 years. AIE is an autoimmune disease that manifests as severe chronic diarrhea.The histological hallmark is villous atrophy. Histology alone is not sufficiently sensitive and consistent. Four different histological patterns are known. There are many differential diagnoses to be considered relating to both histology and symptoms.We present the case of a young woman with fatal AIE and homozygous germline-mutation of the CLEC7A gene. The course of disease is documented in multiple intestinal biopsies, which show a morphological change over time.Histology and symptoms often resemble celiac disease. In order to recognize this rare disease early in its course there is a need for a special awareness among attending physicians and pathologists.
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Affiliation(s)
- A Beck
- Institut für Pathologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Deutschland.
| | - L Schulte
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Deutschland
| | - P Möller
- Institut für Pathologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Deutschland
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11
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Koyama M, Mukhopadhyay P, Schuster IS, Henden AS, Hülsdünker J, Varelias A, Vetizou M, Kuns RD, Robb RJ, Zhang P, Blazar BR, Thomas R, Begun J, Waddell N, Trinchieri G, Zeiser R, Clouston AD, Degli-Esposti MA, Hill GR. MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota. Immunity 2019; 51:885-898.e7. [PMID: 31542340 DOI: 10.1016/j.immuni.2019.08.011] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 05/15/2019] [Accepted: 08/13/2019] [Indexed: 12/30/2022]
Abstract
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
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Affiliation(s)
- Motoko Koyama
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Pamela Mukhopadhyay
- Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Iona S Schuster
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Andrea S Henden
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia
| | - Jan Hülsdünker
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany; Spemann Graduate School of Biology and Medicine, University Freiburg, Freiburg 79085, Germany; Faculty of Biology, University Freiburg, Freiburg 79104, Germany
| | - Antiopi Varelias
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Marie Vetizou
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Rachel D Kuns
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Renee J Robb
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Ping Zhang
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ranjeny Thomas
- Diamantina Institute, Translational Research Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Jakob Begun
- Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Nicola Waddell
- Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany
| | | | - Mariapia A Degli-Esposti
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Geoffrey R Hill
- Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA.
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12
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Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, Herbst RH, Rogel N, Slyper M, Waldman J, Sud M, Andrews E, Velonias G, Haber AL, Jagadeesh K, Vickovic S, Yao J, Stevens C, Dionne D, Nguyen LT, Villani AC, Hofree M, Creasey EA, Huang H, Rozenblatt-Rosen O, Garber JJ, Khalili H, Desch AN, Daly MJ, Ananthakrishnan AN, Shalek AK, Xavier RJ, Regev A. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 2019; 178:714-730.e22. [PMID: 31348891 PMCID: PMC6662628 DOI: 10.1016/j.cell.2019.06.029] [Citation(s) in RCA: 806] [Impact Index Per Article: 134.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/25/2019] [Accepted: 06/18/2019] [Indexed: 11/29/2022]
Abstract
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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Affiliation(s)
| | - Moshe Biton
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Molecular Biology, MGH, Boston, MA, USA
| | - Jose Ordovas-Montanes
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Division of Infectious Diseases and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA
| | - Keri M Sullivan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Grace Burgin
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Daniel B Graham
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA
| | - Rebecca H Herbst
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Noga Rogel
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Michal Slyper
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Julia Waldman
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Malika Sud
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Elizabeth Andrews
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Gabriella Velonias
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Adam L Haber
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Sanja Vickovic
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Junmei Yao
- Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | | | - Danielle Dionne
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Lan T Nguyen
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Alexandra-Chloé Villani
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
| | - Matan Hofree
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Hailiang Huang
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA
| | | | - John J Garber
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Hamed Khalili
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - A Nicole Desch
- Broad Institute, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | - Mark J Daly
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Ashwin N Ananthakrishnan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.
| | - Alex K Shalek
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
| | - Ramnik J Xavier
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA.
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
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13
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Arebro J, Tengroth L, Razavi R, Kumlien Georén S, Winqvist O, Cardell LO. Antigen-presenting epithelial cells can play a pivotal role in airway allergy. J Allergy Clin Immunol 2015; 137:957-60.e7. [PMID: 26560042 PMCID: PMC7112366 DOI: 10.1016/j.jaci.2015.08.053] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 07/25/2015] [Accepted: 08/17/2015] [Indexed: 01/22/2023]
Affiliation(s)
- Julia Arebro
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of ENT Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Lotta Tengroth
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ronia Razavi
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Susanna Kumlien Georén
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ola Winqvist
- Department of Medicine, Unit of Translational Immunology, Karolinska Institutet, Stockholm, Sweden
| | - Lars-Olaf Cardell
- Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of ENT Diseases, Karolinska University Hospital, Stockholm, Sweden.
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14
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Pan D, Das A, Liu D, Veazey RS, Pahar B. Isolation and characterization of intestinal epithelial cells from normal and SIV-infected rhesus macaques. PLoS One 2012; 7:e30247. [PMID: 22291924 PMCID: PMC3266894 DOI: 10.1371/journal.pone.0030247] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Accepted: 12/15/2011] [Indexed: 01/14/2023] Open
Abstract
Impairment of intestinal epithelial barriers contributes to the progression of HIV/SIV infection and leads to generalized HIV-induced immune-cell activation during chronic infection. Rhesus macaques are the major animal model for studying HIV pathogenesis. However, detailed characterization of isolated rhesus epithelial cells (ECs) from intestinal tissues is not well defined. It is also not well documented whether isolated ECs had any other cell contaminants from intestinal tissues during the time of processing that might hamper interpretation of EC preparations or cultures. In this study, we identify and characterize ECs based on flow cytometry and immunohistochemistry methods using various enzymatic and mechanical isolation techniques to enrich ECs from intestinal tissues. This study shows that normal healthy ECs differentially express HLA-DR, CD23, CD27, CD90, CD95 and IL-10R markers. Early apoptosis and upregulation of ICAM-1 and HLA-DR in intestinal ECs are thought to be the key features in SIV mediated enteropathy. The data suggest that intestinal ECs might be playing an important role in mucosal immune responses by regulating the expression of different important regulatory and adhesion molecules and their function.
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Affiliation(s)
- Diganta Pan
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Arpita Das
- Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - David Liu
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Ronald S. Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
- Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Bapi Pahar
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
- Tulane University School of Medicine, New Orleans, Louisiana, United States of America
- * E-mail:
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15
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Stoneman V, Morris A. Induction of intercellular adhesion molecule 1 and class II histocompatibility antigens in colorectal tumour cells expressing activated ras oncogene. Mol Pathol 2010; 48:M326-32. [PMID: 16696033 PMCID: PMC408000 DOI: 10.1136/mp.48.6.m326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Aims-To determine whether there is a correlation between activation of the ras oncogene and the induction of MHC class II antigens and intercellular adhesion molecule 1 (ICAM-1) by interferon-gamma (IFN-gamma).Methods-Expression of class II antigens, ICAM-1 and intracellular ras oncoprotein (p21) in established colorectal cell lines and short term cultures of primary colorectal tumour cells was determined by flow cytometry and mutation in the ras gene by sequencing of amplified segments of the gene.Results-The cell lines showed a variation in their modulation of MHC class II antigens and ICAM-1, ranging from no induction to a 98-fold increase in class II antigen expression in the HT29 cell line. Previous work indicated that most tumours could not be induced to express class II antigens. Four of the five least inducible lines either contained mutant ras or highly expressed the oncoprotein. The four highly inducible cell lines all contained non-mutant ras. Of the 21 tumours studied in primary culture, 10 were inducible, one of which contained mutant ras. Of the remaining non-inducible tumours, four were mutant.Conclusions-Correlations between ras activation and failure to respond to IFN-gamma could not be shown to be significant. Therefore, ras activation, and concomitant subversion of intracellular signalling pathways, is probably not the major determinant in failure to activate class II antigens and ICAM-1.
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Affiliation(s)
- V Stoneman
- Department of Biological Sciences, University of Warwick, Coventry CV4 7AL
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16
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Chung HL, Lee JJ, Kim SG. Cow's milk protein induced changes in the expression of HLA-DR antigens on colonic epithelial cells. Ann Allergy Asthma Immunol 2003; 90:348-50. [PMID: 12669900 DOI: 10.1016/s1081-1206(10)61805-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Normal colonic epithelial cells do not express HLA-DR antigens unless they become inflamed. It is possible that colonic epithelial cells may function as antigen-presenting cells once HLA-DR is induced by infection or inflammation. OBJECTIVE The aim of this study was to investigate whether cow's milk protein (CMP) is capable of inducing changes in HLA-DR expression on colonic epithelial cells, providing indirect evidence that CMP may activate cell-mediated immune mechanisms within intestinal mucosa. METHODS HLA-DR expression was evaluated by flow cytometry on cultured human colonic epithelial cell line (HT-29) before and after treatment with bacterial lipopolysaccharide (LPS) or recombinant gamma interferon (IFN-gamma). Untreated and LPS- or IFN-gamma-treated HT-29 cells were then cultured in the presence of CMP. The changes in epithelial HLA-DR expression induced by CMP on untreated and LPS- or IFN-gamma-treated HT-29 cells were examined. RESULTS Untreated HT-29 cells expressed very little HLA-DR molecule. Bacterial LPS or IFN-gamma induced a significant HLA-DR expression on HT-29 cells. When untreated HT-29 cells were cultured in the presence of CMP, there was little induction of HLA-DR expression. Culture of LPS- or IFN-gamma-treated HT-29 cells in the presence of CMP induced a significant increase in HLA-DR expression, which was much greater than on HT-29 cells treated with bacterial LPS or IFN-gamma only. CONCLUSIONS Our results suggest that CMP initiates an immune response in the intestinal mucosa and may be responsible for the activation of cell-mediated immunity after enteric infection or inflammation.
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Affiliation(s)
- Hai Lee Chung
- Department of Pediatrics, School of Medicine, Catholic University of Taegu, Taegu, Korea.
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17
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Clemett D, Markham A. Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn's disease. Drugs 2000; 59:929-56. [PMID: 10804042 DOI: 10.2165/00003495-200059040-00016] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
UNLABELLED Prolonged-release mesalazine (Pentasa) consists of ethylcellulose-coated microgranules from which mesalazine (known in the US as mesalamine) is released in the small and large intestine in a diffusion-dependent manner. Dose-dependent improvements in clinical and endoscopic parameters have been reported with prolonged-release mesalazine 2 and 4 g/day in clinical trials in patients with mild to moderately active ulcerative colitis. Induction of clinical and endoscopic remission was achieved in more patients receiving a daily dosage of 4 g/day than in those receiving placebo. In patients with ulcerative colitis in remission, prolonged-release mesalazine is effective in reducing the rate of relapse. Higher dosages tend to be more effective, and a 12-month remission rate of 64% has been reported for patients treated with a 4 g daily dosage of this formulation. Comparative data indicate that prolonged-release mesalazine has similar efficacy in maintaining remission to molar equivalent doses of sulfasalazine. Data from a study in patients with mild to moderately active Crohn's disease indicates that higher dosages (4 g/day) of prolonged-release mesalazine are more effective than placebo in reducing disease activity. After 16 weeks' treatment, 64% of patients receiving a 4 g/day dosage experienced clinical improvement and 43% attained remission. In studies of patients in remission of Crohn's disease, the formulation appears to be more effective in preventing relapse in patients with isolated small bowel disease than in those with colonic involvement. The tolerability profile of oral prolonged-release mesalazine is similar to that of placebo and the incidence of adverse events does not appear to be dose-related. Nausea/vomiting, diarrhoea, abdominal pain and dyspepsia occur most frequently, although their incidence is low. Reports of nephrotoxicity during prolonged-release mesalazine treatment are rare. CONCLUSIONS Oral prolonged-release mesalazine is effective for maintenance and induction of remission of mild to moderately active colitis, both in patients with distal disease and in those with pancolitis. The formulation has similar efficacy to that of equimolar concentrations of sulfasalazine. Prolonged-release mesalazine also appears to be effective in the treatment of Crohn's disease, and maintenance therapy is of particular value in patients with isolated small bowel involvement. Evidence suggests that higher dosages (3 to 4 g/day) of prolonged-release mesalazine have additional therapeutic benefits over lower dosages in patients with inflammatory bowel disease without increasing the incidence of adverse events.
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Affiliation(s)
- D Clemett
- Adis International Limited, Mairangi Bay, Auckland, New Zealand.
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18
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Ruemmele FM, Dionne S, Levy E, Seidman EG. Dexamethasone inhibits IFNgamma-induced MHC class II expression of intestinal epithelial cells independently of the TGF-beta1 regulatory pathway. Aliment Pharmacol Ther 1999; 13:595-601. [PMID: 10233182 DOI: 10.1046/j.1365-2036.1999.00532.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND In the presence of inflammation, an increased expression of enterocyte MHC class II is observed, leading to altered mucosal antigen handling. Corticosteroids are potent anti-inflammatory drugs, widely used in treating inflammatory bowel disorders. However, their diverse mechanisms of action are only partially understood. AIM To evaluate effect and mechanisms of corticosteroids on intestinal crypt epithelial cell MHC class II. METHODS The effect of dexamethasone treatment on cytokine-induced MHC class II expression was measured in IEC-6 cells by immunofluorescence and flow cytometry. To determine the role of the TGF-beta1 regulatory pathway in mediating the effects of dexamethasone, neutralizing anti-TGF-beta antibodies were used. Additionally, endogenous and dexamethasone-stimulated IEC-6 cell TGF-beta1 production was measured by ELISA. RESULTS Dexamethasone potently down-regulated IFNgamma-induced class II expression on IEC-6 cells, in a dose-dependent manner. TGF-beta1 had a similar inhibitory effect on class II expression. However, neutralizing anti-TGF-beta antibodies did not alter the effect of dexamethasone. Furthermore, dexamethasone reduced endogenous TGF-beta1 synthesis. CONCLUSIONS Corticosteroids inhibit cytokine-induced MHC class II expression on IEC-6 cells in a TGF-beta1 independent way. This effect may markedly alter enterocytic antigen presentation, reducing the aberrant state of activation of mucosal immune cells.
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Affiliation(s)
- F M Ruemmele
- Intestinal Immunology Laboratory, Ste. Justine Hospital, Departments of Paediatrics and Nutrition, University of Montreal, Quebec, Canada
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19
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D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998; 114:262-7. [PMID: 9453485 DOI: 10.1016/s0016-5085(98)70476-7] [Citation(s) in RCA: 598] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Postoperative recurrence of Crohn's disease may be triggered by agents in the fecal stream. The aim of this study was to examine intestinal mucosal inflammation induced by contact with intestinal fluids in surgically excluded ileum. METHODS The effects of infusion of intestinal luminal contents into excluded ileum in 3 patients with Crohn's disease who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy were studied by histopathology and electron microscopy. RESULTS Contact with intestinal fluids for 8 days induced focal infiltration of mononuclear cells, eosinophils, and polymorphonuclear cells in the lamina propria, small vessels, and epithelium in the excluded neoterminal ileum that was previously normal. Epithelial HLA-DR expression increased, and mononuclear cells expressed the KP-1 antigen associated with activation. Marked up-regulation of RFD-7, RFD-9, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 1 was observed after infusion, reflecting epithelioid transformation and transendothelial lymphocyte recruitment. At the ultrastructural level, dilatation of the endoplasmic reticulum and Golgi apparatus occurred in epithelial cells, where also basally located transport vesicles were identified. CONCLUSIONS Intestinal contents trigger postoperative recurrence of Crohn's disease in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery.
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Affiliation(s)
- G R D'Haens
- Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium
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20
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Zimmerman MJ, Radford-Smith GR, Jewell DP. The effect of interleukin-10 and transforming growth factor beta-1 on HLA-DR expression in colonic epithelial cells. Mediators Inflamm 1998; 7:7-11. [PMID: 9839692 PMCID: PMC1781823 DOI: 10.1080/09629359891315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The aim of this study was to assess whether interleukin-10 (IL-10) and/or transforming growth factor beta-1 (TGFbeta1) downregulate HLA-DR expression using the HT29 cell line as a model of colonic epithelial cells. HLA-DR expression was induced in HT29 cells with gamma-interferon. The effects of IL-10 alone, TGFbeta1 alone, and IL-10 and TGFbeta1 in combination were studied. HLA-DR expression was assessed using flow cytometric analysis. Gamma-interferon induced HLA-DR expression in a dose-dependent fashion. In the absence of gamma-interferon, neither IL-10 nor TGFbeta1 induced HLA-DR expression. In isolation, neither IL-10 nor TGFbeta1 downregulated HLA-DR expression. When IL-10 and TGFbeta1 were added in combination, small (6-30%) statistically significant reductions in HLA-DR expression were seen. The biological significance is unclear.
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Affiliation(s)
- M J Zimmerman
- Gastroenterology Department, Royal Perth Hospital, Western Australia, Australia
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21
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The Efficacy of Intravesical Tice Strain Bacillus Calmette-Guerin in the Treatment of Interstitial Cystitis: A Double-Blind, Prospective, Placebo Controlled Trial. J Urol 1997. [DOI: 10.1016/s0022-5347(01)64682-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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22
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Mitomi H, Atari E, Uesugi H, Nishiyama Y, Igarashi M, Arai N, Ihara A, Okayasu I. Distinctive diffuse duodenitis associated with ulcerative colitis. Dig Dis Sci 1997; 42:684-93. [PMID: 9073157 DOI: 10.1023/a:1018836218391] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- H Mitomi
- Department of Pathology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan
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23
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Waraich T, Sarsfield P, Wright DH. The accessory cell populations in ulcerative colitis: a comparison between the colon and appendix in colitis and acute appendicitis. Hum Pathol 1997; 28:297-303. [PMID: 9042793 DOI: 10.1016/s0046-8177(97)90127-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We present an immunohistochemical study of accessory cells in acute appendicitis and ulcerative colitis (UC). By comparing these two diseases, it is possible to distinguish between changes associated with inflammatory bowel disease and those resulting from nonspecific intestinal inflammation. Nine total colectomy specimens from patients with UC, in which the appendix was also involved, were compared with nine cases of acute appendicitis. Accessory cells were stained for CD68 (PGMI), ACPI (acid cysteine proteinase inhibitor), S100 protein, MAC387 (calgranulin), CD1a, factor XIIIa, and WR18 (HLA class II). In ulcerative colitis, but not acute appendicitis, there was extension of a network of S100 positive dendritic cells into the crptal mucosa, and these S100-positive dendritic cells were closely aligned with the epithelium. The epithelium in UC, but not in acute appendicitis, showed intense upregulation of HLA class II, and this was particularly marked at the crypt bases. Dendritic, MAC387-positive cells were seen only in UC. In both diseases there were abundant ACPI-positive accessory cells in the cryptal areas, a population normally restricted to the dome areas. Factor XIIIa- and PGM1-positive cells, although abundant in both conditions, had distributions similar to those that we had previously shown in normal controls. No CD1a-positive cells were identified in either UC or acute appendicitis. We hypothesize that S100 identifies a subpopulation of activated macrophages. The concentration of this subpopulation, in close contact with the epithelium, which also shows altered expression of HLA class II antigens, suggests that a component of the immune response is targeting this area in UC. In addition, we also suggest that the identification of MAC387-positive dendritic cells in UC reflects increased macrophage turnover in inflammatory bowel disease.
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Affiliation(s)
- T Waraich
- University Department of Pathology, Southampton General Hospital, England
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24
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Chen D, Radford-Smith G, Dipaolo MC, McGowan I, Jewell DP. Cytokine gene transcription of human colonic intraepithelial lymphocytes costimulated with epithelial cells bearing HLA-DR and its inhibition by 5-aminosalicylic acid. J Clin Immunol 1996; 16:237-41. [PMID: 8840226 DOI: 10.1007/bf01541230] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The objectives of this study were to activate human colonic intraepithelial lymphocytes at the transcriptional level with HLA-DR+ human colonic epithelial cell line (HT29) in synergy with CD3 monoclonal antibody and to investigate the molecular mechanism for the therapeutic effects of 5-aminosalicylic acid. Lymphocytes were isolated by a mechanical method from resected colon of 22 cases and then cocultured on 10 ng/ml CD3mAb immobilized plates with HT29 which had been induced to express MHC class II molecules by interferon gamma. Flow cytometry analysis suggested that the lymphocyte population had a CD4/CD8 ratio similar to that observed in intact tissue sections and that there was no HT29 contamination of the lymphocytes isolated again from cocultured cells. The activation of intraepithelial lymphocytes showed the gene transcription of interferon gamma and tumor necrosis factor alpha, as measured by means of the reverse-transcriptase polymerase chain reaction, and this activation was antagonized by 5-aminosalicylic acid. Thus, epithelial cells bearing HLA-DR are capable of enhancing CD3-induced activation of human colonic intraepithelial lymphocytes and subject to inhibition by 5-aminosalicylic acid, the active moiety of salicylates used in inflammatory bowel disease.
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Affiliation(s)
- D Chen
- Gastroenterology Unit, John Radcliffe Hospital, Oxford University, UK
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25
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Veys EM, Mielants H, De Vos M, Cuvelier C. Spondylarthropathies: from gut to target organs. BAILLIERE'S CLINICAL RHEUMATOLOGY 1996; 10:123-46. [PMID: 8674144 DOI: 10.1016/s0950-3579(96)80009-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Recent studies strongly support the concept that gut and joint inflammation are closely related. Progress also has been made in identifying individual mechanisms that contribute to the pathogenesis of joint disease in IBD and in undifferentiated SpAs. However, the interrelationship of these mechanisms that result in chronic disease manifestations at a site distant from the initiating event remain to be elucidated. The local absence of homing molecule receptors in the gut wall combined with an expression of these receptors in target organs can be responsible for the transformation of the synovial membrane and/or the enthesis into an aberrant tertiary lymphoid organ of the gut.
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Affiliation(s)
- E M Veys
- Department of Rheumatology, University Hospital, Ghent, Belgium
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26
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Abstract
Mucinous carcinomas are defined on the basis of the amount of the mucus component in the tumour mass. Apart from this quantitative criterion, a number of clinicopathological parameters (such as localisation, prevalence in different countries and age groups, association with HNPCC and inflammatory processes) and genetic alterations (e.g. frequency of mutation in Ki-ras and p53 genes, level of MUC2 expression) differentiate these tumours from the non-mucinous ones. Since a different set of genetic lesions implies different inducing agents, these observations suggest that there may be a 'mucinous pathway of carcinogenesis'. Further identification of genetic changes characteristic of the mucinous phenotype will help to understand the aetiology of these tumours and possibly establish markers for detection of the high-risk group.
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Affiliation(s)
- C Hanski
- Universitätsklinikum Benjamin Franklin, Department of Gastroenterology, Freie Universität Berlin, Germany
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27
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Leidenius MH, Koskimies SA, Kellokumpu IH, Höckerstedt KA. HLA antigens in ulcerative colitis and primary sclerosing cholangitis. APMIS 1995; 103:519-24. [PMID: 7576567 DOI: 10.1111/j.1699-0463.1995.tb01400.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The aims of this study were to find out whether the alleles of the HLA class I or II region are associated with susceptibility to ulcerative colitis, and to show whether there is a difference or similarity in HLA associations between primary sclerosing cholangitis and ulcerative colitis. HLA-A, B, C and DR antigens were studied using the standard lymphocyte microcytotoxicity test in 24 Finnish patients with primary sclerosing cholangitis, 77 patients with ulcerative colitis, and 106 controls. HLA-B8 (54%) and DR3 (60%) were associated with primary sclerosing cholangitis. HLA-DR1 (46%) and DR6 (20%) seemed more common in ulcerative colitis than in controls. A positive association with Cw7 was common to both ulcerative colitis (25%) and primary sclerosing cholangitis (33%). Our results indicate that ulcerative colitis is more heterogeneous than primary sclerosing cholangitis in its HLA-DR associations.
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Affiliation(s)
- M H Leidenius
- Fourth Department of Surgery, Helsinki University Central Hospital, Finland
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28
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Jones SC, Crabtree JE, Rembacken BJ, Dixon MF, Trejdosiewicz LK, Whicher JT, Axon AT. Mucosal interleukin-6 secretion in ulcerative colitis. Effects of anti-inflammatory drugs and T-cell stimulation. Scand J Gastroenterol 1994; 29:722-8. [PMID: 7973432 DOI: 10.3109/00365529409092500] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by anti-inflammatory agents in inflammatory bowel disease. METHODS In vitro secretion of IL-6 by biopsy specimens from patients with active ulcerative colitis was investigated in the presence of cyclosporin-A (CsA) and drugs that have other anti-inflammatory actions. Biopsy specimens from patients with quiescent ulcerative colitis or controls were stimulated with anti-CD3 antibody to activate mucosal T cells. RESULTS Stimulation of control specimens increased IL-6 secretion (median increase, 147%; p < 0.003), which was prevented by CsA. In quiescent ulcerative colitis there was enhanced spontaneous secretion of IL-6 but a smaller, non-significant increase after T-cell activation (125%). Dexamethasone inhibited secretion in active ulcerative colitis (p < 0.006). 5-Aminosalicylic acid, 6-mercaptopurine, methotrexate, and indomethacin had no effect. There also tended to be a small reduction with CsA, but this just failed to reach statistical significance. CONCLUSIONS In quiescent ulcerative colitis the enhanced spontaneous secretion of IL-6 may be a consequence of mucosal T-cell or macrophage activation: the smaller increase after T-cell stimulation suggests that one or both of these two cell types are already pre-activated.
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Affiliation(s)
- S C Jones
- Centre for Digestive Diseases, General Infirmary, Leeds, UK
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29
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Okazaki K, Yokoyama Y, Yamamoto Y, Kobayashi M, Araki K, Ogata T. T cell cytotoxicity of autologous and allogeneic lymphocytes in a patient with Crohn's disease. J Gastroenterol 1994; 29:415-22. [PMID: 7951850 DOI: 10.1007/bf02361237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We report a 27-year-old male with Crohn's disease (CD) of the small and large intestine, whose peripheral blood lymphocytes (PBL) showed increased cell-mediated cytotoxicity (CTL). Autologous and allogeneic effector cells from PBL and intestinal lymph nodes (LN) were isolated on a Ficoll-Hypaque gradient. Colonic cells were prepared as the target and were incubated for 6h with effector cells, after being labeled with Na(2)51CrO4. The CTL activity [effector/target (E/T) ratio, 100:1] of PBL for autologous targets was increased by 38% compared with that in normal subjects (< 10%), while that shown by LN was not increased (14%). The CTL activity of allogeneic PBL prepared from three of four other CD patients was also increased. Anti-major histocompatibility (MHC) class I and II and CD4 and CD8 monoclonal antibodies (50 micrograms/ml) significantly inhibited CTL activity. Complement-mediated depletion of CD2+ cells significantly reduced CTL activity. These results suggest that MHC-restricted CTL may play a role in mucosal damage in some patients with Crohn's disease.
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Affiliation(s)
- K Okazaki
- First Department of Internal Medicine, Kochi Medical School, Japan
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30
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Abstract
Delivery of 5-aminosalicylic acid to the colon by sulphasalazine, other azo-bonded compounds and controlled-release preparations is introduced in the context of metabolism by epithelial cells and therapeutic efficacy in ulcerative colitis. Potential modes of action are then reviewed, including actions on luminal bacteria, epithelial cell surface receptors, cellular events (such as nitric oxide release or butyrate oxidation), electrolyte transport and epithelial permeability. Evidence for an influence of salicylates on circulating and lamina propria inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides and inflammatory mediators, such as eicosanoids, platelet-activating factor, cytokines or reactive oxygen metabolites. The precise mechanism will remain uncertain as long as the aetiology of ulcerative colitis is unknown, but a pluripotential mode of action of salicylates is an advantage when influencing the network of events that constitute chronic inflammation.
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Affiliation(s)
- S P Travis
- Gastroenterology Unit, Derriford Hospital, Plymouth, U.K
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31
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Morris A, Hewitt C, Young S. The major histocompatibility complex: its genes and their roles in antigen presentation. Mol Aspects Med 1994; 15:377-503. [PMID: 7837935 DOI: 10.1016/0098-2997(94)90041-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- A Morris
- Department of Biological Sciences, University of Warwick, Coventry, U.K
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32
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Baldassano RN, Schreiber S, Johnston RB, Fu RD, Muraki T, MacDermott RP. Crohn's disease monocytes are primed for accentuated release of toxic oxygen metabolites. Gastroenterology 1993; 105:60-6. [PMID: 8390381 DOI: 10.1016/0016-5085(93)90010-a] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Inflammatory bowel disease occurs in regions of the intestine characterized by a bowel content high in bacteria. Intestinal bacteria synthesize cell wall products such as lipopolysaccharide; when normal monocytes or macrophages come in contact with these products, they can be primed to release a number of inflammatory mediators. Mediators such as toxic oxygen metabolites released as part of the respiratory burst may contribute to inflammatory tissue damage. The aim of this study was to determine if monocytes from patients with Crohn's disease are primed by lipopolysaccharide for a greater respiratory burst. METHODS The generation of superoxide anion was measured by superoxide dismutase inhibitable reduction of ferricytochrome c. RESULTS Freshly isolated monocytes from active untreated Crohn's disease patients (n = 8) showed enhanced stimulated release of superoxide anion when compared with normal monocytes (n = 15; 3.80 +/- 0.12 vs. 1.02 +/- 0.06 nmol/5 min; P < 0.001). We tested the hypothesis that the monocyte priming factor in Crohn's disease serum may be lipopolysaccharide by showing that Crohn's disease serum lost its ability to prime normal monocytes after lipopolysaccharide was removed (0.25 +/- 0.25 nmol/5 min, P < 0.001). CONCLUSIONS These studies indicate that bacterial cell wall products may be important proinflammatory molecules involved in the initiation and/or perpetuation of Crohn's disease.
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Affiliation(s)
- R N Baldassano
- Division of Gastroenterology, Children's Hospital of Philadelphia, Pennsylvania
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33
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Liebert M, Wedemeyer G, Stein JA, Washington R, Faerber G, Flint A, Grossman HB. Evidence for urothelial cell activation in interstitial cystitis. J Urol 1993; 149:470-5. [PMID: 8094760 DOI: 10.1016/s0022-5347(17)36121-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Bladder biopsy samples from 17 interstitial cystitis patients and 20 controls were evaluated for urothelial cell activation using a panel of monoclonal antibodies to HLA-DR, intercellular adhesion molecule 1, interleukin 1 alpha and tumor necrosis factor alpha. Urothelial cells in the majority (13 of 16, 81%) of the biopsies from patients with interstitial cystitis showed increased expression of HLA-DR, while fewer samples were positive for intercellular adhesion molecule 1 (3 of 16, 19%), interleukin 1 alpha (2 of 17, 12%) or tumor necrosis factor alpha (1 of 15, 7%). No urothelial cell expression of intercellular adhesion molecule 1, interleukin 1 alpha or tumor necrosis factor alpha was detected in the controls, and only 1 of 20 control samples contained HLA-DR positive urothelial cells. These results suggest that an unusual type of cellular activation is present in interstitial cystitis. In vitro studies with cultured normal urothelial cells indicated that cells activated with gamma interferon and tumor necrosis factor alpha expressed intercellular adhesion molecule 1 and HLA-DR, although increases in intercellular adhesion molecule 1 expression occurred earlier. Urothelial cells in interstitial cystitis patients may be defective in ability to express intercellular adhesion molecule 1. Alternatively, the differential expression of HLA-DR and intercellular adhesion molecule 1 in interstitial cystitis specimens may represent a functional subset of interstitial cystitis or reflect different stages of the disease. Urothelial cell activation in interstitial cystitis may result in aberrant immune responses and immune activation within the bladder. Because HLA-DR can be detected in paraffin-embedded tissues, evaluation of urothelial cell HLA-DR expression, although not specific for interstitial cystitis, may become a useful tool in the pathological evaluation of biopsy tissues from patients with this disease.
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Affiliation(s)
- M Liebert
- Section of Urology, University of Michigan, Ann Arbor 48109
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34
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Okazaki K, Morita M, Nishimori I, Sano S, Toyonaga M, Nakazawa Y, Yamamoto Y, Yamamoto Y. Major histocompatibility antigen-restricted cytotoxicity in inflammatory bowel disease. Gastroenterology 1993; 104:384-91. [PMID: 8425680 DOI: 10.1016/0016-5085(93)90405-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND The role of cytotoxicity mediated by peripheral blood mononuclear cells for colonic epithelial cells in inflammatory bowel disease (IBD) is still controversial. To clarify it, we studied major histocompatibility antigen (MHC)-restricted T cell-mediated cytotoxicity (CTL). METHODS Cytotoxicity was measured by 51Cr release from colonic cells after the 6-hour incubation with peripheral blood mononuclear cells in 11 IBD patients (6 with Crohn's disease and 5 with ulcerative colitis). RESULTS CTL activity (E/T ratio = 200:1 or 100:1) for autologous target cells was significantly increased (22%-40%) in 5 of 6 CD and 4 of 5 UC patients (22%-64%) compared with that for allogeneic target cells. The increase in CTL activity was mainly inhibited by anti-MHC class I and CD8 monoclonal antibodies (50 micrograms/mL), while it was partially inhibited by anti-MHC class II or CD4 antibodies in some patients. Complement-mediated depletion of CD2+ cells also significantly decreased CTL activity. CONCLUSIONS The results indicate that MHC-restricted T cell cytotoxicity may play a role in mucosal damage in some patients of IBD.
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Affiliation(s)
- K Okazaki
- First Department of Internal Medicine, Kochi Medical School, Japan
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35
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Crotty B, Rosenberg WM, Aronson JK, Jewell DP. Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease. Gut 1992; 33:1353-7. [PMID: 1446859 PMCID: PMC1379603 DOI: 10.1136/gut.33.10.1353] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
5-Aminosalicylic acid (5ASA), 4ASA, their N-acetylated metabolites N-acetyl-5ASA and N-acetyl-4ASA, olsalazine, and colchicine impair interferon-gamma (IFN gamma) induced HLA-DR expression on a colonic cell line, HT-29. The mechanism of this effect is now reported. HT-29 cells were cultured with 50 U/ml IFN gamma with or without drug, and northern blot analysis was performed using a probe for the beta chain of the DR molecule. IFN gamma led to a noticeable increase in HLA-DR mRNA which was attenuated by the drugs. Analysis of the specific binding of increasing concentrations of 125I-IFN gamma by non-linear regression showed a Kd of 1.35 x 10(-10) M and 2.3 x 10(5) binding sites per HT-29 cell. Binding of 125I-IFN gamma was reduced by incubation with increasing concentrations of unlabelled IFN gamma but not with IFN alpha. Incubation with therapeutic concentrations of drugs led to the following reductions in binding: 10 mM 5ASA, 20% (p < 0.001); 10 mM N-acetyl-5ASA, 24% (p < 0.01); 10 mM 4ASA, 21% (p < 0.005); 10 mM N-acetyl-4ASA, 29% (p < 0.001); and 1 mM olsalazine, 29% (p < 0.001). Colchicine (10(-7) M) and 10(-5) M prednisolone had no effect. Incubation with higher concentrations of the drugs revealed a dose-response effect on binding with complete inhibition by 100 mM 4ASA and 10 mM olsalazine, and lesser degrees of inhibition by 100 mM 5ASA, N-acetyl-5ASA, and N-acetyl-4ASA. At concentrations found in the rectal lumen, the salicylates used in inflammatory bowel disease impair the binding of IFN gamma to its receptor on colonic epithelial cells.
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Affiliation(s)
- B Crotty
- Gastroenterology Unit, Radcliffe Infirmary, Oxford
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36
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Brandtzaeg P, Halstensen TS, Huitfeldt HS, Krajci P, Kvale D, Scott H, Thrane PS. Epithelial expression of HLA, secretory component (poly-Ig receptor), and adhesion molecules in the human alimentary tract. Ann N Y Acad Sci 1992; 664:157-79. [PMID: 1456647 DOI: 10.1111/j.1749-6632.1992.tb39758.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Epithelial HLA class II is differentially expressed (DR >> DP) only after birth in salivary glands and small intestinal mucosa, in contrast to class I determinants and secretory component (SC) which appear early in gestation. However, there is a brisk postnatal increase in SC expression along with the class II induction, suggesting stimulation by cytokines from activated immune cells. T lymphocytes remain quite scanty in postnatal salivary glands, and the striking SC and class II expression might reflect a synergistic effect of IFN-gamma and TFN-alpha on immature epithelial cells. Enhanced epithelial expression of both SC and class II in salivary glands from sudden infant death victims could be the effect of immunostimulation caused by an infectious agent. Strikingly upregulated SC and epithelial class II expression (DR > DP > DQ) is seen in various inflammatory lesions such as obstructive sialadenitis, Sjögren's syndrome, chronic gastritis, and celiac disease. IFN-gamma and TNF-alpha are most likely involved as the expression patterns can be reproduced with these cytokines in vitro on colonic epithelial cell lines. However, these molecules of the Ig supergene family do not show a selective response in epithelia of inflammatory lesions because increased expression is also seen for lysozyme, lactoferrin and some other proteins. ICAM-1 can be upregulated on epithelial cells by various cytokines in vitro although the situation remains uncertain in mucosal inflammation. The expression pattern in IBD is complicated by dysplastic epithelial changes leading to reduced SC levels which may thus, in turn, jeopardize the poly-Ig transport mechanism. Epithelial class II molecules appear to have antigen-presenting properties, but the immunopathologic role of their increased expression in inflammatory disease in terms of induction of autoimmunity and/or abrogation of oral tolerance is a matter of continuing dispute.
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Affiliation(s)
- P Brandtzaeg
- Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), University of Oslo, National Hospital, Rikshospitalet, Norway
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37
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Hoang P, Crotty B, Dalton HR, Jewell DP. Epithelial cells bearing class II molecules stimulate allogeneic human colonic intraepithelial lymphocytes. Gut 1992; 33:1089-93. [PMID: 1398233 PMCID: PMC1379448 DOI: 10.1136/gut.33.8.1089] [Citation(s) in RCA: 30] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
HLA-DR+ gut epithelial cells may present antigen to intraepithelial lymphocytes (IEL). This study aimed to isolate an IEL population from the human colon to activate CD3 + IEL by a human colonic epithelial cell line (HT-29), bearing different concentrations of class II antigen (HLA-DR). IEL were isolated by a mechanical method from six patients with ulcerative colitis (UC) and from 14 control patients. IEL were cocultured with HT-29 which had been induced to express class II molecules by gamma-interferon (IFN-gamma) in a dose dependent manner. The phenotype and the subsequent expression of activation markers by the IEL were determined to two colour flow cytometry. The IEL population had a CD4/CD8 ratio similar to that seen in tissue sections. In the mixed cell culture, the degree of IEL activation showed a positive correlation with the degree of HLA-DR expression by the HT29 cells and the IEL secreted a IFN-gamma like factor that in turn stimulated the HT-29. Thus, depending on their expression of HLA molecules, colonic epithelial cells are able to activate CD3+CD8+IEL.
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Affiliation(s)
- P Hoang
- Gastroenterology Unit, Radcliffe Infirmary, Oxford
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38
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Geboes K, Rutgeerts P, Ectors N, Mebis J, Penninckx F, Vantrappen G, Desmet VJ. Major histocompatibility class II expression on the small intestinal nervous system in Crohn's disease. Gastroenterology 1992; 103:439-47. [PMID: 1378803 DOI: 10.1016/0016-5085(92)90832-j] [Citation(s) in RCA: 88] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Widespread alterations of the gut autonomic nervous system have been described in Crohn's disease. Immunohistochemistry shows that these alterations are associated with the expression of major histocompatibility (MHC) class II antigens (HLA-DR) on enteroglial cells in the ganglia of the submucous and myenteric plexuses and on the enteroglial sheaths of the nerve extensions. Neuronal cell bodies and extensions do not express MHC class II antigens. The class II expression is associated with the presence of UCHL1-positive T lymphocytes. MHC class II expression can also be found on endothelial cells and vascular smooth muscle cells but not on smooth muscle cells of the muscularis mucosae or propria. The intensity of MHC class II expression on the glial cells of the enteric nervous plexus and on endothelial cells correlates well with the intensity of class II expression on epithelial cells.
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Affiliation(s)
- K Geboes
- Department of Medical Research, University Hospital St. Rafael, Louvain, Belgium
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39
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Trejdosiewicz LK. Intestinal intraepithelial lymphocytes and lymphoepithelial interactions in the human gastrointestinal mucosa. Immunol Lett 1992; 32:13-9. [PMID: 1500079 DOI: 10.1016/0165-2478(92)90192-q] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Although representing a major immunological apparatus, it is not known how the immune system of the intestinal mucosa differentiates between dietary antigens (resulting in systemic tolerance) and potential pathogens. It is thought that intraepithelial T lymphocytes (IEL) may play a central role in local intestinal immunity and are likely to be important in immunity to gastrointestinal neoplasms and rejection responses to gut allografts. However, the biology of IEL and their unusual immunological microenvironments in the gastrointestinal mucosa are little understood. IEL are predominantly CD8+ TcR alpha beta+ CD3+ T cells which differ from lamina propria and peripheral T cells in many respects. IEL show low expression of CD5, CD6, LFA-1 (CD11a/CD18) and VLA-4, and high expression of HML-1. TcR gamma delta + IEL, although a minority population, are also phenotypically distinct, insofar as they are 50% CD8+, mainly V delta 1+ V gamma 9- and CD4- CD5-. IEL show poor proliferative responses to PHA, anti-CD3 and phorbol ester/calcium ionophore in vitro and have no clear functional role: they neither provide helper nor suppressor functions for Ig synthesis by B cells and do not mediate spontaneous cytotoxicity. However, there is evidence that IEL show preferential activation in response to sheep erythrocytes, presumably signalling via CD2. As normal and inflamed intestinal epithelia do not express ICAM-1, it seems unlikely that the LFA-1/ICAM-1 interaction is of importance to IEL activation. Rather, the CD2 (LFA-2) interaction with LFA-3 expressed by enterocytes may serve both to anchor IEL and to provide an accessory stimulus for activation. Nevertheless, the questions of antigenic specificity and immunological role remain unanswered.
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Affiliation(s)
- L K Trejdosiewicz
- Department of Medicine, St. James's University Hospital, University of Leeds, UK
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40
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Lowes JR, Radwan P, Priddle JD, Jewell DP. Characterisation and quantification of mucosal cytokine that induces epithelial histocompatibility locus antigen-DR expression in inflammatory bowel disease. Gut 1992; 33:315-9. [PMID: 1568649 PMCID: PMC1373819 DOI: 10.1136/gut.33.3.315] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Epithelial histocompatibility locus antigen (HLA) class II expression was studied to evaluate its induction by mucosal mononuclear cells in inflammatory bowel disease and to characterise the responsible cytokine. Unstimulated cells of the HT-29 epithelial cell line did not produce class II molecules. After being stimulated with the mitogenic lectin phytohaemagglutinin mucosal mononuclear cells released a cytokine that induced epithelial HLA-DR expression. The cytokine had the physicochemical and immunological characteristics of interferon-gamma, and no additional cytokines were detected.
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Affiliation(s)
- J R Lowes
- Gastroenterology Unit, Radcliffe Infirmary, Oxford
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41
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Sasaki T, Hiwatashi N, Yamazaki H, Noguchi M, Toyota T. The role of interferon gamma in the pathogenesis of Crohn's disease. GASTROENTEROLOGIA JAPONICA 1992; 27:29-36. [PMID: 1555746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
To investigate the role of interferon gamma in the pathogenesis of Crohn's disease, we examined the interferon gamma levels of serum, supernatant of cultured peripheral blood mononuclear cells activated by phytohemagglutinin, and medium of organ culture of colonic mucosa in Crohn's disease. Serum interferon gamma levels in Crohn's disease, especially in active or non-resected Crohn's disease, were more elevated than those in normal subjects. In contrast, the production of interferon gamma by peripheral blood mononuclear cells was reduced in Crohn's disease. In some patients, interferon gamma levels of organ culture medium of colonic mucosal tissue specimens were elevated. When peripheral blood mononuclear cells were preincubated for 72 hours, interferon gamma production in Crohn's disease increased from 23.8% to 62.3% in comparison to levels in healthy controls. These results indicate that elevated serum interferon gamma in Crohn's disease may originate from the intestine, and interferon gamma may be related to the immune reaction and inflammation in the intestine.
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Affiliation(s)
- T Sasaki
- Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan
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42
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Ishii N, Chiba M, Iizuka M, Watanabe H, Ishioka T, Masamune O. Expression of MHC class II antigens (HLA-DR, -DP, and -DQ) on human gastric epithelium. GASTROENTEROLOGIA JAPONICA 1992; 27:23-8. [PMID: 1555745 DOI: 10.1007/bf02775060] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Class II antigen expression on gastric epithelium was investigated using an immunoperoxidase method in relation to the degree of inflammatory cell infiltration in the lamina propria. Sixty-six biopsy specimens from 43 patients with chronic gastritis were examined. The frequency of HLA-DR expression in specimens with cell infiltration was 94%, while that in specimens without cell infiltration was 24%. There was significant difference in the frequency of HLA-DR expression between the two groups (P less than 0.01). HLA-DR was most intensely expressed in the glandular neck portion. The frequency and extent of class II antigen expression on gastric epithelium with cell infiltration were in the following order: DR greater than DP greater than DQ. The extent of DR and DP, but not DQ expression generally paralleled the degree of cell infiltration. Intestinal metaplasia was found in 13 specimens. In the area of intestinal metaplasia, epithelial class II staining was absent except for one specimen. These results suggest that the respective genes of three class II antigens are regulated by different mechanisms and that an immunological mechanism plays a role in the pathogenesis of gastritis.
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Affiliation(s)
- N Ishii
- First Department of Internal Medicine, Akita University School of Medicine, Japan
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43
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Sasaki T, Hiwatashi N, Yamazaki H, Noguchi M, Toyota T. The role of interferony in the pathogenesis of Crohn’s disease. ACTA ACUST UNITED AC 1992. [DOI: 10.1007/bf02775061] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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44
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Bland PW, Whiting CV. Induction of MHC class II gene products in rat intestinal epithelium during graft-versus-host disease and effects on the immune function of the epithelium. Immunol Suppl 1992; 75:366-71. [PMID: 1551699 PMCID: PMC1384721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The induction of major histocompatibility complex (MHC) class II expression in the epithelium of the small intestine of the rat during graft-versus-host disease (GVHD) and the effect of this process on the capacity of isolated epithelial cells to present antigen has been investigated. By immunohistology, increased class II (I-A) was noted in lamina propria cells and villus epithelium and de novo expression in crypt epithelium by Day 7 after transfer of parental spleen cells into irradiated hybrid rats. This increased expression reached a maximum by Day 9 or 10. The kinetics of induction of I-E products paralleled those of I-A in villus epithelium, but I-E was not seen in crypt epithelium. Direct radioimmunoassay of class II in isolated villus and crypt epithelial cells revealed a minor peak of class II, particularly in villus cells, very soon after cell transfer which waned and then increased to a second peak at Days 7-9. Assay of presentation of ovalbumin by isolated enterocytes to primed T cells at the peak of class II induction showed that increased class II expression by villus cells mediated enhanced antigen-presenting activity, whereas increases in crypt cell class II did not enable these cells to present ovalbumin.
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Affiliation(s)
- P W Bland
- Department of Veterinary Medicine, University of Bristol, Langford, U.K
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45
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Crotty B, Hoang P, Dalton HR, Jewell DP. Salicylates used in inflammatory bowel disease and colchicine impair interferon-gamma induced HLA-DR expression. Gut 1992; 33:59-64. [PMID: 1740279 PMCID: PMC1373866 DOI: 10.1136/gut.33.1.59] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colonic epithelial cells express HLA-DR in inflammatory bowel disease. The effect of drugs used in the treatment of inflammatory bowel disease and colchicine on interferon-gamma (IFN-gamma) induced DR expression has been investigated. HT-29 cells were cultured in 25 cm2 flasks. At 48 hours interferon-gamma (0, 50, or 100 U/ml) +/- drug were added. At 120 hours the cells were stained for HLA-DR and analysed by flow cytometry. 10(-2) M 5ASA reduced DR expression induced by 50 U/ml interferon-gamma from 62 (12)% of cells (mean SD) to 29 (20)% (p less than 0.005). Corresponding figures for 10(-2) M N-acetyl 5ASA were 68 (16)% to 39 (17)% (p less than 0.05); for 10(-2) M 4ASA, 61 (4)% to 57 (4)% (p = 0.6); for 10(-2) M N-acetyl 4ASA, 60 (12)% to 35 (13)% (p less than 0.05); for 10(-2) M olsalazine, 72 (9)% to 3 (1)% (p less than 0.001); for 10(-3) M olsalazine, 72 (9)% to 16 (10)% (p less than 0.001); for 10(-6) M colchicine, 62 (13)% to 5 (3)% (p less than 0.001); and for 10(-7) M colchicine, 62 (13)% to 10 (3)%. Similar results were obtained when DR was induced by 100 U/ml of interferon-gamma except with 10(-2) M 4ASA which reduced expression from 77 (4)% to 68 (3)% (p less than 0.05). Sulphapyridine, prednisolone, indomethacin and cyclosporin A had no effect. Concurrent staining with propidium iodide showed that these results were unchanged when viable cells alone were analysed. Prior incubation of cells with drug, followed by washing, had no effect on interferon-gamma induced DR expression. 5ASA, N-acetyl 5ASA, 4ASA, N-acetyl 4ASA, olsalazine and colchicine reduce interferon-gamma induced HLA-DR expression. In inflammatory bowel disease these compounds may impair antigen presentation by the colonic epithelium.
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Affiliation(s)
- B Crotty
- Gastroenterology Unit, Radcliffe Infirmary, Oxford
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46
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Allison MC, Poulter LW. Changes in phenotypically distinct mucosal macrophage populations may be a prerequisite for the development of inflammatory bowel disease. Clin Exp Immunol 1991; 85:504-9. [PMID: 1893632 PMCID: PMC1535603 DOI: 10.1111/j.1365-2249.1991.tb05757.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Previous studies have demonstrated the presence of much more marked macrophage heterogeneity in colonic mucosa affected by the idiopathic inflammatory bowel diseases (ulcerative colitis and Crohn's disease) than in normal mucosa. This study examines the morphology, distribution and phenotypic expression of mucosal macrophage-like cells in biopsies from patients with idiopathic inflammatory bowel disease in comparison with disease control samples from patients with colonic infection or ischaemia. Approximately 80% of macrophage-like cells in histologically normal mucosa co-express the antigens recognized by the monoclonal antibodies RFD1 (an interdigitating cell marker) and RFD7 (a marker for mature tissue macrophages). In idiopathic inflammatory bowel disease, the normal colonic macrophage population is partly replaced by cells staining positively with RFD7 alone, and, to a lesser extent, with RFD1+ dendritic cells. Sections from patients with infections and ischaemia exhibited epithelial HLA-DR positivity and infiltration of the lamina propria by a more heterogeneous population of macrophages than that seen in histologically normal mucosa. However, the displacement of the normal colonic macrophage phenotype by RFD7+ tissue macrophages occurred to a significantly greater extent in idiopathic inflammatory bowel disease than in disease control mucosa. A pathognomonic feature of the ulcerative colitis and Crohn's colitis sections was the clustering of RFD9+ epithelioid cells at the bases of disrupted crypts and adjacent to areas of mucosal damage. It is concluded that a degree of macrophage heterogeneity and macrophage infiltration can occur as a non-specific response to colonic mucosal damage. The distinctive feature of idiopathic inflammatory bowel disease mucosa is the almost complete replacement of the normal colonic mucosal macrophage population by tissue macrophages and epithelioid cells, and this phenomenon may be important in promoting the development of a chronic inflammatory state.
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Affiliation(s)
- M C Allison
- Gastroenterology Unit, Royal Infirmary, Glasgow, UK
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47
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Smart CJ, Calabrese A, Oakes DJ, Howdle PD, Trejdosiewicz LK. Expression of the LFA-1 beta 2 integrin (CD11a/CD18) and ICAM-1 (CD54) in normal and coeliac small bowel mucosa. Scand J Immunol 1991; 34:299-305. [PMID: 1679248 DOI: 10.1111/j.1365-3083.1991.tb01550.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The leucocyte adhesion molecules (beta 2 integrins) comprise CD11 alpha-chains and a common beta-chain (CD18). CD11a (leucocyte function-associated antigen 1, LFA-1) is expressed by most T cells, and is involved in antigen presentation by macrophages via its counter-receptor, intercellular adhesion molecule (ICAM-1, CD54). By criteria of double-label immunofluorescence of cryostat tissue sections, virtually all lamina propria T cells of the normal small bowel were found to express LFA-1 strongly. By contrast, only 30-60% of intra-epithelial lymphocytes (IEL) expressed detectable LFA-1, most of which were LFA-1 weak and CD18-. ICAM-1 was expressed strongly only by vascular endothelium. In coeliac disease, there was a modest increase of diffuse ICAM-1 expression in the lamina propria, mainly in the subepithelial zone, where ICAM-1+ macrophages were occasionally seen. There was also a slight overall increase in CD11a expression by IEL, seen predominantly in surface epithelium and mainly by the CD4+ minority subset, but not by CD4-CD8- (TcR gamma delta +) cells. These data suggest that the LFA-1/ICAM-1-dependent antigen presentation pathway is of minor importance to IEL in the normal small bowel, and does not assume a major role in coeliac disease.
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Affiliation(s)
- C J Smart
- Department of Medicine, St James's University Hospital, University of Leeds, UK
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48
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Deem RL, Shanahan F, Targan SR. Triggered human mucosal T cells release tumour necrosis factor-alpha and interferon-gamma which kill human colonic epithelial cells. Clin Exp Immunol 1991; 83:79-84. [PMID: 1899066 PMCID: PMC1535451 DOI: 10.1111/j.1365-2249.1991.tb05592.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
T cell activation can lead to local tissue injury in organ culture studies of human fetal jejunum, either directly through cytotoxicity or indirectly by the release of cytotoxic cytokines. The goal of this study was to establish in vitro whether cytotoxic cytokines can be released by isolated colonic T cells and what cytokine interactions are required for killing of human colonic epithelial cells. Cytokine-containing supernatants were induced by incubating unseparated lamina propria lymphocytes (LPL) or mucosal T cell subpopulations (separated by indirect panning) with anti-CD3 and/or K562 target cells for 18 h at 37 degrees C. Cytokines were measured by cytotoxicity assays using L929 (murine fibroblast) and HT-29 (human colonic tumour) lines as target cells in combination with blocking anti-cytokine antibodies. Supernatants derived from unseparated, CD4+ (greater than 95% pure) and CD8+ (greater than 90% pure) LPL were cytotoxic to L929 targets (350 U/ml, 230 U/ml and 100 U/ml tumour necrosis factor-alpha, respectively). All or nearly all of the cytotoxicity was due to the presence of tumour necrosis factor-alpha (little or no tumour necrosis factor-beta was detected). These same supernatants were cytotoxic (up to 32% lysis at 1/4 dilution) to HT-29 targets in a 48-h 111In release assay. Recombinant tumour necrosis factor-alpha and interferon-gamma alone produced minimal killing of HT-29, but together killed the HT-29 target cells. Anti-tumour necrosis factor-alpha or anti-interferon-gamma alone blocked killing of HT-29 target cells by LPL-derived supernatants, although anti-tumour necrosis factor-beta had no effect upon killing of HT-29. These results demonstrate that human LPL T cells, triggered by addition of anti-CD3 and target cells, produce tumour necrosis factor-alpha and interferon-gamma, both of which are required for optimal killing of HT-29. Simultaneous release of these cytokines in the vicinity of epithelial cells during immune responses could play an important role in the mucosal damage in chronic inflammatory states such as inflammatory bowel disease.
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Affiliation(s)
- R L Deem
- Department of Medicine, UCLA School of Medicine 90024
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49
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Malizia G, Calabrese A, Cottone M, Raimondo M, Trejdosiewicz LK, Smart CJ, Oliva L, Pagliaro L. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 1991; 100:150-9. [PMID: 1670578 DOI: 10.1016/0016-5085(91)90595-c] [Citation(s) in RCA: 163] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Leukocyte adhesion molecules are important in cell-cell interactions of the immune system. Lymphocyte function-associated antigen 1 (cluster designation 11a) mediates interactions between T cells and mononuclear phagocytes through its ligand, the intercellular adhesion molecule 1 (CD54), whereas complement receptors 3 (CD 11b) and 4 (CD11c) are involved in complement-mediated phagocytosis. Expression of CD11 molecules and intercellular adhesion molecule 1 was studied in colonic biopsy specimens from 20 patients with inflammatory bowel disease and 10 normal controls. In normal colon, few mononuclear phagocytes expressed lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1 at high densities. The major adhesion molecule was CD11c. Thus, the largest population of normal colonic mononuclear phagocytes was represented by quiescent, resident macrophages with likely phagocytic function. In inflammatory bowel disease, mononuclear phagocytes showed only a slight increase in CD11a expression and no significant change in expression of CD11b and CD11c. By contrast, the percentage of mononuclear phagocytes expressing intercellular adhesion molecule 1 was increased from 6.9% +/- 3.9% in controls to 69.2% +/- 12.8% in ulcerative colitis (P less than 0.001) and to 45.7% +/- 22.8% in Crohn's disease (P less than 0.01), showing a close relationship with histological activity. The increased expression of intercellular adhesion molecule 1 in inflammatory bowel disease indicates a state of immunological activation induced by local release of inflammatory cytokines. Such induction of intercellular adhesion molecule 1 on mononuclear phagocytes may be important in the maintenance of chronic inflammation by facilitating interactions with T cells and T-cell antigen recognition.
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Affiliation(s)
- G Malizia
- Divisione di Medicina, Ospedale V. Cervello, Palermo, Italy
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50
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Iizuka M, Chiba M, Horie Y, Masamune O, Ohta H. Lymphoid cell subsets in colonic mucosa and HLA-DR antigens on colonic epithelia in colitis excluding ulcerative colitis and Crohn's disease. GASTROENTEROLOGIA JAPONICA 1990; 25:700-7. [PMID: 2279631 DOI: 10.1007/bf02779183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Lymphoid cell subsets, including T cells as well as Ig-containing cells in the colonic mucosa and HLA-DR antigens on colonic epithelia, were examined in non-IBD colitis (colitis excluding ulcerative colitis (UC) and Crohn's disease) by the indirect immunoperoxidase staining method. Mouse anti-CD5, CD8, CD4, IgG, IgA1, IgA2, IgM, IgD, IgE, HLA-DR, and NuIa monoclonal antibodies were used as the first antibody. The results were compared to those of the normal controls and UC. T cell subsets in non-IBD colitis were almost similar to those of the controls and UC. The number of Ig-containing cells of all classes, except for IgA, tended to be increased in non-IBD colitis. In particular, both IgG- and IgE-containing cells were significantly increased compared to those in the controls. Compared to UC, IgG-containing cells were decreased in non-IBD colitis. Namely, in non-IBD colitis, as well as in UC, the change of Ig-containing cells (B cell lineage) was more pronounced than that of T cells. The frequency of the expression of HLA-DR antigens on colonic epithelia in non-IBD colitis was 70%, which was significantly higher than that in controls (0%), but significantly lower than that in UC (100%). Whether the differences in the number of IgG-containing cells, and the frequency of epithelial HLA-DR expression between non-IBD colitis and UC was due to the differences of the degree of local inflammation or due to the differences of the nature of the two diseases was not elucidated in this study.
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Affiliation(s)
- M Iizuka
- First Department of Internal Medicine, Akita University School of Medicine, Japan
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