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Raftery AL, Pattaroni C, Harris NL, Tsantikos E, Hibbs ML. Environmental and inflammatory factors influencing concurrent gut and lung inflammation. Inflamm Res 2024; 73:2123-2139. [PMID: 39432107 PMCID: PMC11632041 DOI: 10.1007/s00011-024-01953-x] [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: 07/18/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND Crohn's disease and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases that affect the gut and lung respectively and can occur comorbidly. METHODS Using the SHIP-1-/- model of Crohn's-like ileitis and chronic lung inflammation, the two diseases were co-investigated. RESULTS Contrary to prior literature, Crohn's-like ileitis was not fully penetrant in SHIP-1-/- mice, and housing in a specific pathogen-free facility was completely protective. Indeed, ileal tissue from SHIP-1-/- mice without overt ileitis was similar to control ilea. However, SHIP-1-/- mice with ileitis exhibited increased granulocytes in ileal tissue together with T cell lymphopenia and they lacked low abundance Bifidobacteria, suggesting this bacterium protects against ileitis. Lung disease, as defined by inflammation in lung washes, emphysema, and lung consolidation, was present in SHIP-1-/- mice regardless of ileitis phenotype; however, there was a shift in the nature of lung inflammation in animals with ileitis, with increased G-CSF and neutrophils, in addition to type 2 cytokines and eosinophils. Deficiency of G-CSF, which protects against lung disease, protected against the development of ileitis in SHIP-1-/- mice. CONCLUSIONS These studies have defined environmental, immune, and inflammatory factors that predispose to ileitis, and have identified that comorbid lung disease correlates with a granulocyte signature.
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Affiliation(s)
- April L Raftery
- Department of Immunology, School of Translational Medicine, Monash University, 89 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Céline Pattaroni
- Department of Immunology, School of Translational Medicine, Monash University, 89 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Nicola L Harris
- Department of Immunology, School of Translational Medicine, Monash University, 89 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Evelyn Tsantikos
- Department of Immunology, School of Translational Medicine, Monash University, 89 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Margaret L Hibbs
- Department of Immunology, School of Translational Medicine, Monash University, 89 Commercial Road, Melbourne, VIC, 3004, Australia.
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Arnold IC, Munitz A. Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease. Nat Rev Immunol 2024; 24:858-877. [PMID: 38982311 DOI: 10.1038/s41577-024-01048-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 07/11/2024]
Abstract
Eosinophils are bone marrow-derived granulocytes that are traditionally associated with type 2 immune responses, such as those that occur during parasite infections and allergy. Emerging evidence demonstrates the remarkable functional plasticity of this elusive cell type and its pleiotropic functions in diverse settings. Eosinophils broadly contribute to tissue homeostasis, host defence and immune regulation, predominantly at mucosal sites. The scope of their activities primarily reflects the breadth of their portfolio of secreted mediators, which range from cytotoxic cationic proteins and reactive oxygen species to multiple cytokines, chemokines and lipid mediators. Here, we comprehensively review basic eosinophil biology that is directly related to their activities in homeostasis, protective immunity, regeneration and cancer. We examine how dysregulation of these functions contributes to the physiopathology of a broad range of inflammatory diseases. Furthermore, we discuss recent findings regarding the tissue compartmentalization and adaptation of eosinophils, shedding light on the factors that likely drive their functional diversification within tissues.
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Affiliation(s)
- Isabelle C Arnold
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
| | - Ariel Munitz
- Department of Clinical Microbiology and Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
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3
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Zhang K, Xu Y, Yang Y, Guo M, Zhang T, Zong B, Huang S, Suo L, Ma B, Wang X, Wu Y, Brugger D, Chen Y. Gut microbiota-derived metabolites contribute negatively to hindgut barrier function development at the early weaning goat model. ANIMAL NUTRITION 2022; 10:111-123. [PMID: 35663372 PMCID: PMC9136126 DOI: 10.1016/j.aninu.2022.04.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/27/2021] [Accepted: 04/11/2022] [Indexed: 11/24/2022]
Abstract
Early weaning induces intestinal injury, leading to a series of long-term symptoms such as inflammation, malabsorption and diarrhea. In this study, we hypothesized that microbes and their metabolites modulate the host's inflammatory response to early weaning stress in a goat model. A total of 18 female Tibetan goat kids (n = 9) were weaned from their mothers at 28 d (D28) and 60 d (D60) postpartum. D60 and D28 groups were fed the same solid diet ad libitum from weaning to 75 d of age. The colonic epithelium was subject to RNA-sequencing, the caecal digesta metabolomics were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the caecal microbiota composition was analysed by 16S ribosomal RNA gene sequencing. We found that early weaning substantially increased the colonic pro-apoptotic gene expression of B-cell lymphoma associated X (Bax), caspase-9, and caspase-3, and decreased the expression of zonula occludens-1 (ZO-1) and claudin-1 (P < 0.01). In addition, a significant Bacteroides acidifaciens enrichment was observed in the hindgut of early-weaned goats (P < 0.01), which negatively correlated with lysophosphatidylcholine products. Similarly, the chemokine signaling, IL-17 signaling, and peroxisome proliferators-activated receptor (PPAR) signaling pathways were upregulated in the colonic mucosa of the early-weaned goats. By applying caecal microbiota transplantation from goats to defaunated C57/6J mice, we confirmed that caecal microbiota of D28 goat kids increased the relative abundance of B. acidifaciens and significantly up-regulated the genes of Bax, G protein–coupled receptor (GPR) 109A, GPR 43, fatty acid binding protein 6, nuclear receptor subfamily 1 group H member 3, angiotensin converting enzyme 2, and IL-6 expression (P < 0.05), and decreased ZO-1, and claudin-1 protein expression in the mice jejunum and colon (P < 0.001). These results proposed that the hindgut microbiota and metabolites mediate the barrier function weakening during early weaning, and the relative abundance of B. acidifaciens was negatively correlated with the hindgut barrier gene expression. This study demonstrates how weaning stress can affect key host–microbe interaction regulators in the hindgut, in a lysophosphatidylcholine dependent and independent manner. Furthermore, based on our mice data, these results are transferable to other mammal species.
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Mookhoek A, Haasnoot ML, Bredenoord AJ, Ma C, Jairath V, Pai RK. The Clinical Significance of Eosinophils in Ulcerative Colitis: A Systematic Review. J Crohns Colitis 2022; 16:1321-1334. [PMID: 35136998 DOI: 10.1093/ecco-jcc/jjac024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/30/2021] [Accepted: 02/04/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Ulcerative colitis [UC] is characterised by an unpredictable disease course and variable response to therapy. Recent studies suggest a role for eosinophils in both pathogenesis and predicting treatment response. The goal of this study was to determine the association between eosinophils and clinical outcomes in UC. METHODS A systematic review of the literature from database inception to May 2021 was performed to identify all studies evaluating the relationship between eosinophils and/or eosinophil-derived proteins [EDPs] and clinical outcomes, such as disease activity, clinical relapse, severity of disease, and response to treatment. RESULTS A total of 55 studies were identified. Of these, 34 studies evaluated the relationship between eosinophils in colonic tissue and outcomes and 15 in blood. Eighteen studies assessed the relationship between EDPs and outcomes. In 25 of 34 studies, a positive correlation between eosinophils and/or EDPs and disease activity was reported, three studies found a negative correlation, and nine studies found no correlation. Positive correlations between eosinophils and clinical relapse were shown in four of nine studies, and with disease outcome severity in five of seven studies. Four of 15 studies showed that subjects with higher eosinophil levels had a poor response to treatment. CONCLUSIONS These findings suggest that higher eosinophil levels may be associated with increased disease activity and poorer clinical outcomes and response to therapy. Future studies are needed to determine whether a distinct eosinophil-rich UC phenotype exists and whether eosinophil-targeted therapy can alter the disease course.
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Affiliation(s)
- Aart Mookhoek
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Maria L Haasnoot
- Department of Gastroenterology, Amsterdam Medical Center, Amsterdam, The Netherlands
| | - Albert J Bredenoord
- Department of Gastroenterology, Amsterdam Medical Center, Amsterdam, The Netherlands
| | - Christopher Ma
- Department of Gastroenterology and Hepatology, University of Calgary, Calgary, AB, Canada.,Medical Research & Development, Alimentiv Inc., London, ON, Canada
| | - Vipul Jairath
- Medical Research & Development, Alimentiv Inc., London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Rish K Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
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5
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Filippone RT, Dargahi N, Eri R, Uranga JA, Bornstein JC, Apostolopoulos V, Nurgali K. Potent CCR3 Receptor Antagonist, SB328437, Suppresses Colonic Eosinophil Chemotaxis and Inflammation in the Winnie Murine Model of Spontaneous Chronic Colitis. Int J Mol Sci 2022; 23:ijms23147780. [PMID: 35887133 PMCID: PMC9317166 DOI: 10.3390/ijms23147780] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 02/04/2023] Open
Abstract
Eosinophils and their regulatory molecules have been associated with chronic intestinal inflammation and gastrointestinal dysfunctions; eosinophil accumulation in the gut is prominent in inflammatory bowel disease (IBD). The chemokine receptor CCR3 plays a pivotal role in local and systemic recruitment and activation of eosinophils. In this study, we targeted CCR3-ligand interactions with a potent CCR3 receptor antagonist, SB328437, to alleviate eosinophil-associated immunological responses in the Winnie model of spontaneous chronic colitis. Winnie and C57BL/6 mice were treated with SB328437 or vehicle. Clinical and histopathological parameters of chronic colitis were assessed. Flow cytometry was performed to discern changes in colonic, splenic, circulatory, and bone marrow-derived leukocytes. Changes to the serum levels of eosinophil-associated chemokines and cytokines were measured using BioPlex. Inhibition of CCR3 receptors with SB328437 attenuated disease activity and gross morphological damage to the inflamed intestines and reduced eosinophils and their regulatory molecules in the inflamed colon and circulation. SB328437 had no effect on eosinophils and their progenitor cells in the spleen and bone marrow. This study demonstrates that targeting eosinophils via the CCR3 axis has anti-inflammatory effects in the inflamed intestine, and also contributes to understanding the role of eosinophils as potential end-point targets for IBD treatment.
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Affiliation(s)
- Rhiannon T. Filippone
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, VIC 3021, Australia; (R.T.F.); (N.D.); (K.N.)
| | - Narges Dargahi
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, VIC 3021, Australia; (R.T.F.); (N.D.); (K.N.)
| | - Rajaraman Eri
- School of Health Sciences, The University of Tasmania, Launceston, TAS 7248, Australia;
| | - Jose A. Uranga
- Department of Basic Health Sciences, University Rey Juan Carlos (URJC), 28922 Alcorcón, Spain;
- High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut), University Rey Juan Carlos (URJC), 28922 Alcorcón, Spain
| | - Joel C. Bornstein
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, VIC 3021, Australia; (R.T.F.); (N.D.); (K.N.)
- Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Correspondence:
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, VIC 3021, Australia; (R.T.F.); (N.D.); (K.N.)
- Department of Medicine-Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
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Vande Casteele N, Leighton JA, Pasha SF, Cusimano F, Mookhoek A, Hagen CE, Rosty C, Pai RK, Pai RK. Utilizing Deep Learning to Analyze Whole Slide Images of Colonic Biopsies for Associations Between Eosinophil Density and Clinicopathologic Features in Active Ulcerative Colitis. Inflamm Bowel Dis 2022; 28:539-546. [PMID: 34106256 DOI: 10.1093/ibd/izab122] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Eosinophils have been implicated in the pathogenesis of ulcerative colitis and have been associated with disease course and therapeutic response. However, associations between eosinophil density, histologic activity, and clinical features have not been rigorously studied. METHODS A deep learning algorithm was trained to identify eosinophils in colonic biopsies and validated against pathologists' interpretations. The algorithm was applied to sigmoid colon biopsies from a cross-sectional cohort of 88 ulcerative colitis patients with histologically active disease as measured by the Geboes score and Robarts histopathology index (RHI). Associations between eosinophil density, histologic activity, and clinical features were determined. RESULTS The eosinophil deep learning algorithm demonstrated almost perfect agreement with manual eosinophil counts determined by 4 pathologists (interclass correlation coefficients: 0.805-0.917). Eosinophil density varied widely across patients (median 113.5 cells per mm2, interquartile range 108.9). There was no association between eosinophil density and RHI (P = 0.5). Significant differences in eosinophil density were seen between patients with Montreal E3 vs E2 disease (146.2 cells per mm2 vs 88.2 cells per mm2, P = 0.005). Patients on corticosteroids had significantly lower eosinophil density (62.9 cells per mm2 vs 124.1 cells per mm2, P = 0.006). No association between eosinophil density and biologic use was observed (P = 0.5). CONCLUSIONS We developed a deep learning algorithm to quantify eosinophils in colonic biopsies. Eosinophil density did not correlate with histologic activity but did correlate with disease extent and corticosteroid use. Future studies applying this algorithm in larger cohorts with longitudinal follow-up are needed to further elucidate the role of eosinophils in ulcerative colitis.
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Affiliation(s)
- Niels Vande Casteele
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Shabana F Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Frank Cusimano
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Aart Mookhoek
- Department of Pathology, VU Medical Center, Amsterdam, the Netherlands
| | - Catherine E Hagen
- Department of Pathology and Laboratory Medicine, Mayo Clinic Rochester, Rochester, Minnesota, USA
| | - Christophe Rosty
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Reetesh K Pai
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Rish K Pai
- Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
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7
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Menta PLR, Andrade MER, de Castro LF, Trindade LM, Dias MTS, Miyamoto JÉ, Dos Santos RM, Cassali GD, Leal RF, Ribeiro APB, Grimaldi R, Ignacio-Souza LM, Torsoni MA, Torsoni AS, Cardoso VN, Milanski M. Interesterified palm oil increases intestinal permeability, promotes bacterial translocation, alters inflammatory parameters and tight-junction protein genic expression in Swiss mice. Food Res Int 2022; 151:110897. [PMID: 34980418 DOI: 10.1016/j.foodres.2021.110897] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/01/2022]
Abstract
High-fat diets seem to have a negative influence on the development of obesity and the processes associated with low-grade chronic systemic inflammation. In recent years, partial hydrogenated oil, rich in trans isomers, has been associated with deleterious health effects. It has been replaced by interesterified fat (IF). However, there is no evidence whether IF ingestion can exert adverse effects on the intestinal mucosa. Thus, this study aimed to evaluate the effect of IF on the intestinal mucosa of male Swiss mice fed a normal or high-fat diet, focusing on its effects on intestinal permeability and bacterial translocation and its possible damage to the intestinal epithelium. The animals were divided into 4 groups: Control (C) and Interesterified Control (IC) groups (10 En% lipids from unmodified fat or interesterified fat, respectively) and High Fat (HF) and Interesterified High Fat (IHF) groups (45 En% lipids from unmodified fat or interesterified fat, respectively). Compare to C, the IC, HF, and IHF groups presented flattened epithelium, a shorter villi length and a lower percentage of goblet cells, less mucin 2, an increased oxidative stress and more inflammatory cells, higher IL-1β, IL-17, and IL-23 levels. These groups also presented increased intestinal permeability and gene expression of the protein claudin 2, while JAM-A and claudin 1 gene expression was reduced. IC and IHF increased IL-6 levels while reducing occludin expression. In addition, the IC group also presented a mucosa with lesions of low intensity in the ileum, an increased mucin 5ac, TNF-α levels, and reduced occludin expression in the distal jejunum. Moreover, there was a significant increase in bacterial translocation in the IC group to blood, liver, and lungs, while HF and IHF groups presented bacterial translocation which was restricted to the mesenteric lymph nodes. In summary, our results supported the hypothesis that IF added to a normolipidic diet can be considered harmful or even worse when compared to a HF.
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Affiliation(s)
- Penélope Lacrísio Reis Menta
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil.
| | - Maria Emília Rabelo Andrade
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lívia Furquim de Castro
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Luísa Martins Trindade
- Department of Food, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Melissa Tainan Silva Dias
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Josiane Érica Miyamoto
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Raisa Magno Dos Santos
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Geovanni Dantas Cassali
- Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Raquel Franco Leal
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil; IBD Research Laboratory, Colorectal Surgery Unit, School of Medical Sciences, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | | | - Renato Grimaldi
- School of Food Engineering, University of Campinas, UNICAMP, Campinas, Brazil
| | - Letícia Martins Ignacio-Souza
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Marcio Alberto Torsoni
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Adriana Souza Torsoni
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil
| | - Valbert Nascimento Cardoso
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Marciane Milanski
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, SP, Brazil.
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Intestinal eosinophils, homeostasis and response to bacterial intrusion. Semin Immunopathol 2021; 43:295-306. [PMID: 33929602 PMCID: PMC8241669 DOI: 10.1007/s00281-021-00856-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/03/2021] [Indexed: 02/06/2023]
Abstract
Eosinophils are traditionally considered as end-stage effector cells involved in the pathogenesis of Th2 immune-mediated disorders as well as in the protection against parasite infection. However, this restricted view has recently been challenged by a series of studies revealing the highly plastic nature of these cells and implication in various homeostatic processes. Large numbers of eosinophils reside in the lamina propria of the gastrointestinal tract, at the front line of host defence, where they contribute to maintain the intestinal epithelial barrier function in the face of inflammation-associated epithelial cell damage. Eosinophils confer active protection against bacterial pathogens capable of penetrating the mucosal barrier through the release of cytotoxic compounds and the generation of extracellular DNA traps. Eosinophils also integrate tissue-specific cytokine signals such as IFN-γ, which synergise with bacterial recognition pathways to enforce different context-dependent functional responses, thereby ensuring a rapid adaptation to the ever-changing intestinal environment. The ability of eosinophils to regulate local immune responses and respond to microbial stimuli further supports the pivotal role of these cells in the maintenance of tissue homeostasis at the intestinal interface.
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Uyttebroek L, Pype C, Hubens G, Timmermans JP, Van Nassauw L. Effect of TNBS-induced colitis on enteric neuronal subpopulations in adult zebrafish. Eur J Histochem 2020; 64. [PMID: 32875777 PMCID: PMC7459238 DOI: 10.4081/ejh.2020.3161] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/24/2020] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes inflammation of the gastrointestinal (GI) tract and is characterized by periods of acute inflammation and remission. Therapeutic management of IBD is still problematic, because of incomplete understanding its pathogenesis. This study focuses on the effect of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis on changes in enteric neuronal subpopulations in adult zebrafish. These changes are suggested to be related to the altered neuro-immune interactions and GI motility, and in IBD pathogenesis. New insights into neuroplasticity will be instrumental in finding appropriate therapeutic treatments. TNBS was intraluminally administered in the distal intestine (DI) of anesthetized adult zebrafish. A histological time course of the intestinal inflammatory response was created to establish optimal TNBS concentration and acute inflammation phase. Using double immunolabelling on whole mounts, the effect of inflammation on neuronal populations was analyzed. Based on intestinal wall thickening, epithelial fold disruption, reduced goblet cell number, and eosinophil infiltration, our analysis indicated that the optimal TNBS concentration (320 mM in 25% ethanol) inducing non-lethal inflammation reached a peak at 6 h post-induction. The inflammatory response returned to baseline values at 3 days post-induction. At the acute inflammation phase, no influence on the distribution or proportion of nitrergic neurons was observed, while only the proportion of cholinergic neurons was significantly reduced in the DI. The proportion of serotonergic neurons was significantly increased in the entire intestine during inflammation. This study describes a method of TNBS-induced colitis in the adult zebrafish. Given that the acute inflammation phase is accompanied by neuroplasticity comparable to changes observed in IBD patients, and the unique and versatile characteristics of the zebrafish, allows this model to be used alongside IBD animal models to unravel IBD pathology and to test new IBD therapies.
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Affiliation(s)
- Leen Uyttebroek
- Laboratory of Human Anatomy, Faculty of Medicine and Health Sciences, University of Antwerp.
| | - Casper Pype
- Laboratory of Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp.
| | - Guy Hubens
- Laboratory of Human Anatomy, Faculty of Medicine and Health Sciences, University of Antwerp.
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp.
| | - Luc Van Nassauw
- Laboratory of Human Anatomy, Faculty of Medicine and Health Sciences, University of Antwerp.
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10
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Fecal Eosinophil Cationic Protein Is a Diagnostic and Predictive Biomarker in Young Adults with Inflammatory Bowel Disease. J Clin Med 2019; 8:jcm8122025. [PMID: 31756948 PMCID: PMC6947361 DOI: 10.3390/jcm8122025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND AIMS Fecal biomarkers are important non-invasive markers monitoring disease activity in inflammatory bowel disease (IBD). We compared the significance of fecal eosinophil cationic protein (fECP) and fecal calprotectin (fCal). METHODS fECP and fCal were measured in patients with Crohn's disease (CD, n = 97), ulcerative colitis (UC, n = 53), Clostridioides difficile infection (CDI, n = 9), primary food allergy (PFA, n = 11), pollen-associated food allergy (n = 25) and non-inflammatory controls (n = 78). Results were correlated with clinical and endoscopic IBD activity scores. RESULTS fECP was significantly elevated in CD, UC, CDI and PFA compared to controls. fCal was significantly increased in CD, UC and CDI. fECP had lower diagnostic accuracy than fCal (area under the curve (AUC) = 0.88) in differentiating between endoscopically active and inactive patients with IBD (AUC = 0.77, ROC analysis). In contrast to fCal, fECP correlated negatively with age and levels were also elevated in clinically and endoscopically inactive patients with IBD <45 years (endoscopically inactive IBD vs controls; AUC for fECP = 0.86; AUC for fCal = 0.62). However, in those patients with low inflammatory activity (fCal <250 mg/kg), high fECP indicated the need for treatment modification or surgery (fECP <200 µg/kg = 22%; 200-600 µg/kg = 44%; >600 µg/kg = 82%) at month 48 of follow-up. CONCLUSIONS fECP is a diagnostic and prognostic marker in young patients with IBD in remission.
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11
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Loktionov A. Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders. World J Gastroenterol 2019; 25:3503-3526. [PMID: 31367153 PMCID: PMC6658389 DOI: 10.3748/wjg.v25.i27.3503] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/22/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are currently regarded as versatile mobile cells controlling and regulating multiple biological pathways and responses in health and disease. These cells store in their specific granules numerous biologically active substances (cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes) ready for rapid release. The human gut is the main destination of eosinophils that are produced and matured in the bone marrow and then transferred to target tissues through the circulation. In health the most important functions of gut-residing eosinophils comprise their participation in the maintenance of the protective mucosal barrier and interactions with other immune cells in providing immunity to microbiota of the gut lumen. Eosinophils are closely involved in the development of inflammatory bowel disease (IBD), when their cytotoxic granule proteins cause damage to host tissues. However, their roles in Crohn's disease and ulcerative colitis appear to follow different immune response patterns. Eosinophils in IBD are especially important in altering the structure and protective functions of the mucosal barrier and modulating massive neutrophil influx to the lamina propria followed by transepithelial migration to colorectal mucus. IBD-associated inflammatory process involving eosinophils then appears to expand to the mucus overlaying the internal gut surface. The author hypothesises that immune responses within colorectal mucus as well as ETosis exerted by both neutrophils and eosinophils on the both sides of the colonic epithelial barrier act as additional pathogenetic factors in IBD. Literature analysis also shows an association between elevated eosinophil levels and better colorectal cancer (CRC) prognosis, but mechanisms behind this effect remain to be elucidated. In conclusion, the author emphasises the importance of investigating colorectal mucus in IBD and CRC patients as a previously unexplored milieu of disease-related inflammatory responses.
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Filippone RT, Robinson AM, Jovanovska V, Stavely R, Apostolopoulos V, Bornstein JC, Nurgali K. Targeting eotaxin-1 and CCR3 receptor alleviates enteric neuropathy and colonic dysfunction in TNBS-induced colitis in guinea pigs. Neurogastroenterol Motil 2018; 30:e13391. [PMID: 29968270 DOI: 10.1111/nmo.13391] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 05/14/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND The accumulation of eosinophils is mediated by the chemokine receptor-3 (CCR3)-eotaxin axis. Increased expression of eotaxin and its receptor is associated with inflammatory bowel disease (IBD). Activation of eosinophils causes the release of cationic proteins that are neurotoxic such as eosinophil-derived neurotoxin (EDN). Damage to enteric neurons alters neurally controlled functions of the gut correlated with intestinal inflammation. We hypothesized that inhibition of the CCR3-eotaxin axis will prevent inflammation-induced functional changes to the gastrointestinal tract. METHODS Hartley guinea pigs were administered with trinitrobenzene sulfonate (TNBS; 30 mg/kg in 30% ethanol) intrarectally to induce colitis. A CCR3 receptor antagonist (SB 328437 [SB3]) was injected intraperitoneally 1 hour postinduction of colitis. Animals were euthanized 7 days post-treatment and colon tissues were collected for ex vivo studies. The EDN-positive eosinophils in the colon, indicating eosinophil activation, were quantified by immunohistochemistry. Effects of SB3 treatment on gross morphological damage, enteric neuropathy, and colonic dysmotility were determined by histology, immunohistochemistry, and organ bath experiments. KEY RESULTS The number of EDN-positive eosinophils was significantly increased in the lamina propria in close proximity to myenteric ganglia in inflamed colon. The TNBS-induced inflammation caused significant damage to colonic architecture and inhibition of colonic motility. Treatment with SB3 antagonist attenuated inflammation-associated morphological damage in the colon, reduced infiltration of EDN-positive eosinophils and restored colonic motility to levels comparable to control and sham-treated guinea pigs. CONCLUSION & INFERENCES This is the first study demonstrating that inhibition of CCR3-eotaxin axis alleviates enteric neuropathy and restores functional changes in the gut associated with TNBS-induced colitis.
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Affiliation(s)
- R T Filippone
- College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.,Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia
| | - A M Robinson
- College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.,Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia
| | - V Jovanovska
- College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.,Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia
| | - R Stavely
- College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.,Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia
| | - V Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia
| | - J C Bornstein
- Department of Physiology, Melbourne University, Melbourne, Vic., Australia
| | - K Nurgali
- College of Health and Biomedicine, Victoria University, Melbourne, Vic., Australia.,Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia.,Regenerative, Medicine and Stem Cells Program, Department of Medicine Western Health, Melbourne University, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Vic., Australia
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13
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Zammit SC, Cachia M, Sapiano K, Gauci J, Montefort S, Ellul P. Eosinophilic gastrointestinal disorder: is it what it seems to be? Ann Gastroenterol 2018; 31:475-479. [PMID: 29991893 PMCID: PMC6033761 DOI: 10.20524/aog.2018.0263] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/13/2018] [Indexed: 12/14/2022] Open
Abstract
Background Eosinophilic gastroenteropathy is an uncommon condition whose causes can be numerous and non-specific. The aim of the study was to characterize the presence of gastrointestinal disorders in the adult Maltese population and assess the degree of association with atopic diseases. Methods Adult patients with gastrointestinal eosinophilia in the gastrointestinal tract on histology were identified and their clinical case notes were reviewed. Patients were interviewed and asked questions regarding asthma, allergic rhinitis, and eczema. Results Sixty-six patients (39 female) were recruited. The most common clinical symptoms were diarrhea (42.4%) and abdominal pain (33.3%). The sites involved were stomach (10.6%), colon (56.1%), small bowel (10.6%), small bowel and colon (18.2%), esophagus (1.5%), and esophagus and colon (1.5%). Forty percent had persistent lower gastrointestinal symptoms and a repeat ileocolonoscopy was performed within 12 months. These patients were diagnosed with ulcerative colitis (n=10; 47.6%), Crohn's disease (n=6; 28.6%), indeterminate colitis (n=1; 4.8%) or microscopic colitis (n=4; 19%). Allergic rhinitis was present in 39.4% of the study group, eczema in 26.1%, and asthma in 19.7%. These findings were compared with local data for atopic conditions and the study group was found to have a significantly higher prevalence of allergic rhinitis (P=0.002), but not of asthma (P=0.62) or eczema (P=0.19). Conclusions A high proportion of patients with eosinophilic gastrointestinal infiltration were subsequently diagnosed with inflammatory bowel disease. Patients persistently symptomatic or who do not respond to treatment should be reassessed to exclude inflammatory bowel disease, given its high prevalence in this group of patients.
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Affiliation(s)
- Stefania Chetcuti Zammit
- Division of Gastroenterology, Department of Medicine (Stefania Chetcuti Zammit, Pierre Ellul), Mater Dei Hospital, Malta
| | - Monique Cachia
- Department of Medicine (Monique Cachia, Karen Sapiano, Julia Gauci), Mater Dei Hospital, Malta
| | - Karen Sapiano
- Department of Medicine (Monique Cachia, Karen Sapiano, Julia Gauci), Mater Dei Hospital, Malta
| | - Julia Gauci
- Department of Medicine (Monique Cachia, Karen Sapiano, Julia Gauci), Mater Dei Hospital, Malta
| | - Stephen Montefort
- Division of Respiratory Medicine, Department of Medicine (Stephen Montefort), Mater Dei Hospital, Malta
| | - Pierre Ellul
- Division of Gastroenterology, Department of Medicine (Stefania Chetcuti Zammit, Pierre Ellul), Mater Dei Hospital, Malta
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14
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van der Star BJ, van Dijk CE, Zock JP, Smit LAM, Baliatsas C, Heederik DJJ, Yzermans CJ. Healthcare utilisation prior to the diagnosis of inflammatory bowel diseases and the influence of livestock exposure: A longitudinal case-control study. PLoS One 2018; 13:e0195305. [PMID: 29630633 PMCID: PMC5890991 DOI: 10.1371/journal.pone.0195305] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 03/20/2018] [Indexed: 12/23/2022] Open
Abstract
An increased prevalence of the inflammatory bowel diseases, ulcerative colitis and Crohn's disease, was found amongst residents in a livestock dense area. We hypothesised that exposure to livestock farms might be a substantial environmental factor that contributes to the development of these diseases and that in the lead up to inflammatory bowel diseases potential risk factors can be identified. This study aimed to investigate the contribution of livestock exposure to the development of these diseases and the clinical events prior to the diagnosis. Electronic health records from 2006-2013 of general practices were used. The study population consisted of patients with a new diagnosis of inflammatory bowel diseases resident in areas with a high (n = 141) or lower (n = 109) livestock density. Patients with low back pain (n = 10,469) were used as controls. For those in a livestock dense area, distance to livestock farms was determined. Associations between morbidities and drug prescriptions in the reporting year and three years previous to the diagnosis, and the residential proximity to livestock exposure were investigated with multivariable logistic regression analyses. Acute and chronic morbidity of the gastrointestinal tract and associated drug prescriptions were predictive for the development of inflammatory bowel diseases. In addition, a positive association was found between infections and living within 500 meter of poultry farms and the development of inflammatory bowel diseases [OR: 3.3 (1.1-9.9)]. Nonetheless, overall livestock exposure contributed little to the development of these diseases. These results suggest that exposure to livestock farms on its own contributes minimal to the development of inflammatory bowel diseases. Nonetheless, having infections appeared to be a risk factor for neighbouring residents of poultry farms. More research is warranted to explain the increased prevalence of inflammatory bowel diseases amongst residents in areas with a high density of livestock.
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Affiliation(s)
- Baukje J. van der Star
- Netherlands Institute for Health Services Research, NIVEL, Utrecht, The Netherlands
- * E-mail:
| | - Christel E. van Dijk
- Netherlands Institute for Health Services Research, NIVEL, Utrecht, The Netherlands
| | - Jan-Paul Zock
- Netherlands Institute for Health Services Research, NIVEL, Utrecht, The Netherlands
| | - Lidwien A. M. Smit
- Institute for Risk Assessment Sciences, IRAS, Utrecht University, Utrecht, The Netherlands
| | - Christos Baliatsas
- Netherlands Institute for Health Services Research, NIVEL, Utrecht, The Netherlands
| | - Dick J. J. Heederik
- Institute for Risk Assessment Sciences, IRAS, Utrecht University, Utrecht, The Netherlands
| | - C. Joris Yzermans
- Netherlands Institute for Health Services Research, NIVEL, Utrecht, The Netherlands
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15
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Muñoz-Mendoza D, Chapa-Rodríguez A, Bahna SL. Eosinophilic Esophagitis Clinical Manifestations and Differential Diagnosis. Clin Rev Allergy Immunol 2018; 55:7-18. [PMID: 29290036 DOI: 10.1007/s12016-017-8663-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
As a chronic inflammatory disease with eosinophilic infiltrate of the esophagus, eosinophilic esophagitis (EoE) causes a variety of gastrointestinal (GI) clinical manifestations. None of the symptoms, endoscopic features, or biopsy findings is pathognomonic of the disease, even with high degrees of esophageal eosinophilia. The pathogenesis has been explored by several studies, yet it still far from being completely understood. Evidence supports a role of allergen-driven Th2 lymphocyte mechanism, though not in every patient. This article addresses the disease's clinical manifestations, endoscopic findings, diagnosis, and differential diagnoses. In addition to the current diagnostic criteria, we summarize some recently emerging procedures that promise of enhancing more precise diagnosis and institution of early appropriate management, with consequent better quality of life and reduction of complications.
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Affiliation(s)
- Diana Muñoz-Mendoza
- Department of Pediatrics, Allergy and Immunology Section, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA
| | - Adrián Chapa-Rodríguez
- Department of Pediatrics, Gastroenterology and Nutrition Section, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA, USA
| | - Sami L Bahna
- Department of Pediatrics, Allergy and Immunology Section, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA.
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16
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Classification of eosinophilic disorders of the small and large intestine. Virchows Arch 2017; 472:15-28. [PMID: 29127496 DOI: 10.1007/s00428-017-2249-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/19/2017] [Accepted: 10/18/2017] [Indexed: 12/26/2022]
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17
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Conner JR, Kirsch R. The pathology and causes of tissue eosinophilia in the gastrointestinal tract. Histopathology 2017; 71:177-199. [DOI: 10.1111/his.13228] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- James R Conner
- Department of Pathology and Laboratory Medicine; Mount Sinai Hospital; Toronto ON Canada
| | - Richard Kirsch
- Department of Pathology and Laboratory Medicine; Mount Sinai Hospital; Toronto ON Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto ON Canada
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18
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Ye X, Liu S, Hu M, Song Y, Huang H, Zhong Y. CCR5 expression in inflammatory bowel disease and its correlation with inflammatory cells and β-arrestin2 expression. Scand J Gastroenterol 2017; 52:551-557. [PMID: 28140695 DOI: 10.1080/00365521.2017.1281435] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/07/2017] [Accepted: 01/08/2017] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To elucidate the correlation of expression of CC chemokine receptor 5 (CCR5) with degrees of inflammatory cells infiltration and expression of β-arrestin2 in biopsic intestinal mucosa of the patients with inflammatory bowel disease (IBD). METHODS Paraffin sections were derived from 53 patients with active IBD, 26 patients with remissive IBD and 30 healthy people. Immunohistochemical envision two-step method was used to test the expression of CCR5 and β-arrestin2 in biopsic intestinal mucosa. HE and toluidine blue staining were used to detect the pathological cytological analysis and classification in lamina propria of colonic mucosa. RESULTS The positive rate, strong positive rate and immunohistochemical score of CCR5 expression in active IBD were significantly higher than that in normal controls and remissive IBD (p < .05). CCR5 expression had no obvious correlation with clinical severity, lesion distribution and endoscopic classification of active IBD. Neutrophils, eosinophils and lymphocytes in active IBD were significantly higher than that in normal controls and remissive IBD (p < .05), while the lymphocyte grade had a positive correlation with CCR5 expression (p = .042, r = .286). Mastocytes in active IBD, remissive IBD and normal controls had no obvious difference (p > .05). β-arrestin2 expression was significantly lower in active IBD than that in remissive IBD and normal controls, and it had a negative correlation with CCR5 expression (p = .01, r = -.247). CONCLUSIONS CCR5 is highly expressed in active IBD, and it has positive correlation with lymphocyte grade and negative correlation with expression of β-arrestin2.
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Affiliation(s)
- Xiaoyan Ye
- a Department of Gastroenterology and Hepatology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
- b Department of Gastroenterology and Hepatology , the First Affiliated Hospital of Guangdong Pharmaceutical University , Guangzhou , China
| | - Sixue Liu
- a Department of Gastroenterology and Hepatology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
- c Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes of Sun Yat-Sen University , Guangzhou , China
| | - Mei Hu
- a Department of Gastroenterology and Hepatology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
- c Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes of Sun Yat-Sen University , Guangzhou , China
| | - Yangda Song
- a Department of Gastroenterology and Hepatology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
- c Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes of Sun Yat-Sen University , Guangzhou , China
| | - Huarong Huang
- c Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes of Sun Yat-Sen University , Guangzhou , China
- d Department of Pediatrics , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - Yingqiang Zhong
- a Department of Gastroenterology and Hepatology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
- c Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes of Sun Yat-Sen University , Guangzhou , China
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Diny NL, Rose NR, Čiháková D. Eosinophils in Autoimmune Diseases. Front Immunol 2017; 8:484. [PMID: 28496445 PMCID: PMC5406413 DOI: 10.3389/fimmu.2017.00484] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/07/2017] [Indexed: 12/15/2022] Open
Abstract
Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.
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Affiliation(s)
- Nicola L Diny
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Noel R Rose
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniela Čiháková
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Canavese G, Villanacci V, Antonelli E, Cadei M, Sapino A, Rocca R, Daperno M, Suriani R, Di Santo MG, Cassoni P, Bernardini N, Bassotti G. Eosinophilia - associated basal plasmacytosis: an early and sensitive histologic feature of inflammatory bowel disease. APMIS 2017; 125:179-183. [PMID: 28120414 DOI: 10.1111/apm.12639] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 10/14/2016] [Indexed: 12/30/2022]
Abstract
Basal plasmacytosis is an early-onset and highly predictive feature of inflammatory bowel disease (IBD), but may have several restrictions in routine histology. Considering evidences about cooperation between eosinophils and plasma cells in IBD pathogenesis, we investigated immunostain of these two cells as a marker of disease. 343 samplings from 83 patients (52 IBD, 31 non-IBD colitis) were evaluated. The sections were stained with monoclonal antibodies against plasma cells (CD138 and MUM1), and eosinophils (CD193). Eosinophilia-associated basal plasmacytosis (EBP) was related with the histologic diagnosis of IBD (90.3% IBD and 35.4% non-IBD colitides, p < 0.005, sensitivity 90.4%). A strong relation was detected between the occurrence of EBP and (i) the achieving of a complete endoscopic mapping; (ii) the presence of other characteristic lesions of IBD in single segmental sampling, although EBP was evident in more than 40% of samples without other IBD-related lesions. EBP is a sensitive histologic feature of IBD, especially at the first endoscopic sampling, even in the absence of the other characteristic histologic lesions, and may help in formulating a more precise diagnosis in this setting.
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Affiliation(s)
- Gabriella Canavese
- Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
| | | | | | - Moris Cadei
- Institute of Pathology, Spedali Civili di Brescia, Brescia, Italy
| | - Anna Sapino
- Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
| | - Rodolfo Rocca
- Gastroenterology Department, Ospedale Mauriziano, Torino, Italy
| | - Marco Daperno
- Gastroenterology Department, Ospedale Mauriziano, Torino, Italy
| | - Renzo Suriani
- Gastroenterology Department, Ospedale Mauriziano, Torino, Italy
| | - Maria Giulia Di Santo
- Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
| | - Paola Cassoni
- Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
| | - Nunzia Bernardini
- Histology and Medical Embryology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
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Adar T, Shteingart S, Ben-Ya'acov A, Shitrit ABG, Livovsky DM, Shmorak S, Mahamid M, Melamud B, Vernea F, Goldin E. The Importance of Intestinal Eotaxin-1 in Inflammatory Bowel Disease: New Insights and Possible Therapeutic Implications. Dig Dis Sci 2016; 61:1915-24. [PMID: 26874691 DOI: 10.1007/s10620-016-4047-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 01/18/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND Involvement of eotaxin-1 in inflammatory bowel disease has been previously suggested and increased levels of eotaxin-1 have been described in both ulcerative colitis and in Crohn's disease. The association between serum levels of eotaxin-1 and that within the colonic mucosa has not been well defined, as is the potential therapeutic value of targeting eotaxin-1. AIMS To characterize serum and intestinal wall eotaxin-1 levels in various inflammatory bowel disease patients and to explore the effect of targeting eotaxin-1 by specific antibodies in dextran sodium sulfate-induced colitis model. METHODS Eotaxin-1 levels were measured in colonic biopsies and in the sera of 60 ulcerative colitis patients, Crohn's disease patients and healthy controls. We also followed in experimental colitis the effect of targeting eotaxin-1 by a monoclonal antibody. RESULTS Colon eotaxin-1 levels were significantly increased in active but not in quiescent ulcerative colitis and Crohn's disease patients compared to healthy controls. Levels of eotaxin-1 in the colon were correlated with eosinophilia only in tissues from active Crohn's disease patients. Our results did not show any statistically significant change in serum eotaxin-1 levels among ulcerative colitis, Crohn's disease and healthy controls. Moreover, we demonstrate that in dextran sodium sulfate-induced colitis, targeting of eotaxin-1 with 2 injections of anti eotaxin-1 monoclonal antibody ameliorates disease activity along with decreasing colon weight and improving histologic inflammation. CONCLUSION Eotaxin-1 is increasingly recognized as a major mediator of intestinal inflammation. Our preliminary human and animal results further emphasize the value of targeting eotaxin-1 in inflammatory bowel disease.
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Affiliation(s)
- Tomer Adar
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel.
| | - Shimon Shteingart
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Ami Ben-Ya'acov
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Ariella Bar-Gill Shitrit
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Dan M Livovsky
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Shimrit Shmorak
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Mahmud Mahamid
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Bernardo Melamud
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
| | - Fiona Vernea
- Department of Pathology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Eran Goldin
- Digestive Diseases Institute, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, 12 Bayit St., 91031, Jerusalem, Israel
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Elian SDA, Souza ELS, Vieira AT, Teixeira MM, Arantes RME, Nicoli JR, Martins FS. Bifidobacterium longum subsp. infantis BB-02 attenuates acute murine experimental model of inflammatory bowel disease. Benef Microbes 2016; 6:277-86. [PMID: 25391346 DOI: 10.3920/bm2014.0070] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory conditions, characterised by remissions and relapses episodes, whose main manifestations are ulcerative colitis and Crohn's disease. Ulcerative colitis (UC), one of the main forms of IBD, has as standard treatment the use of corticosteroids and anti-inflammatory drugs. The use of antibiotics has been also reported, but the possible adverse effects, such as disturbance of the indigenous microbiota or resistance induction, should be taken into consideration, and thus the use of probiotics emerges as a possible alternative option of treatment. In this study, the oral administration of Bifidobacterium longum subsp. infantis BB-02 was evaluated as a preventive strategy for acute experimental UC induced in female BALB/c mice by ingestion of 3.5% dextran sulphate sodium in drinking water during 7 days. During this time, the daily disease activity index was evaluated, and on the seventh day the animals were euthanised to collect intestines and liver for analysis. Treatment with the probiotic resulted in clinical improvement of the animals. The histological and morphometric analyses showed a reduction of lesions and oedema in the gut, but there was no increase in the production of mucin. The dosage of secretory immunoglobulin A was significantly higher in the colitis group and reduced in the group treated with the probiotic. There was also a reduction in the inflammation of the colon, as demonstrated by a decrease in neutrophils infiltration, and KC/CXCL-1 levels. The intestinal permeability, which is typically increased during the onset of IBD, was also reduced by treatment with probiotic. Based on these data, it can be concluded that the bacterium B. infantis BB-02 has a probiotic potential for the attenuation of UC, but further studies should be conducted to verify the mechanism of protective action of the bacterium.
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Affiliation(s)
- S D A Elian
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - E L S Souza
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - A T Vieira
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - M M Teixeira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - R M E Arantes
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - J R Nicoli
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
| | - F S Martins
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos 6627, Pampulha Campus UFMG, 31270-901 Belo Horizonte, MG, Brazil
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Bass JA, Friesen CA, Deacy AD, Neilan NA, Bracken JM, Shakhnovich V, Singh V. Investigation of potential early Histologic markers of pediatric inflammatory bowel disease. BMC Gastroenterol 2015; 15:129. [PMID: 26463759 PMCID: PMC4604710 DOI: 10.1186/s12876-015-0359-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/25/2015] [Indexed: 12/30/2022] Open
Abstract
Background Early manifestations of pediatric inflammatory bowel disease (IBD) can be relatively nonspecific. Initial mucosal biopsies may not be conclusive, delaying the diagnosis until subsequent biopsies demonstrate typical histologic features of IBD. We hypothesized that certain inflammatory cell types may be utilized as early histologic indicators of IBD in children. Methods A retrospective analysis compared histologic findings from initially inconclusive or negative endoscopic studies in 22 patients who were subsequently diagnosed with IBD (after diagnostic endoscopy) to those of 20 comparison patients with functional abdominal pain matched for age, gender, and study type. A pediatric pathologist, blinded to study group, reviewed biopsies for histologic abnormalities. Eosinophil densities were obtained from the stomach, duodenum, and rectosigmoid areas. Immunohistochemistry (IHC) staining for tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) was performed on the stomach and rectosigmoid areas. Results Gastritis and colonic crypt distortion were present in the IBD group at a greater rate (61 % vs. 22 %, p = 0.020; 34 % vs. 4 %, p = 0.008, respectively). Peak and mean eosinophil densities in the rectosigmoid area were greater in the IBD group (17.0/hpf vs. 5.0/hpf, p = 0.0063; 12.3/hpf vs. 4.2/hpf, p = 0.0106, respectively). TNF-α and MMP-9 staining did not reveal any significant differences. Conclusions Our data suggests that significantly greater inflammation in the stomach, crypt distortion in the colon, and eosinophilia in the rectosigmoid distinguished the IBD group from the comparison group at the time of the initial endoscopic evaluation.
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Affiliation(s)
- Julie A Bass
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Craig A Friesen
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Amanda D Deacy
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA. .,Division of Developmental and Behavioral Sciences, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Nancy A Neilan
- Division of Infectious Disease, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Julia M Bracken
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Valentina Shakhnovich
- Division of Gastroenterology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA. .,Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
| | - Vivekanand Singh
- Department of Pathology, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.
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Withdrawal of indium-111: implications for white-cell imaging. The nuclear medicine community must act. Nucl Med Commun 2015; 35:789-91. [PMID: 24979589 DOI: 10.1097/mnm.0000000000000138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Zezos P, Patsiaoura K, Nakos A, Mpoumponaris A, Vassiliadis T, Giouleme O, Pitiakoudis M, Kouklakis G, Evgenidis N. Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy. Colorectal Dis 2014; 16:O420-O430. [PMID: 25040651 DOI: 10.1111/codi.12725] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 06/05/2014] [Indexed: 12/16/2022]
Abstract
AIM Eosinophils are potent proinflammatory cells that are involved in the pathogenesis of ulcerative colitis (UC). We evaluated the infiltration of eosinophils into the lamina propria in patients with active and inactive ulcerative colitis (UC) and investigated its clinical significance, among other variables, in predicting the outcome of medical treatment in active disease. METHOD We studied colorectal biopsy specimens from 18 UC patients with disease in long-standing remission, from 22 patients with active disease who responded to therapy (12 with complete response and 10 with partial response) and from 10 patients who were nonresponders. Demographic information was obtained at baseline, and clinical, endoscopic and laboratory data were obtained at baseline and 12 weeks post-treatment. We evaluated five histological features: mucosal ulceration; mucosal erosions; crypt abscesses; cryptitis; and eosinophilic infiltration of the lamina propria. The severity of these lesions was graded as: none or minimal; mild; moderate; or severe. Statistical analyses were performed between responders and nonresponders for differences in demographic, clinical, laboratory, endoscopic and histological parameters. RESULTS Laboratory, endoscopic and histological parameters were significantly improved after treatment only in the complete responders group. Analyses of baseline data revealed no significant differences in parameters between complete or partial responders and nonresponders, except for a less severe eosinophilic infiltration of lamina propria in complete responders (P < 0.05). Multiple logistic regression analysis showed that severe eosinophilic infiltration in colonic biopsies was the most significant predictor of poor response to medical therapy. CONCLUSION Assessing the severity of eosinophilic infiltration in the lamina propria of colonic biopsies in patients with ulcerative colitis could be a valuable predictive tool of response to medical therapy.
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Affiliation(s)
- P Zezos
- Division of Gastroenterology, 2nd Propaedeutic Department of Internal Medicine, "Hippokration" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; Gastrointestinal Endoscopy Unit, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
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Adar T, Shteingart S, Ben Ya'acov A, Bar-Gil Shitrit A, Goldin E. From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation. Clin Immunol 2014; 153:199-208. [PMID: 24786916 DOI: 10.1016/j.clim.2014.04.012] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 04/17/2014] [Accepted: 04/22/2014] [Indexed: 02/06/2023]
Abstract
Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation.
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Affiliation(s)
- Tomer Adar
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel.
| | - Shimon Shteingart
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Ariella Bar-Gil Shitrit
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Eran Goldin
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
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Abstract
PURPOSE The intestinal mucosal immune cells such as the mast cells and eosinophils play an important role in the pathogenesis of ulcerative colitis (UC). The aim of present study was to compare the number of mast cells and eosinophils in patients with active and non-active ulcerative colitis. Another purpose was to found whether the number of eosinophils could correlate with number of mast cells in both tested groups. MATERIAL AND METHODS The twenty-five of formalin-fixed, paraffin-embedded tissue specimens of active ulcerative colitis, the twenty of non-active ulcerative colitis and the ten of controls were retrieved from archival material. Tryptase and chymase immunopositive cells were detected using immunohistochemical method. Additionally, the number of mast cells and eosinophils were detected using the most common histochemical methods. RESULTS The number of eosinophils and toluidine blue stained and tryptase immunopositive mast cells was significantly increased in active UC compared to non-active UC. In active stage of UC positive correlation between the number of mast cells stained with toluidine blue and the number of chymase and tryptase immunopositive mast cells were observed. Moreover, the number of eosinophils was significantly correlated with number of mast cells stained with toluidine blue and number of tryptase- and chymase immunopositive mast cells. In non-active stage of UC positive correlation was observed only between the number of mast cells stained with toluidine blue and chymase immunopositive cells and eosinophils. CONCLUSIONS In conclusion, our findings confirmed that mast cells and eosinophils are functionally involved in the course of UC.
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Abstract
BACKGROUND Our previous studies have demonstrated that B cells in human inflammatory bowel disease (IBD) are highly activated and produce copious amounts of chemokines. Here, we showed that B cells produce eotaxin-1, a selective chemokine for acute eosinophilia. Increased levels of activated eosinophils have been found in the intestinal mucosa in patients with IBD, but their role(s) and the regulation of their migration patterns remain poorly defined. METHODS To determine how B-cell secretion of eotaxin-1 influences eosinophil activation and migration, we performed immunoepidemiological approaches coupled with in vitro studies. B cells and eosinophils from patients with Crohn's disease and ulcerative colitis were isolated, and responses to Toll-like receptor ligands (TLR) were measured and assessed for the relationship with clinical disease. RESULTS Eotaxin-1 from recirculating B cells, and TLR ligands, regulated eosinophil homing mechanisms in IBD. B cells stimulated with hypo-acylated lipopolysaccharide (LPS) produced copious amounts of eotaxin-1, which influenced eosinophil activation profiles in the bloodstream. We also found that hexa-acylated LPS, such Escherichia coli LPS, directly activated TLR2-expressing and TLR4-expressing eosinophils from patients with IBD to express a different repertoire of mucosal homing receptors, namely CCR9 and CCR10. Whereas B-cell production of eotaxin-1 was correlated with reduced disease activity, eosinophil activation by hexa-acylated LPS was associated with increased disease activity. CONCLUSIONS These results suggest that systemic TLR ligands influence eosinophil migration patterns, both directly and indirectly, through B cells. Our report uncovers unexpected mechanisms of cross talk between certain immune cells that shed new light on IBD immunology.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel diseases (IBDs, e.g., Crohn's disease and ulcerative colitis) are thought to be a consequence of an uncontrolled inflammatory response against luminal antigens, including commensal bacteria. The observed link between eosinophil levels and severity and remission rates in IBD has led to speculation that eosinophils may contribute to the antimicrobial inflammatory response in IBD. RECENT FINDINGS Eosinophils express the necessary cellular machinery (innate immune receptors, proinflammatory cytokines, antibacterial proteins, and DNA traps) to mount an efficient antibacterial response; however, the rapid decline in eosinophil numbers following acute systemic bacterial infection suggests a very limited role for eosinophils in bacterial responses. SUMMARY We describe the clinical evidence of eosinophil involvement in IBD, summarize the in-vitro and in-vivo evidence of eosinophil antibacterial activity and the biology of eosinophils focusing on eosinophil-mediated bactericidal mechanisms and the involvement of eosinophil-derived granule proteins in this response, and conceptualize the contribution of eosinophils to a response against commensal bacteria in IBD.
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Affiliation(s)
- Simon P Hogan
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
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Biagi P, Abate L, Mellone C, Salvadori S, Peccetti A, Ginori A. Eosinophilic gastroenteritis: a case report and review of the literature. ITALIAN JOURNAL OF MEDICINE 2012. [DOI: 10.1016/j.itjm.2012.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Blom K, Rubin J, Halfvarson J, Törkvist L, Rönnblom A, Sangfelt P, Lördal M, Jönsson UB, Sjöqvist U, Håkansson LD, Venge P, Carlson M. Eosinophil associated genes in the inflammatory bowel disease 4 region: Correlation to inflammatory bowel disease revealed. World J Gastroenterol 2012; 18:6409-6419. [PMID: 23197886 PMCID: PMC3508635 DOI: 10.3748/wjg.v18.i44.6409] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP).
METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn’s disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5’-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP® system as described by the manufacturer. Statistical tests for calculations of results were χ2 test, Fisher’s exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant.
RESULTS: The genotype frequency for males with UC and with an age of disease onset of ≥ 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject’s genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29%,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of ≥ 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in μg/106 eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes.
CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.
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Clinical significance of eosinophilia and chronic inflammatory infiltrate in children's rectal biopsies. J Pediatr Gastroenterol Nutr 2012; 55:519-22. [PMID: 22543436 DOI: 10.1097/mpg.0b013e31825b3169] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIMS The aim of the present study was to determine the clinical significance of an incidental finding of eosinophilia (EOS) and chronic inflammatory infiltrate (CINF) in rectal biopsies of children investigated for suspected Hirschsprung disease (HSCR). METHODS A retrospective study (2000-2010) of children incidentally found to have EOS and CINF was performed. HSCR cases were excluded. Presence of gastrointestinal (GI) symptoms and nutritional status (weight-for-age z score) were investigated and compared with a matched cohort with normal biopsy. RESULTS Of 364 children undergoing rectal biopsy for suspected HSCR, 109 had confirmed HSCR, whereas 255 children had normal ganglia. Forty-four of 255 (17%) children had EOS and/or CINF incidentally reported and are the subject of the present study. In 13 of 44 (29%) children, the biopsy was performed neonatally. At follow-up (4.6 months [1-22]), 21 (48%) had food and/or milk allergy, 30 (68%) had constipation and/or other GI symptoms. There was no change in weight-for-age z score (P = 0.85) at follow-up and 8 (20%) had failure to thrive. Only 10 of 44 (P = 0.0001 vs patients with EOS and/or CINF) children with normal biopsy had persistent constipation at follow-up (9.7 months [0.5-84.7]) and 1 patient had atopy. Patients with normal biopsy exhibited an increase in weight-for-age z score at follow-up (P = 0.003) and only 3 patients (7%) had failure to thrive. CONCLUSIONS EOS and CINF are found in 17% of children who had rectal biopsies negative for HSCR. Half of these children will need further medical input for the presence of persisting GI symptoms, food/milk allergy and failure to thrive, and the possibility to develop inflammatory bowel disease later in life.
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Gotlib J, Akin C. Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders. Semin Hematol 2012; 49:128-37. [PMID: 22449623 DOI: 10.1053/j.seminhematol.2012.01.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mast cells and eosinophils often travel in the same biologic circles. In non-clonal states, such as allergic and inflammatory conditions, cell-to-cell contact and the pleiotropic actions of multiple cytokines and chemokines, derived from local tissues or mast cells themselves, foster the co-recruitment of these cells to the same geographic cellular niche. While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis, these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors. The dysregulated tyrosine kinases, D816V KIT and FIP1L1-PDGFRA, are the prototypic oncogenic lesions resulting in systemic mastocytosis (SM) and chronic eosinophilic leukemia, respectively. We review the pathobiology of these myeloproliferative neoplasms (MPNs) with a focus on the relationship between mast cells and eosinophils, and discuss murine models, which further elucidate how the phenotype of these diseases can be influenced by stem cell factor (SCF) and expression of the potent eosinophilopoietic cytokine, interleukin-5 (IL-5). Therapy of SM and FIP1L1-PDGFRA-positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed.
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Affiliation(s)
- Jason Gotlib
- Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA, USA
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Curran CS, Bertics PJ. Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1α and MCP-1 in GM-CSF-treated human primary eosinophils. J Interferon Cytokine Res 2012; 32:450-61. [PMID: 22731992 DOI: 10.1089/jir.2011.0111] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Eosinophils are multifunctional immune cells that contribute to innate and adaptive immune/repair responses. Lactoferrin (LF) is an iron-binding protein indicated to alter cell adhesion and immune function by receptor-mediated interactions or by participating in redox mechanisms. The eosinophil adhesion molecules, αMβ2 and α4β1, are differentially expressed following exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and various redox agents. We hypothesized that LF can alter the function and production of proteins involved in adhesion/migration. Utilizing eosinophil peroxidase activity or fluorescent labeling adhesion assays, LF reduced GM-CSF-induced eosinophil adhesion in the presence of fibronectin or vascular adhesion molecule-1 compared with GM-CSF treatment alone. Flow cytometric analysis of eosinophil αM (CD11b) and α4 (CD49d) integrins revealed that cotreatments (24 h) with LF plus GM-CSF induced a significant increase in CD11b compared with control and GM-CSF treatments but a significant decrease in CD49d compared with control and GM-CSF treatments. These changes in CD11b and CD49d levels were significantly correlated with the increased production of chemokines (macrophage inflammatory Protein-1α, monocyte chemotactic protein-1) and an identified increase in S100A9 production. Thus, LF release at sites of inflammation may alter eosinophil recruitment/activation and possibly the progression of diseases such as cancer and asthma where significant eosinophil influx has been described.
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Affiliation(s)
- Colleen S Curran
- Department of Molecular Biology, University of Wisconsin, Madison, Wisconsin 53706, USA.
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Cançado GGL, Fiuza JA, de Paiva NCN, Lemos LDCD, Ricci ND, Gazzinelli-Guimarães PH, Martins VG, Bartholomeu DC, Negrão-Corrêa DA, Carneiro CM, Fujiwara RT. Hookworm products ameliorate dextran sodium sulfate-induced colitis in BALB/c mice. Inflamm Bowel Dis 2011; 17:2275-86. [PMID: 21290484 DOI: 10.1002/ibd.21629] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 12/08/2010] [Indexed: 12/26/2022]
Abstract
BACKGROUND Several lines of evidence have shown that helminthiasis can significantly reduce disease severity in animal models of intestinal inflammation, airway inflammation/hyperreactivity, diabetes, and multiple sclerosis. Identification and characterization of helminth-derived immunomodulatory molecules that contribute to anticolitis effects could lead to new therapeutic approaches in inflammatory bowel diseases (IBDs) without the need for helminth infection. We evaluated the therapeutic potential of adult human hookworm, Ancylostoma ceylanicum, crude (Aw) and excreted/secreted (ES) products on dextran sulfate sodium (DSS)-induced colitis in BALB/c mice. METHODS Colitis was induced by 5% DSS oral administration for 7 days. Clinical disease severity was monitored daily during concomitant intraperitoneal treatment with helminth-derived products. Additionally, several pathways of immunological modulation induced by A. ceylanicum products (MPO, EPO, Th1, Th2, and Th17 cytokine responses) in the inflamed intestinal microenvironment were assessed. Finally, the histopathological profile of the colon was characterized. RESULTS Hookworm products are able to modulate the potent proinflammatory response induced by DSS, mainly through the downregulation of Th1 and Th17 cytokines. These proteins also reduce clinical and colonic microscopic inflammation scores as well as EPO and MPO activity. CONCLUSIONS Ancylostoma ceylanicum Aw and ES mediators have an important therapeutic potential in experimental colitis in mice, which may provide a more socially acceptable form of therapy for patients with IBDs as opposed to using living worms. Our results support the urgency of further isolation and recombinant expression of active hookworm products responsible for the beneficial effects on colitis.
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Saad AG. Normal quantity and distribution of mast cells and eosinophils in the pediatric colon. Pediatr Dev Pathol 2011; 14:294-300. [PMID: 21341989 DOI: 10.2350/10-07-0878-oa.1] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The normal number and distribution of mast cells (MCs) and eosinophils in colonic mucosa are largely unknown. Accordingly, we examined colonic biopsies obtained during endoscopic examinations of pediatric patients. The study included 41 patients (21 males and 20 females). The mean age was 11.72 years (range 3.3-19.7 years). Patients were followed for a mean time of 23.4 months (range 12-50 months). Our results showed a gradual decrease in the number of eosinophils in the lamina propria from the cecum to the descending colon (14.2 ± 6.1 and 10.7 ± 5.6 eosinophils//high-power field [hpf], respectively), with another peak in the rectosigmoid (12.4 ± 6.1 eosinophils/hpf). Eosinophils within the surface and crypt epithelium were more commonly encountered in the cecum and the rectosigmoid. Eosinophils clusters were rare but were more frequently found in the cecum and rectosigmoid. The largest number of MCs was observed in the descending colon and the lowest in the rectosigmoid (17.56 ± 7.28 and 14.5 ± 6.35 MCs/hpf, respectively). No MCs were identified within the surface epithelium. Very rare MCs were observed within the crypt epithelium, with the highest number observed in the cecum (0.34 ± 0.53 MCs/hpf) and the lowest number observed in the descending colon (0.02 ± 0.16 MCs/hpf). More MCs were present in the cecum and descending colon of females vs males (P = 0.02 and 0.04, respectively). Our results establish baseline gastrointestinal eosinophils and MC counts in various parts of the pediatric colon.
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Affiliation(s)
- Ali G Saad
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
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Katsanos KH, Zinovieva E, Lambri E, Tsianos EV. Eosinophilic-Crohn overlap colitis and review of the literature. J Crohns Colitis 2011; 5:256-61. [PMID: 21575892 DOI: 10.1016/j.crohns.2011.02.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 02/11/2011] [Accepted: 02/12/2011] [Indexed: 02/08/2023]
Abstract
Eosinophilic colitis is an idiopathic inflammation of the alimentary canal and is characterized by infiltration of the intestinal wall by eosinophils, massive submucosal edema, and peripheral eosinophilia. However, the presence of eosinophils in a colon biopsy requires thorough searching for secondary causes and eosinophilic colitis remains a diagnosis of exclusion. A 67-year-old male patient underwent a diagnostic ileocolonoscopy because of recurrent episodes of diarrhea for the last six months. Colonoscopy revealed a normal terminal ileum while in the entire colon an erythematous mucosa with very slight edema on a continuous pattern that was more pronounced in the left colon. The laboratory workup demonstrated eosinophils slightly elevated, biochemical tests were unremarkable and further clinical and laboratory workup was unremarkable. Histology showed overlapping findings of eosinophilic colitis and Crohn's colitis. Patient started on mesalazine 2.4 with very good results. A review of the literature shows that the spectrum of eosinophil involvement in inflammatory bowel disease as well as in eosinophilic colitis is largely varying, including also some exceptional cases that parallel the case described herein.
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Affiliation(s)
- Konstantinos H Katsanos
- 1st Division of Internal Medicine and Hepato-gastroenterology Unit, Medical School, University of Ioannina, GR 45110, Greece
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Waddell A, Ahrens R, Steinbrecher K, Donovan B, Rothenberg ME, Munitz A, Hogan SP. Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:5993-6003. [PMID: 21498668 PMCID: PMC3423906 DOI: 10.4049/jimmunol.1003844] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent genome-wide association studies of pediatric inflammatory bowel disease have implicated the 17q12 loci, which contains the eosinophil-specific chemokine gene CCL11, with early-onset inflammatory bowel disease susceptibility. In the current study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that dextran sodium sulfate (DSS) treatment promotes the recruitment of F4/80(+)CD11b(+)CCR2(+)Ly6C(high) inflammatory monocytes into the colon. F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6C(high) intestinal inflammatory macrophages revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4, Cxcl2, Arg1, Chi3l3, Ccl11, and Il10, respectively. Attenuation of DSS-induced F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocyte recruitment to the colon in CCR2(-/-) mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation, and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6C(high)CCR2(+) inflammatory monocyte/macrophage-derived CCL11.
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MESH Headings
- Animals
- Antigens, Differentiation/genetics
- Antigens, Ly/analysis
- Antigens, Ly/immunology
- Bone Marrow Cells
- CD11b Antigen/immunology
- Chemokine CCL11/genetics
- Chemokine CCL11/immunology
- Chemokine CCL11/metabolism
- Colitis/chemically induced
- Colitis/immunology
- Colitis/metabolism
- Colon/immunology
- Dextran Sulfate/pharmacology
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Eosinophilia/immunology
- Female
- Gene Expression Regulation
- Inflammatory Bowel Diseases/immunology
- Inflammatory Bowel Diseases/metabolism
- Macrophages/cytology
- Macrophages/immunology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Fluorescence
- Monocytes/drug effects
- Monocytes/immunology
- Polymerase Chain Reaction
- Receptors, CCR2/analysis
- Receptors, CCR2/immunology
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Affiliation(s)
- Amanda Waddell
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Richard Ahrens
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Kris Steinbrecher
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Burke Donovan
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Marc E. Rothenberg
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Ariel Munitz
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
- Department of Microbiology and Clinical Immunology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Simon P. Hogan
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
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Albert EJ, Duplisea J, Dawicki W, Haidl ID, Marshall JS. Tissue eosinophilia in a mouse model of colitis is highly dependent on TLR2 and independent of mast cells. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 178:150-60. [PMID: 21224053 DOI: 10.1016/j.ajpath.2010.11.041] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Revised: 07/22/2010] [Accepted: 09/09/2010] [Indexed: 12/20/2022]
Abstract
The mechanisms initiating eosinophil influx into sites of inflammation have been well studied in allergic disease but are poorly understood in other settings. This study examined the roles of TLR2 and mast cells in eosinophil accumulation during a nonallergic model of eosinophilia-associated colitis. TLR2-deficient mice (TLR2(-/-)) developed a more severe colitis than wild-type mice in the dextran sodium sulfate (DSS) model. However, they had significantly fewer eosinophils in the submucosa of the cecum (P < 0.01) and mid-colon (P < 0.01) than did wild-type mice after DSS treatment. Decreased eosinophilia in TLR2(-/-) mice was associated with lower levels of cecal CCL11 (P < 0.01). Peritoneal eosinophils did not express TLR2 protein, but TLR2 ligand injection into the peritoneal cavity induced local eosinophil recruitment, indicating that TLR2 activation of other cell types can mediate eosinophil recruitment. After DSS treatment, mast cell-deficient (Kit(W-sh/W-sh)) mice had similar levels of intestinal tissue eosinophilia were observed as those in wild-type mice. However, mast cell-deficient mice were partially protected from DSS-induced weight loss, an effect that was reversed by mast cell reconstitution. Overall, this study indicates a critical role for indirect TLR2-dependent pathways, but not mast cells, in the generation of eosinophilia in the large intestine during experimental colitis and has important implications for the regulation of eosinophils at mucosal inflammatory sites.
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Affiliation(s)
- Eric J Albert
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
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Abstract
Eosinophilic gastrointestinal disorders (EGIDs) are a diverse group of disorders whose diagnosis is on the rise and are characterized by symptoms caused by infiltration by eosinophils of the different sections of the digestive tract. Although little is known of their etiology, it seems to be multifactorial. Alteration of the immunological capacity of the digestive mucosa is determined by the exposure of genetically predisposed individuals to potential airborne or food allergens. EGIDs are classified based on the location of the inflammatory response even though their symptoms, prognosis, and treatment vary considerably. Eosinophilic esophagitis is the most widely recognized entity in this family and is characterized by exclusive eosinophilic infiltration of the esophagus. Breakthroughs in understanding its etiopathogeny have been extrapolated to eosinophilic gastroenteritis, a rare disease identified many years ago commonly involving the stomach and small bowel which should be distinguished from hypereosinophilic syndrome. Eosinophilic colitis, which usually affects children, could be considered a specific non-IgE-mediated allergy to food protein. The physiopathological bases of these entities need to be established in order to define specific treatment aimed at preventing and altering their clinical evolution.
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Affiliation(s)
- Alfredo J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, (Ciudad Real), Spain.
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Characterisation of the inflammatory reaction in equine idiopathic focal eosinophilic enteritis and diffuse eosinophilic enteritis. Equine Vet J 2010; 40:386-92. [DOI: 10.2746/042516408x312112] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Vieira AT, Fagundes CT, Alessandri AL, Castor MGM, Guabiraba R, Borges VO, Silveira KD, Vieira ELM, Gonçalves JL, Silva TA, Deruaz M, Proudfoot AEI, Sousa LP, Teixeira MM. Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:2382-91. [PMID: 19893035 DOI: 10.2353/ajpath.2009.090093] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Eosinophils are multifunctional leukocytes implicated in numerous inflammatory diseases. The present study was conducted to clarify the precise role of eosinophils in the development of colitis by using eosinophil-depleted mice and a novel chemokine-binding protein that neutralizes CCL11 action. Colitis was induced by administration of dextran sodium sulfate (DSS) to wild-type and eosinophil-deficient DeltadblGATA-1 mice. Accumulation of eosinophils in the gut of mice given DSS paralleled worsening of clinical score and weight loss. In response to DSS, DeltadblGATA-1 mice showed virtual absence of eosinophil recruitment, amelioration of clinical score, weight loss, and tissue destruction, and no lethality. There was a decrease in CXCL1 and CCL3 production and decreased neutrophil influx in the intestine of DeltadblGATA-1 mice. Transfer of bone marrow cells from wild-type mice reconstituted disease manifestation in DSS-treated DeltadblGATA-1 mice, and levels of CCL11 were increased after DSS treatment and localized to inflammatory cells. Treatment with the chemokine-binding protein evasin-4 at a dose that prevented the function of CCL11 greatly ameliorated clinical score, weight loss, overall tissue destruction, and death rates. In conclusion, the influx of eosinophils is critical for the induction of colitis by DSS. Treatment with a novel chemokine-binding protein decreased eosinophil influx and greatly ameliorated colitis, suggesting that strategies that interfere with the recruitment of eosinophils may be useful as therapy for colitis.
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Affiliation(s)
- Angélica T Vieira
- Laboratório de Imunofarmacologia, Colégio Técnico, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
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Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009; 124:3-20; quiz 21-2. [PMID: 19560575 PMCID: PMC4266989 DOI: 10.1016/j.jaci.2009.05.038] [Citation(s) in RCA: 1226] [Impact Index Per Article: 76.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Revised: 05/22/2009] [Accepted: 05/27/2009] [Indexed: 02/08/2023]
Abstract
The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.
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Affiliation(s)
- Katherine R. Groschwitz
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Simon P. Hogan
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
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Fireman E, Masarwy F, Groisman G, Shtark M, Kopelman Y, Kivity S, Fireman Z. Induced sputum eosinophilia in ulcerative colitis patients: the lung as a mirror image of intestine? Respir Med 2009; 103:1025-32. [PMID: 19230639 DOI: 10.1016/j.rmed.2009.01.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Accepted: 01/15/2009] [Indexed: 12/30/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a systemic disease of unknown etiology with extra-intestinal manifestation. Induced sputum (IS) non-invasively assesses extrapulmonary involvement in Crohn's disease. We sought to determine whether there is a cellular marker of lung injury in UC patients detectable by IS. METHODS Nineteen UC patients (mean age 46.4+/-11.3 years, disease duration 8.6+/-7.5 years [range 1-25 years] 68.4% males) were studied, 6 with active disease and 13 in remission. Eleven received 5-ASA, 5 received steroids and/or azathioprine and 3 patients were untreated. UC patients were compared with 27 healthy non-smoker controls. IS was recovered after 20 min inhalation of 3% saline with an ultrasonic nebulizer by the selecting plugs method, and 300 cells were differentially cell counted in cytospin Giemsa-stained slides. CD4/CD8 subsets were identified by FACS. Pulmonary function tests were performed by the Jaeger Masterlab spirometer. RESULTS UC patients' IS contained higher %eosinophils than controls (p=0.05) and lower FEV(1)/FVC ratios (p=0.001). Steroid- and/or azathioprine-treated patients had significantly lower FEV(1)/FVC ratios than only 5-ASA-treated patients (p=0.019). Eosinophil infiltration in airways was high in 5-ASA-treated patients compared to those receiving steroids and/or azathioprine (p=0.046) and those with less extensive disease (p=0.05). Using a cutoff of 3% eosinophils, IS had a sensitivity of 67% and specificity of 73% to differentiate patients with a cutoff of 70 eosinophils/mm(2) in biopsy. CONCLUSIONS The percentage of sputum eosinophils is significantly different between UC patients with proctitis and pancolitis. These immune abnormalities may be a common pattern that is present throughout the mucosae.
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Affiliation(s)
- Elizabeth Fireman
- Department of Pulmonary and Allergic Diseases, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel-Aviv 64239, Israel
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Abstract
Eosinophilic gastrointestinal (GI) diseases (EGIDs) are characterized by a rich eosinophilic inflammation of the GI tract. Clinical and experimental studies suggest that eosinophils have a pathogenic role in EGIDs; however, the function of eosinophils in these diseases remains an enigma. This article describes eosinophil immunoregulatory and effector function and discusses the possible involvement of these pathways in EGIDs.
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Affiliation(s)
- Simon P Hogan
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
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Ahrens R, Waddell A, Seidu L, Blanchard C, Carey R, Forbes E, Lampinen M, Wilson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP. Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:7390-9. [PMID: 18981162 PMCID: PMC2728352 DOI: 10.4049/jimmunol.181.10.7390] [Citation(s) in RCA: 137] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn's disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2(-/-) and eotaxin-1/2(-/-) mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80(+)CD11b(+) macrophages in DSS-induced epithelial injury and to CD68(+) intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.
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Affiliation(s)
- Richard Ahrens
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Amanda Waddell
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Luqman Seidu
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Carine Blanchard
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Rebecca Carey
- Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Elizabeth Forbes
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Maria Lampinen
- Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
| | - Tara Wilson
- Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Elizabeth Cohen
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Keith Stringer
- Division of Pathology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Edgar Ballard
- Division of Pathology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Ariel Munitz
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Huan Xu
- Division of Biomedical Informatics, Department of Pediatrics, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Nancy Lee
- Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259
| | - James J. Lee
- Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259
| | - Marc E. Rothenberg
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Lee Denson
- Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
| | - Simon P. Hogan
- Division of Allergy and Immunology, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229
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Abstract
Diagnosis of eosinophilic gastrointestinal diseases is based on morphological evaluation with regard to localization and density of eosinophil infiltration of the mucosa and/or deeper parts of the oesophagus, stomach, and bowel in biopsy or resection specimens. As with eosinophils in any tissue, in the majority of diseases they are probably a sequel of acute inflammation and do not indicate any specific disease. Eosinophil morphology includes intact cells with bilobated nuclei and eosinophil granules in the cytoplasm and extracellular tissue following activation/degranulation. There is no fixed number of eosinophils that can be used as a cut-off criterion to define disease. Associated histopathological features observed in eosinophilic gastrointestinal disease depend on the site of manifestation and primary disease. Eosinophils are typically increased in allergy-associated colitis in adults and allergic proctocolitis in infants, eosinophilic gastroenteritis and eosinophilic oesophagitis. Their presence can also suggest a drug-induced eosinophilia or the presence of a parasitic infection. In general, eosinophils are increased in inflammatory bowel disease (IBD). They are seen in reflux oesophagitis, coeliac disease, and microscopic and infectious colitis. Eosinophils may be a feature of polyarteriitis nodosa and Churg-Strauss syndrome, and can accompany connective-tissue disease as well as malignant lymphomas and adenocarcinomas of gastrointestinal mucosa.
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Wedemeyer J, Vosskuhl K. Role of gastrointestinal eosinophils in inflammatory bowel disease and intestinal tumours. Best Pract Res Clin Gastroenterol 2008; 22:537-49. [PMID: 18492570 DOI: 10.1016/j.bpg.2007.12.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Eosinophils have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Immunohistopathological studies have revealed accumulation and activation of eosinophils in actively inflamed intestinal mucosa of Crohn's disease and ulcerative colitis patients. Elevated levels of chemokines relevant for eosinophil chemotaxis and mediator release from eosinophils can be detected in serum and faeces of patients with active IBD. Animal studies have revealed that abrogation of chemokines (such as eotaxin) promoting eosinophil chemotaxis and circulation results in decreased severity of murine experimental colitis, suggesting a pro-inflammatory role for eosinophils in IBD. Furthermore, selective deletion of certain eosinophil-specific granule products results in attenuation of experimental intestinal inflammation. Shortly after their initial discovery by Ehrlich, eosinophils have been associated with intestinal tumours. However, as only very few studies have addressed the role of eosinophils in intestinal cancerogenesis, their impact on intestinal tumour development remains obscure; in particular, functional data are missing.
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Affiliation(s)
- Jochen Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine, Medical School of Hannover, Carl Neuberg Strasse 1, Hannover, Germany.
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Haley KJ, Sunday ME, Porrata Y, Kelley C, Twomey A, Shahsafaei A, Galper B, Sonna LA, Lilly CM. Ontogeny of the eotaxins in human lung. Am J Physiol Lung Cell Mol Physiol 2007; 294:L214-24. [PMID: 18055844 DOI: 10.1152/ajplung.00086.2007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The ontogeny of the C-C chemokines eotaxin-1, eotaxin-2, and eotaxin-3 has not been fully elucidated in human lung. We explored a possible role for eotaxin in developing lung by determining the ontogeny of eotaxin-1 (CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), and the eotaxin receptor, CCR3. We tested discarded surgical samples of developing human lung tissue using quantitative RT-PCR (QRT-PCR) and immunostaining for expression of CCL11, CCL24, CCL26, and CCR3. We assessed possible functionality of the eotaxin-CCR3 system by treating lung explant cultures with exogenous CCL11 and analyzing the cultures for evidence of changes in proliferation and activation of ERK1/2, a signaling pathway associated with CCR3. QRT-PCR analyses of 22 developing lung tissue samples with gestational ages 10-23 wk demonstrated that eotaxin-1 mRNA is most abundant in developing lung, whereas mRNAs for eotaxin-2 and eotaxin-3 are minimally detectable. CCL11 mRNA levels correlated with gestational age (P < 0.05), and immunoreactivity was localized predominantly to airway epithelial cells. QRT-PCR analysis detected CCR3 expression in 16 of 19 developing lung samples. Supporting functional capacity in the immature lung, CCL11 treatment of lung explant cultures resulted in significantly increased (P < 0.05) cell proliferation and activation of the ERK signaling pathway, which is downstream from CCR3, suggesting that proliferation was due to activation of CCR3 receptors by CCL11. We conclude that developing lung expresses the eotaxins and functional CCR3 receptor. CCL11 may promote airway epithelial proliferation in the developing lung.
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Affiliation(s)
- Kathleen J Haley
- Brigham and Women's Hospital, Division of Pulmonary and Critical Care Medicine, 75 Francis Street, Boston, MA 02115, USA.
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