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Chatrizeh M, Tian J, Rogers M, Feturi F, Wu G, Firek B, Nikonov R, Cass L, Sheppeck A, Ramos-Jiménez RG, Ohja L, Caroll A, Henkel M, Azar J, Aneja RK, Campfield B, Simon D, Morowitz MJ. Plant based enteral nutrition outperforms artificial nutrition in mitigating consequences of antibiotic-induced dysbiosis in mice and humans. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.19.25323813. [PMID: 40166543 PMCID: PMC11957089 DOI: 10.1101/2025.03.19.25323813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Malnutrition, gut inflammation, and antibiotic induced dysbiosis (AID) are omnipresent risk factors for poor clinical outcomes among critically ill patients. We previously showed that commercially available plant-based enteral nutrition (PBEN) preserves a commensal microbiome when compared to commonly used forms of commercially available artificial enteral nutrition (AEN). This study reveals that PBEN is superior to artificial enteral nutrition (AEN) in recovering from antibiotic-induced dysbiosis (AID) in mice and humans. PBEN effectively mitigates anemia, leukopenia, restores naïve lymphocyte populations, and reduces bone marrow myeloid cell expansion. Animals randomized to PBEN also fared better in response to infectious challenges after antibiotics. A pilot clinical study validated these findings, showing increased gut commensals, reduced pathogens, and improved leukocyte balance in critically ill patients receiving PBEN compared to AEN. These results suggest PBEN offers a practical dietary approach to mitigate antibiotic-associated complications and improve clinical outcomes among hospitalized patients requiring supplemental nutrition.
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2
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Hada A, Xiao Z. Ligands for Intestinal Intraepithelial T Lymphocytes in Health and Disease. Pathogens 2025; 14:109. [PMID: 40005486 PMCID: PMC11858322 DOI: 10.3390/pathogens14020109] [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: 12/26/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
The intestinal tract is constantly exposed to a diverse mixture of luminal antigens, such as those derived from commensals, dietary substances, and potential pathogens. It also serves as a primary route of entry for pathogens. At the forefront of this intestinal defense is a single layer of epithelial cells that forms a critical barrier between the gastrointestinal (GI) lumen and the underlying host tissue. The intestinal intraepithelial T lymphocytes (T-IELs), one of the most abundant lymphocyte populations in the body, play a crucial role in actively surveilling and maintaining the integrity of this barrier by tolerating non-harmful factors such as commensal microbiota and dietary components, promoting epithelial turnover and renewal while also defending against pathogens. This immune balance is maintained through interactions between ligands in the GI microenvironment and receptors on T-IELs. This review provides a detailed examination of the ligands present in the intestinal epithelia and the corresponding receptors expressed on T-IELs, including T cell receptors (TCRs) and non-TCRs, as well as how these ligand-receptor interactions influence T-IEL functions under both steady-state and pathological conditions. By understanding these engagements, we aim to shed light on the mechanisms that govern T-IEL activities within the GI microenvironment. This knowledge may help in developing strategies to target GI ligands and modulate T-IEL receptor expression, offering precise approaches for treating intestinal disorders.
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Affiliation(s)
| | - Zhengguo Xiao
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA;
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3
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Feng X, Xu Y. The recent progress of γδ T cells and its targeted therapies in rheumatoid arthritis. Int J Rheum Dis 2024; 27:e15381. [PMID: 39467001 DOI: 10.1111/1756-185x.15381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/03/2024] [Accepted: 10/08/2024] [Indexed: 10/30/2024]
Abstract
Rheumatoid arthritis (RA) is an autoimmune condition that mostly impacts the joints. During the advanced phases of the disorder, it may be accompanied by other problems. While the precise cause of RA is uncertain, various research has been conducted to gain a better understanding of the immunological processes involved in the development of RA. T cells are acknowledged as significant contributors to the progression of RA because of their roles in cytokine secretion, antigen presentation, and facilitating B cells in the manufacture of antibodies. γδ T cells are a small subset of T cells that have significant functions in the context of infection and diseases linked with tumors. γδ T cells have been the subject of investigation in autoimmune disorders in recent years. This review focused on the involvement of γδ T lymphocytes in the development of RA. In this article, we provide an analysis of the immunological capabilities of γδ T cells, intending to comprehend their significance in RA, which could be pivotal in the creation of innovative clinical treatments.
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Affiliation(s)
- Xue Feng
- Department of Bone and Joint Surgery, The First Bethune Hospital of Jilin University, Changchun, China
| | - Yan Xu
- Department of Bone and Joint Surgery, The First Bethune Hospital of Jilin University, Changchun, China
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Jin XY, Li DD, Quan W, Chao Y, Zhang B. Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability? Front Immunol 2024; 15:1347901. [PMID: 38571963 PMCID: PMC10987687 DOI: 10.3389/fimmu.2024.1347901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/07/2024] [Indexed: 04/05/2024] Open
Abstract
Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.
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Affiliation(s)
- Xi-ya Jin
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Dan-dan Li
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Quan
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Chao
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bin Zhang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
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5
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Feakins R, Borralho Nunes P, Driessen A, Gordon IO, Zidar N, Baldin P, Christensen B, Danese S, Herlihy N, Iacucci M, Loughrey MB, Magro F, Mookhoek A, Svrcek M, Rosini F. Definitions of Histological Abnormalities in Inflammatory Bowel Disease: an ECCO Position Paper. J Crohns Colitis 2024; 18:175-191. [PMID: 37607017 PMCID: PMC10896637 DOI: 10.1093/ecco-jcc/jjad142] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Indexed: 08/24/2023]
Abstract
Histological assessment of endoscopic biopsies in inflammatory bowel disease [IBD] plays an important role in clinical management, investigative studies, and clinical trials. Scoring schemes consisting of multiple histological items and offering considerable precision are widely available. However, definitions of histological abnormalities are often inconsistent. Furthermore, interobserver variability for their recognition and assessment may be high. The European Crohn's and Colitis Organisation [ECCO] formed an expert panel to explore definitions of histological abnormalities in IBD, with the aim of improving the quality of diagnosis and facilitating development of scoring schemes. The process confirmed that the current definitions often have no evidence base and vary between sources. Using available evidence and expert knowledge, the panel produced a series of ECCO consensus position statements on histological features in IBD.
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Affiliation(s)
- Roger Feakins
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust; University College London; London, UK
| | - Paula Borralho Nunes
- Department of Pathology, Hospital Cuf Descobertas, Lisboa and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ann Driessen
- Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium
| | - Ilyssa O Gordon
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Nina Zidar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Pamela Baldin
- Department of Pathology, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Britt Christensen
- Royal Melbourne Hospital Melbourne, Department of Gastroenterology, Parkville; University of Melbourne, Department of Medicine, Melbourne, Victoria, Australia
| | - Silvio Danese
- IRCCS Ospedale and University Vita-Salute San Raffaele, Department of Gastroenterology, Milan, Italy
| | - Naoimh Herlihy
- Department of Cellular Pathology, University College London Hospital NHS Foundation Trust, London, UK
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Maurice B Loughrey
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast; Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust;Belfast,UK
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Aart Mookhoek
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Magali Svrcek
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Department of Pathology, Paris, France
| | - Francesca Rosini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Cronin SK, Barnard AM, Dietz SJ, Lawrence M, Kramer AE, Gressley TF. Effect of short-term abomasal corn starch infusions on postruminal fermentation and blood measures. J Dairy Sci 2023; 106:8658-8669. [PMID: 37641271 DOI: 10.3168/jds.2022-23180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 06/15/2023] [Indexed: 08/31/2023]
Abstract
It is possible that some of the systemic responses to subacute ruminal acidosis (SARA) may be caused by increased intestinal starch fermentation. The objective of this experiment was to evaluate the effect of abomasal infusion of up to 3 g of corn starch/kg body weight (approximately 1.6 kg of starch/d) on fecal measures of fermentation, plasma acute phase proteins, and white blood cell populations. Six ruminally cannulated cows in late lactation were randomly assigned to duplicate 3 × 3 Latin squares with 21-d periods. Cows were fed a 20.6% starch TMR twice daily and during the last 7 d of each period cows were abomasally infused with corn starch at 0 (CON), 1 (ST1), or 3 (ST3) g/kg body weight split into 2 bolus infusions, provided every 12 h. Fecal samples were collected at 0, 6, 12, and 18 h following feeding on d 21 and were analyzed for pH, VFA, lactic acid, and lipopolysaccharide (LPS). Composite fecal samples were used to estimate apparent total-tract nutrient digestibility using undigested neutral detergent fiber as an internal marker. Blood samples were collected at 0 and 6 h relative to feeding on d 14, 18, and 21 of each period. Concentrations of haptoglobin and serum amyloid A in plasma were measured in all samples, 0 h samples on d 14 and 21 were used to measure white blood cell populations, and 0 h samples from d 14, 18, and 21 were used for flow cytometric analysis of γδ T cells. Data were analyzed in SAS using models that included fixed effects of treatment and period and the random effects of cow and square. For blood measures, d 14 samples collected before the initiation of abomasal infusions were included as covariates. Time (d or h) was added as a repeated measure in variables that included multiple samples during the abomasal infusion period. A contrast was used to determine the linear effect of increasing abomasal corn starch. Abomasal corn starch linearly decreased fecal pH and linearly increased fecal total VFA and LPS, but effects were modest, with fecal pH, total VFA, and LPS changing from 6.96, 57.7 mM, and 4.14 log10 endotoxin units (EU) per gram for the CON treatment to 6.69, 64.1 mM, and 4.58 log10 EU/g for the ST3 treatment, respectively. This suggests that we did not induce hindgut acidosis. There were no effects of treatment on apparent total-tract starch digestibility or fecal starch content (mean of 96.9% and 2.2%, respectively). Treatment did not affect serum acute phase proteins or most circulating white blood cells, but the proportion of circulating γδ T cells tended to linearly decrease from 6.69% for CON to 4.61% for ST3. Contrary to our hypothesis, increased hindgut starch fermentation did not induce an inflammatory response in this study.
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Affiliation(s)
- S K Cronin
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716
| | - A M Barnard
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716
| | - S J Dietz
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716
| | - M Lawrence
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716
| | - A E Kramer
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716
| | - T F Gressley
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716.
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Hu Y, Hu Q, Li Y, Lu L, Xiang Z, Yin Z, Kabelitz D, Wu Y. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther 2023; 8:434. [PMID: 37989744 PMCID: PMC10663641 DOI: 10.1038/s41392-023-01653-8] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/23/2023] Open
Abstract
The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell immunology and its role in diseases. Initially, we elucidate functional differences between γδ T cells and their αβ T cell counterparts. We also provide an overview of major milestones in γδ T cell research since their discovery in 1984. Furthermore, we delve into the intricate biological processes governing their origin, development, fate decisions, and T cell receptor (TCR) rearrangement within the thymus. By examining the mechanisms underlying the anti-tumor functions of distinct γδ T cell subtypes based on γδTCR structure or cytokine release, we emphasize the importance of accurate subtyping in understanding γδ T cell function. We also explore the microenvironment-dependent functions of γδ T cell subsets, particularly in infectious diseases, autoimmune conditions, hematological malignancies, and solid tumors. Finally, we propose future strategies for utilizing allogeneic γδ T cells in tumor immunotherapy. Through this comprehensive review, we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers of γδ T cells, ultimately contributing to further advancements in harnessing the therapeutic potential of γδ T cells.
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Affiliation(s)
- Yi Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Qinglin Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Zheng Xiang
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Zhinan Yin
- Biomedical Translational Research Institute, Jinan University, Guangzhou, Guangdong, 510632, China.
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China.
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8
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Hsu NY, Nayar S, Gettler K, Talware S, Giri M, Alter I, Argmann C, Sabic K, Thin TH, Ko HBM, Werner R, Tastad C, Stappenbeck T, Azabdaftari A, Uhlig HH, Chuang LS, Cho JH. NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures. Gut 2023; 72:654-662. [PMID: 36191961 PMCID: PMC9998338 DOI: 10.1136/gutjnl-2021-326305] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 08/20/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined. DESIGN ROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury. RESULTS TNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation. CONCLUSIONS NOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.
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Affiliation(s)
- Nai-Yun Hsu
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shikha Nayar
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kyle Gettler
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sayali Talware
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, USA
- The Icahn Genomic Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Mamta Giri
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Isaac Alter
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Carmen Argmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ksenija Sabic
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tin Htwe Thin
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Huai-Bin Mabel Ko
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Robert Werner
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher Tastad
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thaddeus Stappenbeck
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Aline Azabdaftari
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Ling-Shiang Chuang
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judy H Cho
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics. Nat Genet 2022; 54:1479-1492. [PMID: 36175791 PMCID: PMC9910198 DOI: 10.1038/s41588-022-01187-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/18/2022] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.
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10
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Jiang X, Wu J, Guo C, Song W. Key LncRNAs Associated With Oxidative Stress Were Identified by GEO Database Data and Whole Blood Analysis of Intervertebral Disc Degeneration Patients. Front Genet 2022; 13:929843. [PMID: 35937989 PMCID: PMC9353269 DOI: 10.3389/fgene.2022.929843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain, but the onset and progression of IDD are unknown. Long non-coding RNA (lncRNA) has been validated to play a critical role in IDD, while an increasing number of studies have linked oxidative stress (OS) to the initiation and progression of IDD. We aim to investigate key lncRNAs in IDD through a comprehensive network of competing endogenous RNA (ceRNA) and to identify possible underlying mechanisms. Methods: We downloaded IDD-related gene expression data from the Gene Expression Omnibus (GEO) database and obtained differentially expressed-lncRNAs (DE-lncRNA), -microRNAs (DE-miRNA), and -messenger RNAs (DE-mRNA) by bioinformatics analysis. The OS-related lncRNA-miRNA-mRNA ceRNA interaction axis was constructed and key lncRNAs were identified based on ceRNA theory. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses on mRNAs regulated by lncRNAs in the ceRNA network. Single sample gene set enrichment analysis (ssGSEA) was used to reveal the immune landscape. Expression of key lncRNAs in IDD was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: In this study, 111 DE-mRNAs, 20 DE-lncRNAs, and 502 DE-miRNAs were identified between IDD patients and controls, and 16 OS-related DE-lncRNAs were also identified. The resulting lncRNA-miRNA-mRNA network consisted of eight OS-related DE-lncRNA nodes, 24 DE-miRNA nodes, 70 DE-mRNA nodes, and 183 edges. Functional enrichment analysis suggested that the ceRNA network may be involved in regulating biological processes related to cytokine secretion, lipid, and angiogenesis. We also identified four key lncRNAs, namely lncRNA GNAS-AS1, lncRNA MIR100HG, lncRNA LINC01359, and lncRNA LUCAT1, which were also found to be significantly associated with immune cells. Conclusion: These results provide novel insights into the potential applications of OS-related lncRNAs in patients with IDD.
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11
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Enhanced oxidative phosphorylation of IgG plasma cells can contribute to hypoxia in the mucosa of active ulcerative colitis. Histochem Cell Biol 2022; 158:335-344. [PMID: 35716204 DOI: 10.1007/s00418-022-02122-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2022] [Indexed: 11/04/2022]
Abstract
Mucosal hypoxia is detected in the mucosa of ulcerative colitis (UC), however the mechanism and the cause of hypoxia is not fully understood, while a dense infiltration of plasma cells is observed in the inflamed mucosa of UC. When differentiating from a B cell to a plasma cell, the energy metabolism dramatically shifts from glycolysis to oxidative phosphorylation, which results in a large amount of oxygen consumption of the plasma cell. We hypothesized that the plasma cell infiltration into the inflamed mucosa contributes to the mucosal hypoxia in UC in part. We examined the association between mucosal hypoxia and plasma cell infiltration in UC. More IgG plasma cells (but not IgA plasma cells) were distributed, and the nuclear and cell sizes were enlarged in hypoxic mucosa compared to normoxic mucosa in UC. Oxidative phosphorylation signature genes of these IgG plasma cells were markedly upregulated compared to those of other lymphoid cells infiltrating the lamina propria of inflamed mucosa of UC. Enlarged IgG plasma cells, which increase in number in the inflamed mucosa of UC, can be related to the hypoxic state of the inflamed mucosa of UC.
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12
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Ma X, Su J, Wang B, Jin X. Identification of Characteristic Genes in Whole Blood of Intervertebral Disc Degeneration Patients by Weighted Gene Coexpression Network Analysis (WGCNA). COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:6609901. [PMID: 35069789 PMCID: PMC8776439 DOI: 10.1155/2022/6609901] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022]
Abstract
Intervertebral disc degeneration (IDD) is a major cause of lower back pain. However, to date, the molecular mechanism of the IDD remains unclear. Gene expression profiles and clinical traits were downloaded from the Gene Expression Omnibus (GEO) database. Firstly, weighted gene coexpression network analysis (WGCNA) was used to screen IDD-related genes. Moreover, least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine (SVM) algorithms were used to identify characteristic genes. Furthermore, we further investigated the immune landscape by the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm and the correlations between key characteristic genes and infiltrating immune cells. Finally, a competing endogenous RNA (ceRNA) network was established to show the regulatory mechanisms of characteristic genes. A total of 2458 genes were identified by WGCNA, and 48 of them were disordered. After overlapping the genes obtained by LASSO and SVM-RFE algorithms, genes including LINC01347, ASAP1-IT1, lnc-SEPT7L-1, B3GNT8, CHRNB3, CLEC4F, LOC102724000, SERINC2, and LOC102723649 were identified as characteristic genes of IDD. Moreover, differential analysis further identified ASAP1-IT1 and SERINC2 as key characteristic genes. Furthermore, we found that the expression of both ASAP1-IT1 and SERINC2 was related to the proportions of T cells gamma delta and Neutrophils. Finally, a ceRNA network was established to show the regulatory mechanisms of ASAP1-IT1 and SERINC2. In conclusion, the present study identified ASAP1-IT1 and SERINC2 as the key characteristic genes of IDD through integrative bioinformatic analyses, which may contribute to the diagnosis and treatment of IDD.
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Affiliation(s)
- Xiaobo Ma
- Department of Orthopaedics, Yuncheng Central Hospital, Shanxi University, Yuncheng, China 044000
| | - Junqiang Su
- Department of Orthopaedics, Yuncheng Central Hospital, Shanxi University, Yuncheng, China 044000
| | - Bo Wang
- Department of Orthopaedics, Yuncheng Central Hospital, Shanxi University, Yuncheng, China 044000
| | - Xiasheng Jin
- Department of Orthopaedics, Yuncheng Central Hospital, Shanxi University, Yuncheng, China 044000
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Jagadeesh KA, Dey KK, Montoro DT, Mohan R, Gazal S, Engreitz JM, Xavier RJ, Price AL, Regev A. Identifying disease-critical cell types and cellular processes across the human body by integration of single-cell profiles and human genetics. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.03.19.436212. [PMID: 34845454 PMCID: PMC8629197 DOI: 10.1101/2021.03.19.436212] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Genome-wide association studies (GWAS) provide a powerful means to identify loci and genes contributing to disease, but in many cases the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. Here, we introduce sc-linker, a framework for integrating single-cell RNA-seq (scRNA-seq), epigenomic maps and GWAS summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. We analyzed 1.6 million scRNA-seq profiles from 209 individuals spanning 11 tissue types and 6 disease conditions, and constructed gene programs capturing cell types, disease progression, and cellular processes both within and across cell types. We evaluated these gene programs for disease enrichment by transforming them to SNP annotations with tissue-specific epigenomic maps and computing enrichment scores across 60 diseases and complex traits (average N= 297K). Cell type, disease progression, and cellular process programs captured distinct heritability signals even within the same cell type, as we show in multiple complex diseases that affect the brain (Alzheimer’s disease, multiple sclerosis), colon (ulcerative colitis) and lung (asthma, idiopathic pulmonary fibrosis, severe COVID-19). The inferred disease enrichments recapitulated known biology and highlighted novel cell-disease relationships, including GABAergic neurons in major depressive disorder (MDD), a disease progression M cell program in ulcerative colitis, and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease progression immune cell type programs were associated, whereas for epithelial cells, disease progression programs were most prominent, perhaps suggesting a role in disease progression over initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.
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Gryglewski A, Richter P, Szczepanik M. Changes in γδT Cells in Peripheral Blood of Patients with Ulcerative Colitis Exacerbations. Arch Immunol Ther Exp (Warsz) 2021; 69:18. [PMID: 34287711 PMCID: PMC8295081 DOI: 10.1007/s00005-021-00620-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
The role of γδT cells in ulcerative colitis (UC) is well confirmed in experimental animals and demonstrated in many clinical observations. Recent investigations have indicated that UC is associated with several forms of immune imbalance, such as an imbalance between effector T cells and regulatory T cells. However, little is known about the cellular aspect of clinical colitis exacerbations. We observed 140 patients with histologically confirmed UC over the course of 8 years. We investigated the percentage of γδT and αβT cells in peripheral blood of patients and also the expression of various surface markers (CD25, CD54, CD62L). Patients were assembled into stable colitis and exacerbated colitis groups. The percentage of γδT and αβT cells was evaluated by Ortho Cytorone Absolute flow cytometer. In patients with exacerbated colitis we observed a decrease of γδT cells in peripheral blood and an increased ratio of αβT/γδT. Additionally, we found that exacerbation results in a significant increase of percentage of γδTCD25, γδTCD54 and γδTCD62L lymphocytes in peripheral blood when compared to patients with stable colitis. Exacerbation of ulcerative colitis results in a decreased percentage of γδT cells in peripheral blood with increase of CD25, CD54 and CD62L expressing γδT cells. This may represent the effect of cell activation and migration, similar to that observed after the surgical trauma. We hope that this observation may help to predict exacerbations in colitis patients.
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Affiliation(s)
- Andrzej Gryglewski
- Department of Anatomy and Department of General Surgery, Gastroenterology, Oncology and Transplantology, Jagiellonian University Medical College, Kraków, Poland.
| | - Piotr Richter
- Department of General Surgery, Gastroenterology, Oncology and Transplantology, Jagiellonian University Medical College, Kraków, Poland
| | - Marian Szczepanik
- Department of Medical Biology, Jagiellonian University Medical College, Kraków, Poland.
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15
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Suppression of plasmacytoid dendritic cell migration to colonic isolated lymphoid follicles abrogates the development of colitis. Biomed Pharmacother 2021; 141:111881. [PMID: 34246191 DOI: 10.1016/j.biopha.2021.111881] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear. METHODS 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice. FINDINGS Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy. INTERPRETATION pDCs accumulated in the colon of colitis mice, and As-IV and Oxy ameliorated colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.
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Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol 2021; 14:793-802. [PMID: 33753873 DOI: 10.1038/s41385-021-00389-4] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023]
Abstract
Gut-associated lymphoid tissues (GALT) are the key antigen sampling and adaptive immune inductive sites within the intestinal wall. Human GALT includes the multi-follicular Peyer's patches of the ileum, the vermiform appendix, and the numerous isolated lymphoid follicles (ILF) which are distributed along the length of the intestine. Our current understanding of GALT diversity and function derives primarily from studies in mice, and the relevance of many of these findings to human GALT remains unclear. Here we review our current understanding of human GALT diversity, structure, and composition as well as their potential for regulating intestinal immune responses during homeostasis and inflammatory bowel disease (IBD). Finally, we outline some key remaining questions regarding human GALT, the answers to which will advance our understanding of intestinal immune responses and provide potential opportunities to improve the treatment of intestinal diseases.
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17
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Sumida H. Recent advances in roles of G-protein coupled receptors in intestinal intraepithelial lymphocytes. BIOSCIENCE OF MICROBIOTA FOOD AND HEALTH 2020; 39:77-82. [PMID: 32775124 PMCID: PMC7392907 DOI: 10.12938/bmfh.2019-053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/23/2020] [Indexed: 12/20/2022]
Abstract
Intestinal intraepithelial lymphocytes (IELs) potentially provide the first line of immune defense against enteric pathogens. In addition, there is growing evidence supporting the
involvement of IELs in the pathogenesis of gut disorders such as inflammatory bowel diseases. Various kinds of molecules are involved in the dynamics of IELs, such as homing to the
intestinal epithelium and retention in the intestinal mucosa. G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors and regulate many biological
responses. Although some GPCRs, like CCR9, have been implicated to have roles in IEL homing, little is still known regarding the functional roles of GPCRs in IEL biology. In this
review, we provide a concise overview of recent advances in the roles of novel GPCRs like GPR55 and GPR18 in the dynamics of IELs.
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Affiliation(s)
- Hayakazu Sumida
- 1Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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18
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Yang X, Geng J, Meng H. Glucocorticoid receptor modulates dendritic cell function in ulcerative colitis. Histol Histopathol 2020; 35:1379-1389. [PMID: 32706033 DOI: 10.14670/hh-18-241] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Ulcerative colitis (UC) is a serious form of inflammatory bowel disease (IBD) occurring worldwide. Although anti-TNF therapy is found to be effective in over 70% of patients with UC, nearly one-third are still deprived of effective treatment. Because glucocorticoids (GC) can effectively inhibit granulocyte-recruitment into the mucosa, cytokine secretion and T cell activation, they are used widely in the treatment of UC. However, remission is observed in only 55% of the patients after one year of steroid use due to a condition known as steroid response. Additionally, it has been noted that 20%-40% of the patients with UC do not respond to GC treatment. Researchers have revealed that the number of dendritic cells (DCs) in patients with UC tends to increase in the colonic mucosa. Many studies have determined that the removal of peripheral DCs through the adsorption and separation of granulocytes and monocytes could improve tolerance of the intestine to its symbiotic flora. Based on these results, further insights regarding the beneficial effects of Adacolumn apheresis in patients subjected to this treatment could be revealed. GC can effectively inhibit the activation of DCs by reducing the levels of major histocompatibility complex class II (MHC II) molecules, which is critical for controlling the recruitment of granulocytes. Therefore, alternative biological and new individualized therapies based on these approaches need to be evaluated to counter UC. In this review, progress in research associated with the regulatory effect of glucocorticoid receptors on DCs under conditions of UC is discussed, thus providing insights and identifying potential targets which could be employed in the treatment strategies against UC.
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Affiliation(s)
- Xinxin Yang
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jingshu Geng
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongxue Meng
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.,Department of Pathology, Harbin Medical University, Harbin, China.
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19
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Gröschel C, Prinz-Wohlgenannt M, Mesteri I, Karuthedom George S, Trawnicek L, Heiden D, Aggarwal A, Tennakoon S, Baumgartner M, Gasche C, Lang M, Marculescu R, Manhardt T, Schepelmann M, Kallay E. Switching to a Healthy Diet Prevents the Detrimental Effects of Western Diet in a Colitis-Associated Colorectal Cancer Model. Nutrients 2019; 12:E45. [PMID: 31877961 PMCID: PMC7019913 DOI: 10.3390/nu12010045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 01/19/2023] Open
Abstract
Inflammatory bowel disease increases the odds of developing colitis-associated cancer. We hypothesized that Western-style diet (WD) aggravates azoxymethane (AOM)/dextran sulfate sodium salt (DSS)-induced colitis-associated tumorigenesis and that switching to the standard AIN93G diet will ameliorate disease symptoms even after cancer initiation. Female BALB/c mice received either WD (WD group) or standard AIN93G diet (AIN group) for the whole experimental period. After five weeks, the mice received 12.5 mg/kg AOM intraperitoneally, followed by three DSS cycles. In one group of mice, the WD was switched to AIN93G the day before starting the first DSS cycle (WD/AIN group). Feeding the WD during the whole experimental period aggravated colitis symptoms, shortened the colon (p < 0.05), changed microbiota composition and increased tumor promotion. On molecular level, the WD reduced proliferation (p < 0.05) and increased expression of the vitamin D catabolizing enzyme Cyp24a1 (p < 0.001). The switch to the AIN93G diet ameliorated this effect, reflected by longer colons, fewer (p < 0.05) and smaller (p < 0.01) aberrant colonic crypt foci, comparable with the AIN group. Our results show that switching to a healthy diet, even after cancer initiation is able to revert the deleterious effect of the WD and could be an effective preventive strategy to reduce colitis symptoms and prevent tumorigenesis.
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Affiliation(s)
- Charlotte Gröschel
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Maximilian Prinz-Wohlgenannt
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Ildiko Mesteri
- Institute of Pathology Überlingen, 88662 Überlingen, Germany;
| | - Sobha Karuthedom George
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Lena Trawnicek
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Denise Heiden
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Abhishek Aggarwal
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Samawansha Tennakoon
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Maximilian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Michaela Lang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria;
| | - Teresa Manhardt
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Martin Schepelmann
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Enikö Kallay
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
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20
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Costa RG, Caro PL, de Matos‐Neto EM, Lima JD, Radloff K, Alves MJ, Camargo RG, Pessoa AFM, Simoes E, Gama P, Cara DC, da Silva AS, O. Pereira W, Maximiano LF, de Alcântara PS, Otoch JP, Trinchieri G, Laviano A, Muscaritoli M, Seelaender M. Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa. J Cachexia Sarcopenia Muscle 2019; 10:1116-1127. [PMID: 31307125 PMCID: PMC6818537 DOI: 10.1002/jcsm.12449] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 04/09/2019] [Accepted: 04/17/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia-related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. METHODS Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® xMAP) analyses. RESULTS There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL-6) and IL-8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL-7, IL-13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte-colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL-13 and transforming growth factor beta 3. CONCLUSIONS The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.
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Affiliation(s)
- Raquel G.F. Costa
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
- Cancer and Inflammation ProgramNational Cancer Institute, National Institutes of HealthBethesdaMDUSA
| | - Paula L. Caro
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Emídio M. de Matos‐Neto
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
- Department of Physical EducationFederal University of PiauiTeresinaPIBrazil
| | - Joanna D.C.C. Lima
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Katrin Radloff
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Michele J. Alves
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Rodolfo G. Camargo
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Ana Flávia M. Pessoa
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Estefania Simoes
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Patrícia Gama
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
| | - Denise C. Cara
- Department of MorphologyFederal University of Minas GeraisBelo HorizonteMGBrazil
| | | | - Welbert O. Pereira
- School of Medicine, Faculdade Isaraelita de Ciências da Saúde Albert Einstein (FICSAE)São PauloBrazil
| | - Linda F. Maximiano
- Department of SurgeryUniversity Hospital, University of São PauloSão PauloBrazil
- Department of SurgeryUniversity of São Paulo Medical School (FMUSP)São PauloBrazil
| | | | - José P. Otoch
- Department of SurgeryUniversity Hospital, University of São PauloSão PauloBrazil
- Department of SurgeryUniversity of São Paulo Medical School (FMUSP)São PauloBrazil
| | - Giorgio Trinchieri
- Cancer and Inflammation ProgramNational Cancer Institute, National Institutes of HealthBethesdaMDUSA
| | | | | | - Marília Seelaender
- Department of Cell and Developmental Biology, Institute of Biomedical SciencesUniversity of São Paulo (USP)São PauloBrazil
- Department of SurgeryUniversity of São Paulo Medical School (FMUSP)São PauloBrazil
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21
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Abstract
Intestinal intraepithelial lymphocytes (IELs) are one of the largest populations of lymphocytes and comprised of heterogeneous populations with varying phenotypes and physiological/pathological functions. IELs located between the basolateral surfaces of the epithelial cells and then potentially provide a first line of immune defense against enteric pathogens, although, the precise roles of each IEL populations are not well defined. A variety of molecules are involved in the IEL-homing to the intestinal epithelium. Conventional IELs originate from circulating T cells activated in lymphoid organs and imprinted for gut homing. On the other hand, unconventional IELs derive from thymocytes and migrate to the intestinal epithelium, although, some of them may arise extrathymically. Regarding the interaction between IELs and epithelial cells, IELs are known to be highly motile and actively migrate along the basement membrane, suggesting their roles in immune surveillance. In addition, there has been growing evidence to support that IELs are involved in the pathogenesis of gut disorders such as celiac disease and inflammatory bowel diseases. In this review, we provide a comprehensive overview of IEL dynamics and their clinical significance.
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Affiliation(s)
- Hayakazu Sumida
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
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22
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GLM, a novel luteolin derivative, attenuates inflammatory responses in dendritic cells: Therapeutic potential against ulcerative colitis. Biochem Biophys Res Commun 2019; 518:87-93. [PMID: 31402120 DOI: 10.1016/j.bbrc.2019.08.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/05/2019] [Indexed: 12/13/2022]
Abstract
GLM, a luteolin derivative, shows anti-melanogenic effect via regulation of various signal molecules; however, it is unclear whether it also exerts anti-inflammatory effect. This study investigated the mechanisms of the anti-inflammatory effect of GLM on activated dendritic cells (DCs) to elucidate its therapeutic potential for ulcerative colitis. The anti-inflammatory effect of GLM was firstly investigated based on its effect on DCs maturation and T cells proliferation/activation. GLM treatment downregulated pro-inflammatory cytokine productions, surface molecule expression, and antigen-presenting ability for MHC-II complex in LPS-activated DCs. Importantly, anti-inflammatory effect induced by GLM treatment were independent of MAPK/NF-κB signaling pathways. Furthermore, DCs that were co-treated with LPS and GLM impaired the proliferation and activation of naïve CD4+ T cells. Interestingly, GLM exerted in vivo protective effect in DSS-induced colitis models by decreasing Th1, Th2, and Th17 cells and myeloperoxidase (MPO) levels, as well as restoring body weight, disease activity, and DSS-induced pathology. Based on these results, GLM was shown to be a potential candidate treatment for ulcerative colitis.
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23
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Boshagh MA, Foroutan P, Moloudi MR, Fakhari S, Malakouti P, Nikkhoo B, Jalili A. ELR positive CXCL chemokines are highly expressed in an animal model of ulcerative colitis. J Inflamm Res 2019; 12:167-174. [PMID: 31417300 PMCID: PMC6599894 DOI: 10.2147/jir.s203714] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/16/2019] [Indexed: 12/21/2022] Open
Abstract
Background: The presence of neutrophil-rich inflammation in colon tissues of patients with ulcerative colitis (UC) is one of the most important histological characteristics of this disease. However, the expression of CXCL chemokines governing the infiltration of neutrophils in UC has not been well elucidated. Materials and methods: In this experimental study, the UC model was induced in Wistar rats by administration of 2 mL 4% acetic acid into the large colon through the rectum. Animals were anesthetized after 48 hrs; their colon tissue samples were isolated for macroscopic and histopathological examinations. The expression of CXCL family was assessed by reverse transcription polymerase chain reaction (qRT-PCR) technique. Results: Heavy infiltration of neutrophils, coagulation necrosis, and ulcers were observed in H&E staining, which pathologically proved the UC model. qRT-PCR results showed that ELR+ CXC chemokines such as CXCL6 and CXCL3 had the highest expression in the UC group, which was 49 and 28 times higher than that of the control group, respectively. In addition, other chemokines of this group including CXCL1, CXCL2, and CXCL7 had a significant increase compared to the control group (P≤0.05). However, ELR− CXC chemokines such as CXCL4, CXCL13, and CXCL16 showed a smaller upregulation, while CXCL14 chemokine showed a significant decrease compared to the control group (P≤0.05). However, the expression of CXCL9-12 and CXCL17 did not change. Conclusion: The results showed that the ELR+ CXC chemokines, especially CXCL6 and CXCL3, many involved in the pathogenesis of UC; therefore, CXCL6 and CXCL3 chemokines can be used as therapeutic targets for UC, although more studies using human samples are required.
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Affiliation(s)
- Mohammad Amin Boshagh
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology & Hematology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Poorya Foroutan
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology & Hematology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Raman Moloudi
- Liver and Digestive Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Shohreh Fakhari
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Parisa Malakouti
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bahram Nikkhoo
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ali Jalili
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology & Hematology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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24
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Abstract
Cholesterol is an essential molecule for life. It is a component of the cell membrane, and it is a precursor molecule for bile acids, vitamin D and steroid hormones. Cholesterol is actively metabolized, but the impact of endogenous cholesterol metabolites on immune function, especially in the intestine, is poorly understood. In this review, I focus on oxysterols, hydroxylated forms of cholesterol, and their specialized functions in intestinal immunity. Oxysterols act through various intracellular and extracellular receptors and serve as key metabolic signals, coordinating immune activity and inflammation. Our recent work has identified an unexpected link between cholesterol metabolism, innate lymphoid cell function and intestinal homeostasis. We discovered that oxysterol sensing through the G protein-coupled receptor 183 (GPR183) directs the migration of innate lymphoid cells, which is essential for the formation of lymphoid tissue in the colon. Moreover, we found that the interaction of GPR183 with oxysterols regulates intestinal inflammation. I will discuss the therapeutic potential of oxysterols and future possibilities of treating inflammatory bowel disease through the modulation of cholesterol metabolism.
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Affiliation(s)
- T. Willinger
- Department of Medicine HuddingeCenter for Infectious MedicineKarolinska InstitutetStockholmSweden
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25
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Van Kaer L, Olivares-Villagómez D. Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes. THE JOURNAL OF IMMUNOLOGY 2019; 200:2235-2244. [PMID: 29555677 PMCID: PMC5863587 DOI: 10.4049/jimmunol.1701704] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 01/25/2018] [Indexed: 12/13/2022]
Abstract
The intestine is continuously exposed to commensal microorganisms, food, and environmental agents and also serves as a major portal of entry for many pathogens. A critical defense mechanism against microbial invasion in the intestine is the single layer of epithelial cells that separates the gut lumen from the underlying tissues. The barrier function of the intestinal epithelium is supported by cells and soluble factors of the intestinal immune system. Chief among them are intestinal intraepithelial lymphocytes (iIELs), which are embedded in the intestinal epithelium and represent one of the single largest populations of lymphocytes in the body. Compared with lymphocytes in other parts of the body, iIELs exhibit unique phenotypic, developmental, and functional properties that reflect their key roles in maintaining the intestinal epithelial barrier. In this article, we review the biology of iIELs in supporting normal health and how their dysregulation can contribute to disease.
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Affiliation(s)
- Luc Van Kaer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
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26
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Yoshimura T, McLean MH, Dzutsev AK, Yao X, Chen K, Huang J, Gong W, Zhou J, Xiang Y, H Badger J, O'hUigin C, Thovarai V, Tessarollo L, Durum SK, Trinchieri G, Bian XW, Wang JM. The Antimicrobial Peptide CRAMP Is Essential for Colon Homeostasis by Maintaining Microbiota Balance. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 200:2174-2185. [PMID: 29440355 PMCID: PMC5931736 DOI: 10.4049/jimmunol.1602073] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 12/21/2017] [Indexed: 01/05/2023]
Abstract
Commensal bacteria are critical for physiological functions in the gut, and dysbiosis in the gut may cause diseases. In this article, we report that mice deficient in cathelin-related antimicrobial peptide (CRAMP) were defective in the development of colon mucosa and highly sensitive to dextran sulfate sodium (DSS)-elicited colitis, as well as azoxymethane-mediated carcinogenesis. Pretreatment of CRAMP-/- mice with antibiotics markedly reduced the severity of DSS-induced colitis, suggesting CRAMP as a limiting factor on dysbiosis in the colon. This was supported by observations that wild-type (WT) mice cohoused with CRAMP-/- mice became highly sensitive to DSS-induced colitis, and the composition of fecal microbiota was skewed by CRAMP deficiency. In particular, several bacterial species that are typically found in oral microbiota, such as Mogibacterium neglectum, Desulfovibrio piger, and Desulfomicrobium orale, were increased in feces of CRAMP-/- mice and were transferred to WT mice during cohousing. When littermates of CRAMP+/- parents were examined, the composition of the fecal microbiota of WT pups and heterozygous parents was similar. In contrast, although the difference in fecal microbiota between CRAMP-/- and WT pups was small early on after weaning and single mouse housing, there was an increasing divergence with prolonged single housing. These results indicate that CRAMP is critical in maintaining colon microbiota balance and supports mucosal homeostasis, anti-inflammatory responses, and protection from carcinogenesis.
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Affiliation(s)
- Teizo Yoshimura
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702;
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
| | - Mairi H McLean
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom
| | - Amiran K Dzutsev
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing 400038, China
| | - Keqiang Chen
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Jiaqiang Huang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
- College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, Beijing 100044, China
| | - Wanghua Gong
- Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702; and
| | - Jiamin Zhou
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Yi Xiang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Jonathan H Badger
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Colm O'hUigin
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Vishal Thovarai
- Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702; and
| | - Lino Tessarollo
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Scott K Durum
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing 400038, China
| | - Ji Ming Wang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702;
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27
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Hashash JG, Hartman DJ. Inflammatory cells implicated in neoplasia development in idiopathic inflammatory bowel disease. Cell Immunol 2017; 343:103720. [PMID: 29221690 DOI: 10.1016/j.cellimm.2017.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 11/08/2017] [Indexed: 11/29/2022]
Abstract
The inflammatory mechanisms that lead to the clinical symptoms that are grouped under the term inflammatory bowel disease have not been fully characterized. Although a specific mechanism has not been identified, inflammatory bowel disease is believed to be related to an inability by the immune system to shut active inflammation within the intestine. Many contributing factors have been implicated in the disease process. Based on population studies, patients with inflammatory bowel disease have an increased risk for neoplastic development. Although no specific immune cell has been implicated in neoplastic development within this patient population, several immune cells have been implicated as possible etiologies in inflammatory bowel disease. In this review, we will review the clinical evidence about the risk for neoplastic development in inflammatory bowel disease and the current clinical guidelines to survey this patient population. We will also review the pathologic assessment of inflammation within this patient population as well the underlying immune cells and cytokines that have been implicated in the etiology of inflammatory bowel disease.
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Affiliation(s)
- Jana G Hashash
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; American University of Beirut, Beirut, Lebanon
| | - Douglas J Hartman
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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28
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Catalan-Serra I, Sandvik AK, Bruland T, Andreu-Ballester JC. Gammadelta T Cells in Crohn's Disease: A New Player in the Disease Pathogenesis? J Crohns Colitis 2017; 11:1135-1145. [PMID: 28333360 DOI: 10.1093/ecco-jcc/jjx039] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 03/15/2017] [Indexed: 02/08/2023]
Abstract
Crohn's disease [CD] is a chronic relapsing systemic disease affecting the gastrointestinal tract. An altered immune response to commensal intestinal bacteria takes place in genetically predisposed individuals, resulting in chronic inflammation in the gut. Several alterations in the innate immunity mechanisms have been described in recent years. Thus, the study of the immunological aspects of CD, specifically the role of lymphocytes, is a key element for understanding the pathogenesis of the disease.Gammadelta T cells [γδ T cells] constitute only a small proportion of the lymphocytes that circulate in the blood and peripheral organs and they are present mainly in the epithelia, where they can constitute up to 40% of intraepithelial lymphocytes [IEL] in the intestinal mucosa. Due to their lack of major histocompatibility complex [MHC] restriction and their unique plasticity and immune-regulating properties, they are considered key cells in the first line of defence against infections and in wound healing in the gut. Although there is growing experimental and clinical evidence of their implication in inflammatory bowel disease [IBD], including CD, their clinical relevance is still unclear.In this review, we address the possible involvement of γδ T cells in the pathogenesis of CD, reviewing their role against infections and in inflammation and the current evidence suggesting their implication in CD, offering a novel potential target for immunotherapy in IBD.
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Affiliation(s)
- Ignacio Catalan-Serra
- Hospital Arnau de Vilanova de Valencia, Aparato Digestivo Valencia; Department of Cancer Research and Molecular Medicine, Centre for Molecular Inflammation Research, Norwegian University of Science and Technology; Department of Medicine [Gastroenterology], Levanger Hospital, Levanger, Norway
| | - Arne Kristian Sandvik
- Department of Cancer Research and Molecular Medicine, Centre for Molecular Inflammation Research, Norwegian University of Science and Technology; Department of Gastroenterology. St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Torunn Bruland
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology; Clinic of Medicine, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
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29
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Galler A, Rütgen BC, Haas E, Saalmüller A, Hirt RA, Gerner W, Schwendenwein I, Richter B, Thalhammer JG, Luckschander-Zeller N. Immunophenotype of Peripheral Blood Lymphocytes in Dogs with Inflammatory Bowel Disease. J Vet Intern Med 2017; 31:1730-1739. [PMID: 28862348 PMCID: PMC5697185 DOI: 10.1111/jvim.14812] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 06/12/2017] [Accepted: 07/24/2017] [Indexed: 01/18/2023] Open
Abstract
Background Inflammatory bowel disease (IBD) is common in dogs. Despite the known importance of intestinal lymphocytes in its pathogenesis, little is known about the role of peripheral blood lymphocytes (PBLs) in IBD. Objectives The aims of this study were (1) comparison of PBLs analyzed by flow cytometry (FCM) in IBD dogs and healthy controls and (2) comparison of PBLs in IBD dogs at the time of diagnosis and in dogs in clinical remission. Animals Whole blood samples of 19 IBD dogs at the time of diagnosis and blood samples of 6 dogs in clinical remission were collected. Ten healthy dogs served as controls. Methods In this prospective observational study, PBLs were analyzed with multicolor FCM by staining with a panel of anticanine and cross‐reactive monoclonal antibodies against T‐ and B‐cell differentiation antigens, including CD45, CD3, CD4, CD8α, CD8β, TCRαβ, TCRγδ, CD79αcy, and CD21. Results The IBD patients’ PBLs had significantly decreased percentages of TCRγδ+ T lymphocytes (median: healthy dogs, 3.32; IBD dogs, 0.97; P = 0.03) and CD21+ B cells (median: healthy dogs, 27.61; IBD dogs, 17.26; P = 0.04). There were no significant differences in PBLs between pretreatment and follow‐up samples. Conclusions and Clinical Importance The differences between PBLs in healthy and IBD dogs analyzed by FCM indicate an imbalance of lymphocytes with different immunologic functions and emphasize the potential value of this technique in a larger cohort of dogs. The PBLs did not differ between IBD dogs before treatment and clinically well‐controlled dogs after treatment.
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Affiliation(s)
- A Galler
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
| | - B C Rütgen
- Department of Pathobiology, Clinical Pathology Platform, University of Veterinary Medicine, Vienna, Austria
| | - E Haas
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
| | - A Saalmüller
- Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine, Vienna, Austria
| | - R A Hirt
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
| | - W Gerner
- Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine, Vienna, Austria
| | - I Schwendenwein
- Department of Pathobiology, Clinical Pathology Platform, University of Veterinary Medicine, Vienna, Austria
| | - B Richter
- Department of Pathobiology, Institute of Pathology and Forensic Veterinary Medicine, University of Veterinary Medicine, Vienna, Austria
| | - J G Thalhammer
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
| | - N Luckschander-Zeller
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
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30
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Wiede F, Dudakov JA, Lu KH, Dodd GT, Butt T, Godfrey DI, Strasser A, Boyd RL, Tiganis T. PTPN2 regulates T cell lineage commitment and αβ versus γδ specification. J Exp Med 2017; 214:2733-2758. [PMID: 28798028 PMCID: PMC5584121 DOI: 10.1084/jem.20161903] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 05/26/2017] [Accepted: 06/28/2017] [Indexed: 01/18/2023] Open
Abstract
During early thymocyte development, coordinated JAK/STAT5 and SFK/pre-TCR signaling is critical for T cell lineage commitment and αβ versus γδ specification. Wiede et al. show a role for the tyrosine phosphatase PTPN2 in attenuating SRC family kinase LCK and STAT5 signaling to regulate αβ and γδ T cell development. In the thymus, hematopoietic progenitors commit to the T cell lineage and undergo sequential differentiation to generate diverse T cell subsets, including major histocompatibility complex (MHC)–restricted αβ T cell receptor (TCR) T cells and non–MHC-restricted γδ TCR T cells. The factors controlling precursor commitment and their subsequent maturation and specification into αβ TCR versus γδ TCR T cells remain unclear. Here, we show that the tyrosine phosphatase PTPN2 attenuates STAT5 (signal transducer and activator of transcription 5) signaling to regulate T cell lineage commitment and SRC family kinase LCK and STAT5 signaling to regulate αβ TCR versus γδ TCR T cell development. Our findings identify PTPN2 as an important regulator of critical checkpoints that dictate the commitment of multipotent precursors to the T cell lineage and their subsequent maturation into αβ TCR or γδ TCR T cells.
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Affiliation(s)
- Florian Wiede
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia .,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Jarrod A Dudakov
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Kun-Hui Lu
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Garron T Dodd
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Tariq Butt
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Dale I Godfrey
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia.,Department of Microbiology and Immunology and Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Andreas Strasser
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Richard L Boyd
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Tony Tiganis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia .,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.,Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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31
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Al-Kofahi M, Yun JW, Minagar A, Alexander JS. Anatomy and roles of lymphatics in inflammatory diseases. ACTA ACUST UNITED AC 2017. [DOI: 10.1111/cen3.12400] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Mahmoud Al-Kofahi
- Department of Experimental and Clinical Pharmacology; College of Pharmacy; University of Minnesota; Minneapolis MN USA
| | - J. Winny Yun
- Department of Molecular and Cellular Physiology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
| | - Alireza Minagar
- Department of Neurology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
| | - J. Steven Alexander
- Department of Molecular and Cellular Physiology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
- Department of Neurology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
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32
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Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis. Nat Commun 2017; 8:15069. [PMID: 28452361 PMCID: PMC5414353 DOI: 10.1038/ncomms15069] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022] Open
Abstract
Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αβ T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis. Bcl-3 modulates effector T cell responses, but the importance of Bcl-3 in T regulatory cells and autoimmunity is not clear. Here the authors show that Bcl-3 impedes NF-κB DNA binding to alter T regulatory cell development and function, causing spontaneous colitis in mice.
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33
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Sun X, Cai Y, Fleming C, Tong Z, Wang Z, Ding C, Qu M, Zhang HG, Suo J, Yan J. Innate γδT17 cells play a protective role in DSS-induced colitis via recruitment of Gr-1 +CD11b + myeloid suppressor cells. Oncoimmunology 2017. [PMID: 28638741 DOI: 10.1080/2162402x.2017.1313369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Innate γδ T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, γδ T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, γδ T cells are a heterogeneous population. IL-17-producing versus IFNγ-producing γδ T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of γδ T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδ T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1+CD11b+ myeloid cells into the sites of inflammation in mice lacking γδT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1+CD11b+ myeloid cell recruitment. In vitro T cell suppressive assay indicated that this Gr-1+CD11b+ population was immunosuppressive. Depletion of Gr-1+CD11b+ myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving γδT17-dependent recruitment of Gr-1+CD11b+ myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression.
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Affiliation(s)
- Xuan Sun
- Department of Gastrointestinal Surgery, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Yihua Cai
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Chris Fleming
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Zan Tong
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Zhenglong Wang
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Chuanlin Ding
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Minye Qu
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Huang-Ge Zhang
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Jun Yan
- Department of Medicine and Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
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34
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Sanderlin EJ, Leffler NR, Lertpiriyapong K, Cai Q, Hong H, Bakthavatchalu V, Fox JG, Oswald JZ, Justus CR, Krewson EA, O'Rourke D, Yang LV. GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochim Biophys Acta Mol Basis Dis 2016; 1863:569-584. [PMID: 27940273 DOI: 10.1016/j.bbadis.2016.12.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/13/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023]
Abstract
GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.
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Affiliation(s)
- Edward J Sanderlin
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Nancy R Leffler
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA
| | - Qi Cai
- Department of Pathology, Brody School of Medicine, East Carolina University, USA
| | - Heng Hong
- Department of Pathology, Brody School of Medicine, East Carolina University, USA
| | | | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, USA
| | - Joani Zary Oswald
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA
| | - Calvin R Justus
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Elizabeth A Krewson
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA
| | - Dorcas O'Rourke
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA.
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35
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Uzzan M, Colombel JF, Cerutti A, Treton X, Mehandru S. B Cell-Activating Factor (BAFF)-Targeted B Cell Therapies in Inflammatory Bowel Diseases. Dig Dis Sci 2016; 61:3407-3424. [PMID: 27655102 DOI: 10.1007/s10620-016-4317-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/13/2016] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel diseases (IBD) involve dysregulated immune responses to gut antigens in genetically predisposed individuals. While a better elucidation of IBD pathophysiology has considerably increased the number of treatment options, the need for more effective therapeutic strategies remains a pressing priority. Defects of both non-hematopoietic (epithelial and stromal) and hematopoietic (lymphoid and myeloid) cells have been described in patients with IBD. Within the lymphoid system, alterations of the T cell compartment are viewed as essential in the pathogenesis of IBD. However, growing evidence points to the additional perturbations of the B cell compartment. Indeed, the intestinal lamina propria from IBD patients shows an increased presence of antibody-secreting plasma cells, which correlates with enhanced pro-inflammatory immunoglobulin G production and changes in the quality of non-inflammatory IgA responses. These B cell abnormalities are compounded by the emergence of systemic antibody responses to various autologous and microbial antigens, which predates the clinical diagnosis of IBD and identifies patients with complicated disease. It is presently unclear whether such antibody responses play a pathogenetic role, as B cell depletion with the CD20-targeting monoclonal antibody rituximab did not ameliorate ulcerative colitis in a clinical trial. However, it must be noted that unresponsiveness to rituximab is also observed also in some patients with autoimmune disorders usually responsive to B cell-depleting therapies. In this review, we discussed mechanistic aspects of B cell-based therapies and their potential role in IBD with a special interest on BAFF and BAFF-targeting therapies buoyed by the success of anti-BAFF treatments in rheumatologic disorders.
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Affiliation(s)
- Mathieu Uzzan
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Departments of Medicine and Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrea Cerutti
- The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xavier Treton
- Department of Gastroenterology, Beaujon Hospital, APHP, Denis Diderot University, Paris, France
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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36
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Lankes K, Hundorfean G, Harrer T, Pommer AJ, Agaimy A, Angelovska I, Tajmir-Riahi A, Göhl J, Schuler G, Neurath MF, Hohenberger W, Heinzerling L. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis. Oncoimmunology 2016; 5:e1128611. [PMID: 27471608 DOI: 10.1080/2162402x.2015.1128611] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 11/27/2015] [Accepted: 11/30/2015] [Indexed: 12/11/2022] Open
Abstract
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
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Affiliation(s)
- Katharina Lankes
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Gheorghe Hundorfean
- Department of Gastroenterology, Pneumology and Endocrinology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Thomas Harrer
- Department of Medicine 3, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Ansgar J Pommer
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Abbas Agaimy
- Institute of Pathology, University Hospital Erlangen , Krankenhausstraße 8-10 , Erlangen, Germany
| | - Irena Angelovska
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Azadeh Tajmir-Riahi
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Jonas Göhl
- Department of Surgery, University Hospital Erlangen , Krankenhausstraße 12 , Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Markus F Neurath
- Department of Gastroenterology, Pneumology and Endocrinology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
| | - Werner Hohenberger
- Department of Surgery, University Hospital Erlangen , Krankenhausstraße 12 , Erlangen, Germany
| | - Lucie Heinzerling
- Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany
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Harpel K, Leung S, Rice PF, Jones M, Barton JK, Bommireddy R. Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. Phys Med Biol 2016; 61:N60-9. [PMID: 26758693 DOI: 10.1088/0031-9155/61/3/n60] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non-steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation.
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Affiliation(s)
- Kaitlin Harpel
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, 85721, USA
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38
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Duriancik DM, Comstock SS, Langohr IM, Fenton JI. High levels of fish oil enhance neutrophil development and activation and influence colon mucus barrier function in a genetically susceptible mouse model. J Nutr Biochem 2015; 26:1261-72. [PMID: 26297475 DOI: 10.1016/j.jnutbio.2015.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 05/28/2015] [Accepted: 06/04/2015] [Indexed: 12/23/2022]
Abstract
Dietary fatty acids influence immunologic homeostasis, but their effect on initiation of colitis, an immune-mediated disease, is not well established. Previously, our laboratory demonstrated that high doses of dietary fish oil (FO) increased colon inflammation and dysplasia in a model of infection-induced colitis. In the current study, we assessed the effects of high-dose dietary FO, 6% by weight, on colon inflammation, neutrophil recruitment and function, and mucus layer integrity in a genetically susceptible, colitis-prone mouse model in the absence of infection. FO-fed SMAD3(-/-) mice had increased colon inflammation evidenced by increased numbers of systemic and local neutrophils and increased neutrophil chemoattractant and inflammatory cytokine gene expression in the colon. Mucus layer thickness in the cecum and goblet cell numbers in the cecum and colon in FO-fed mice were reduced compared to control. FO consumption affected colitis in male and female mice differently. Compared to female control mice, neutrophils from FO-fed female mice had reduced reactive oxygen species (ROS) upon ex vivo stimulation with phorbol myristate acetate while FO-fed male mice produced increased ROS compared to control-fed male mice. In summary, dietary FO impaired mucus layer integrity and was associated with colon inflammation characterized by increased neutrophil numbers and altered neutrophil function. High-dose FO may have detrimental effects in populations genetically susceptible for inflammatory bowel disease and these effects may differ between males and females.
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Affiliation(s)
- David M Duriancik
- Department of Food Science & Human Nutrition, Michigan State University East Lansing, MI, 48824
| | - Sarah S Comstock
- Department of Food Science & Human Nutrition, Michigan State University East Lansing, MI, 48824
| | - Ingeborg M Langohr
- Department of Pathobiological Sciences Louisiana State University, Baton Rouge, LA, 70803
| | - Jenifer I Fenton
- Department of Food Science & Human Nutrition, Michigan State University East Lansing, MI, 48824.
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Abstract
γδ T cells represent a small population of overall T lymphocytes (0.5-5%) and have variable tissue distribution in the body. γδ T cells can perform complex functions, such as immune surveillance, immunoregulation, and effector function, without undergoing clonal expansion. Heterogeneous distribution and anatomic localization of γδ T cells in the normal and inflamed tissues play an important role in alloimmunity, autoimmunity, or immunity. The cross-talk between γδ T cells and other immune cells and phenotypic and functional plasticity of γδ T cells have been given recent attention in the field of immunology. In this review, we discussed the cellular and molecular interaction of γδ T cells with other immune cells and its mechanism in the pathogenesis of various autoimmune diseases.
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Affiliation(s)
- Sourav Paul
- National Centre for Cell Science, Pune University Campus, Pune, India
| | - Shilpi
- National Centre for Cell Science, Pune University Campus, Pune, India
| | - Girdhari Lal
- National Centre for Cell Science, Pune University Campus, Pune, India
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40
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Akitsu A, Kakuta S, Saijo S, Iwakura Y. Rag2-deficient IL-1 Receptor Antagonist-deficient Mice Are a Novel Colitis Model in Which Innate Lymphoid Cell-derived IL-17 Is Involved in the Pathogenesis. Exp Anim 2014; 63:235-46. [PMID: 24770649 PMCID: PMC4160983 DOI: 10.1538/expanim.63.235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Il1rn−/− mice spontaneously develop arthritis and aortitis by
an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism.
Here, we show that Rag2−/−Il1rn−/−
mice develop spontaneous colitis with high mortality, making a contrast to the suppression
of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells
(ILC3s) was observed in the colon of
Rag2−/−Il1rn−/− mice.
IL-17A-deficiency prolonged the survival of
Rag2−/−Il1rn−/− mice, suggesting
a pathogenic role of this cytokine in the development of intestinal inflammation. Although
IL-17A-producing T cells were increased in Il1rn−/− mice,
these mice did not develop colitis, because CD4+Foxp3+ regulatory T
cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A
from ILC3s cause colitis in Rag2−/−Il1rn−/− mice in
which Treg cells are absent. These observations suggest that the balance between
IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the
colon.
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Affiliation(s)
- Aoi Akitsu
- Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Haas E, Rütgen BC, Gerner W, Richter B, Tichy A, Galler A, Bilek A, Thalhammer JG, Saalmüller A, Luckschander-Zeller N. Phenotypic characterization of canine intestinal intraepithelial lymphocytes in dogs with inflammatory bowel disease. J Vet Intern Med 2014; 28:1708-15. [PMID: 25250556 PMCID: PMC4895640 DOI: 10.1111/jvim.12456] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 07/29/2014] [Accepted: 08/12/2014] [Indexed: 01/08/2023] Open
Abstract
Background Many dogs suffering from inflammatory bowel disease (IBD) are presented to veterinary clinics. These patients are diagnosed based on a history of chronic gastrointestinal signs and biopsy‐confirmed histopathologic intestinal inflammation. Intestinal intraepithelial lymphocytes (IEL) are part of the first line of defense in the gastrointestinal immune system. Alterations in IEL subsets may play a role in the pathogenesis of IBD. Hypothesis The aim of this study was to characterize the phenotypes of IEL in dogs with IBD compared with healthy control dogs. Animals Intestinal intraepithelial lymphocytes subpopulations of control dogs (n = 5) obtained from endoscopic biopsies (EB) were compared to those obtained from full thickness biopsies (FTB) on the same day. In addition, the phenotypes of IEL from FTB of control dogs (n = 10) were compared with EB of IBD dogs (n = 10). Each participant was scored clinically using the canine inflammatory bowel disease activity index (CIBDAI), and all samples were graded histopathologically. Three‐color flow cytometry of isolated IEL was performed using monoclonal antibodies against T‐ and B‐lymphocyte subpopulations. Results No significant differences in the composition of IEL subpopulations were found in control dogs based on method of biopsy. The IBD dogs had significantly higher CIBDAI and histopathologic scores compared with control dogs and their IEL contained a significantly higher frequency TCRγδ T‐cells. Conclusions and Clinical Importance Endoscopic biopsies provide suitable samples for 3‐color flow cytometry when studying canine intestinal IEL and IBD patients show significant changes of major T‐cell subsets compared to healthy control dogs.
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Affiliation(s)
- E Haas
- Department for Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine, Vienna, Austria
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Pitzalis C, Jones GW, Bombardieri M, Jones SA. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol 2014; 14:447-62. [PMID: 24948366 DOI: 10.1038/nri3700] [Citation(s) in RCA: 516] [Impact Index Per Article: 46.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
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Affiliation(s)
- Costantino Pitzalis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Gareth W Jones
- Cardiff Institute for Infection and Immunity, The School of Medicine, Cardiff University, The Tenovus Building, Heath Campus, Cardiff CF14 4XN, Wales, UK
| | - Michele Bombardieri
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Simon A Jones
- Cardiff Institute for Infection and Immunity, The School of Medicine, Cardiff University, The Tenovus Building, Heath Campus, Cardiff CF14 4XN, Wales, UK
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Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, Weih F, Weber C, Gerdes N, Habenicht AJ. Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis. Circ Res 2014; 114:1772-87. [PMID: 24855201 DOI: 10.1161/circresaha.114.301137] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Tertiary lymphoid organs emerge in tissues in response to nonresolving inflammation. Recent research characterized artery tertiary lymphoid organs in the aorta adventitia of aged apolipoprotein E–deficient mice. The atherosclerosis-associated lymphocyte aggregates are organized into distinct compartments, including separate T-cell areas harboring conventional, monocyte-derived, lymphoid, and plasmacytoid dendritic cells, as well as activated T-cell effectors and memory cells; B-cell follicles containing follicular dendritic cells in activated germinal centers; and peripheral niches of plasma cells. Artery tertiary lymphoid organs show marked neoangiogenesis, aberrant lymphangiogenesis, and extensive induction of high endothelial venules. Moreover, newly formed lymph node–like conduits connect the external lamina with high endothelial venules in T-cell areas and also extend into germinal centers. Mouse artery tertiary lymphoid organs recruit large numbers of naïve T cells and harbor lymphocyte subsets with opposing activities, including CD4
+
and CD8
+
effector and memory T cells, natural and induced CD4
+
regulatory T cells, and memory B cells at different stages of differentiation. These data suggest that artery tertiary lymphoid organs participate in primary immune responses and organize T- and B-cell autoimmune responses in advanced atherosclerosis. In this review, we discuss the novel concept that pro- and antiatherogenic immune responses toward unknown arterial wall–derived autoantigens may be organized by artery tertiary lymphoid organs and that disruption of the balance between pro- and antiatherogenic immune cell subsets may trigger clinically overt atherosclerosis.
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Affiliation(s)
- Sarajo Kumar Mohanta
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Changjun Yin
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Li Peng
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Prasad Srikakulapu
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Vineela Bontha
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Desheng Hu
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Falk Weih
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Christian Weber
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Norbert Gerdes
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
| | - Andreas J.R. Habenicht
- From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (S.K.M., C.Y., C.W., N.G., A.J.R.H.); Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany (L.P., P.S., V.B., F.W.); and Institute of Molecular Immunology, Helmholtz Center Munich, Neuherberg, Germany (D.H.)
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Nochi T, Denton PW, Wahl A, Garcia JV. Cryptopatches are essential for the development of human GALT. Cell Rep 2013; 3:1874-84. [PMID: 23791525 DOI: 10.1016/j.celrep.2013.05.037] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/14/2013] [Accepted: 05/22/2013] [Indexed: 12/19/2022] Open
Abstract
Abnormal gut-associated lymphoid tissue (GALT) in humans is associated with infectious and autoimmune diseases, which cause dysfunction of the gastrointestinal (GI) tract immune system. To aid in investigating GALT pathologies in vivo, we bioengineered a human-mouse chimeric model characterized by the development of human GALT structures originating in mouse cryptopatches. This observation expands our mechanistic understanding of the role of cryptopatches in human GALT genesis and emphasizes the evolutionary conservation of this developmental process. Immunoglobulin class switching to IgA occurs in these GALT structures, leading to numerous human IgA-producing plasma cells throughout the intestinal lamina propria. CD4+ T cell depletion within GALT structures results from HIV infection, as it does in humans. This human-mouse chimeric model represents the most comprehensive experimental platform currently available for the study and for the preclinical testing of therapeutics designed to repair disease-damaged GALT.
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Affiliation(s)
- Tomonori Nochi
- Division of Infectious Diseases, Center for AIDS Research, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
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45
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Junginger J, Lemensieck F, Moore PF, Schwittlick U, Nolte I, Hewicker-Trautwein M. Canine gut dendritic cells in the steady state and in inflammatory bowel disease. Innate Immun 2013; 20:145-60. [PMID: 23723379 DOI: 10.1177/1753425913485475] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Alongside the intestinal border, dendritic cells (DCs) sample large amounts of endogenous and potentially pathogenic antigens followed by initiation of protective immune responses or induction of tolerance. Breakdown of oral tolerance towards commensal bacteria is suggested to be crucial for the development of both human and canine inflammatory bowel disease (IBD). The aim of this study was to investigate canine intestinal DCs in the steady state and in dogs with IBD using multicolour immunofluorescence. In the healthy gut, DC-like cells expressed MHC II, CD1a8.2 and CD11c, and, in lower amounts, CD11b, within lamina propria, Peyer's patches (PPs) and mesenteric lymph nodes (MLNs), whereas those expressing CD80 and CD86 were only present in PPs and MLNs. Occasionally, DC-like cells were in contact with the intestinal lumen through transepithelial projections. In canine IBD, CD1a8.2+, CD11b+ and CD11c+ DC-like cells were decreased within the stomach, duodenum and colon, whereas the colonic mucosa revealed elevation of CD86+ DC-like cells. The complex network of DC-like cells in the gut indicates their important role in canine mucosal immunity, including active sampling of luminal antigens. Furthermore, their shift in diseased dogs suggests a pathogenetic significance for canine IBD.
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Affiliation(s)
- Johannes Junginger
- 1Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
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46
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Kuchipudi SV, Tellabati M, Nelli RK, White GA, Perez BB, Sebastian S, Slomka MJ, Brookes SM, Brown IH, Dunham SP, Chang KC. 18S rRNA is a reliable normalisation gene for real time PCR based on influenza virus infected cells. Virol J 2012; 9:230. [PMID: 23043930 PMCID: PMC3499178 DOI: 10.1186/1743-422x-9-230] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 10/05/2012] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND One requisite of quantitative reverse transcription PCR (qRT-PCR) is to normalise the data with an internal reference gene that is invariant regardless of treatment, such as virus infection. Several studies have found variability in the expression of commonly used housekeeping genes, such as beta-actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), under different experimental settings. However, ACTB and GAPDH remain widely used in the studies of host gene response to virus infections, including influenza viruses. To date no detailed study has been described that compares the suitability of commonly used housekeeping genes in influenza virus infections. The present study evaluated several commonly used housekeeping genes [ACTB, GAPDH, 18S ribosomal RNA (18S rRNA), ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide (ATP5B) and ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9) (ATP5G1)] to identify the most stably expressed gene in human, pig, chicken and duck cells infected with a range of influenza A virus subtypes. RESULTS The relative expression stability of commonly used housekeeping genes were determined in primary human bronchial epithelial cells (HBECs), pig tracheal epithelial cells (PTECs), and chicken and duck primary lung-derived cells infected with five influenza A virus subtypes. Analysis of qRT-PCR data from virus and mock infected cells using NormFinder and BestKeeper software programmes found that 18S rRNA was the most stable gene in HBECs, PTECs and avian lung cells. CONCLUSIONS Based on the presented data from cell culture models (HBECs, PTECs, chicken and duck lung cells) infected with a range of influenza viruses, we found that 18S rRNA is the most stable reference gene for normalising qRT-PCR data. Expression levels of the other housekeeping genes evaluated in this study (including ACTB and GPADH) were highly affected by influenza virus infection and hence are not reliable as reference genes for RNA normalisation.
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Affiliation(s)
- Suresh V Kuchipudi
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, College Road, Loughborough, Leicestershire LE12 5RD, UK.
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Abstract
Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options.
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Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol 2012; 33:297-305. [PMID: 22622061 PMCID: PMC7106385 DOI: 10.1016/j.it.2012.04.006] [Citation(s) in RCA: 296] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 04/17/2012] [Accepted: 04/17/2012] [Indexed: 01/07/2023]
Abstract
The lymph nodes (LNs) and spleen have an optimal structure that allows the interaction between T cells, B cells and antigen-presenting dendritic cells (DCs) on a matrix made up by stromal cells. Such a highly organized structure can also be formed in tertiary lymphoid organs (TLOs) at sites of infection or chronic immune stimulation. This review focuses on the molecular mechanisms of TLO formation and maintenance, the controversies surrounding the nature of the inducing events, and the functions of these structures in infection, transplantation and autoimmunity.
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McCaskey SJ, Rondini EA, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI. Increased presence of effector lymphocytes during Helicobacter hepaticus-induced colitis. World J Gastroenterol 2012; 18:1459-69. [PMID: 22509077 PMCID: PMC3319941 DOI: 10.3748/wjg.v18.i13.1459] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 11/12/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify and characterize drosophila mothers against decapentaplegic (SMAD)3-dependent changes in immune cell populations following infection with Helicobacter hepaticus (H. hepaticus).
METHODS: SMAD3-/- (n = 19) and colitis-resistant SMAD3+/- (n = 24) mice (8-10 wk of age) were infected with H. hepaticus and changes in immune cell populations [T lymphocytes, natural killer (NK) cells, T regulatory cells] were measured in the spleen and mesenteric lymph nodes (MsLNs) at 0 d, 3 d, 7 d and 28 d post-infection using flow cytometry. Genotype-dependent changes in T lymphocytes and granzyme B+ cells were also assessed after 28 d in proximal colon tissue using immunohistochemistry.
RESULTS: As previously observed, SMAD3-/-, but not SMAD3+/- mice, developed colitis, peaking at 4 wk post-infection. No significant changes in T cell subsets were observed in the spleen or in the MsLNs between genotypes at any time point. However, CD4+ and CD8+/CD62Llo cells, an effector T lymphocyte population, as well as NK cells (NKp46/DX5+) were significantly higher in the MsLNs of SMAD3-/- mice at 7 d and 28 d post-infection. In the colon, a higher number of CD3+ cells were present in SMAD3-/- compared to SMAD3+/– mice at baseline, which did not significantly change during infection. However, the number of granzyme B+ cells, a marker of cytolytic lymphocytes, significantly increased in SMAD3-/- mice 28 d post-infection compared to both SMAD3+/- mice and to baseline values. This was consistent with more severe colitis development in these animals.
CONCLUSION: Data suggest that defects in SMAD3 signaling increase susceptibility to H. hepaticus-induced colitis through aberrant activation and/or dysregulation of effector lymphocytes.
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Abstract
The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.
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