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Tian T, Zhu Y, Shi J, Shang K, Yin Z, Shi H, He Y, Ding J, Zhang F. The development of a human Brucella mucosal vaccine: What should be considered? Life Sci 2024; 355:122986. [PMID: 39151885 DOI: 10.1016/j.lfs.2024.122986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Brucellosis is a chronic infectious disease that is zoonotic in nature. Brucella can infect humans through interactions with livestock, primarily via the digestive tract, respiratory tract, and oral cavity. This bacterium has the potential to be utilized as a biological weapon and is classified as a Category B pathogen by the Centers for Disease Control and Prevention. Currently, there is no approved vaccine for humans against Brucella, highlighting an urgent need for the development of a vaccine to mitigate the risks posed by this pathogen. Brucella primarily infects its host by adhering to and penetrating mucosal surfaces. Mucosal immunity plays a vital role in preventing local infections, clearing microorganisms from mucosal surfaces, and inhibiting the spread of pathogens. As mucosal vaccine strategies continue to evolve, the development of a safe and effective mucosal vaccine against Brucella appears promising.This paper reviews the immune mechanism of mucosal vaccines, the infection mechanism of Brucella, successful Brucella mucosal vaccines in animals, and mucosal adjuvants. Additionally, it elucidates targeting and optimization strategies for mucosal vaccines to facilitate the development of human vaccines against Brucella.
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Affiliation(s)
- Tingting Tian
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Yuejie Zhu
- Reproductive Fertility Assistance Center, First Afffliated Hospital of Xinjiang Medical University, China
| | - Juan Shi
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Kaiyu Shang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Zhengwei Yin
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Huidong Shi
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Yueyue He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Jianbing Ding
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China
| | - Fengbo Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated hospital of Xinjiang Medical University, China; Department of Clinical laboratory, The First Affiliated hospital of Xinjiang Medical University, China.
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Nossol C, Landgraf P, Oster M, Kahlert S, Barta-Böszörmenyi A, Kluess J, Wimmers K, Isermann B, Stork O, Dieterich DC, Dänicke S, Rothkötter HJ. Deoxynivalenol triggers the expression of IL-8-related signaling cascades and decreases protein biosynthesis in primary monocyte-derived cells. Mycotoxin Res 2024; 40:279-293. [PMID: 38498144 PMCID: PMC11043135 DOI: 10.1007/s12550-024-00528-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/01/2024] [Accepted: 03/09/2024] [Indexed: 03/20/2024]
Abstract
Humans and their immune system are confronted with mold-contaminated food and/or mold-contaminated air in daily life and indoor activities. This results in metabolic stress and unspecific disease symptoms. Other studies provided evidence that exposure to mold is associated with the etiology of allergies. Deoxynivalenol (DON) is of great concern due to its frequent occurrence in toxically relevant concentrations. The exposure to this toxin is a permanent health risk for both humans and farm animals because DON cannot be significantly removed during standard milling and processing procedures. However, the direct effect on immunity or hematology is poorly defined because most investigations could not separate the effect of DON-contaminated feed intake. Due to the widespread distribution of DON after rapid absorption, it is not surprising that DON is known to affect the immune system. The immune system of the organism has one important function, to defend against the invasion of unknown substances/organisms. This study shows for the first time a synergistic effect of both-low physiological DON-doses in combination with low LPS-doses with the focus on the IL-8 expression on protein and RNA level. Both doses were found in vivo. IL-8 together with other anorectic cytokines like IL-1β can affect the food intake and anorexia. We could also show that a calcium-response is not involved in the increased IL-8 production after acute DON stimulation with high or low concentrations.
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Affiliation(s)
- Constanze Nossol
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany.
| | - P Landgraf
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - M Oster
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - S Kahlert
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
| | - A Barta-Böszörmenyi
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
| | - J Kluess
- Institute of Animal Nutrition, Friedrich-Loeffler-Institute (FLI), Federal Research Institute for Animal Health, Bundesallee 50, 38116, Braunschweig, Germany
| | - K Wimmers
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - B Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Paul-List-Str. 13-15, 04103, Leipzig, Germany
| | - O Stork
- Institute of Biology, Faculty of Natural Science, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
| | - D C Dieterich
- Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - S Dänicke
- Institute of Animal Nutrition, Friedrich-Loeffler-Institute (FLI), Federal Research Institute for Animal Health, Bundesallee 50, 38116, Braunschweig, Germany
| | - H-J Rothkötter
- Institute of Anatomy, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
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3
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Zhang Y, Zhao M, He J, Chen L, Wang W. In vitro and in vivo immunomodulatory activity of acetylated polysaccharides from Cyclocarya paliurus leaves. Int J Biol Macromol 2024; 259:129174. [PMID: 38181912 DOI: 10.1016/j.ijbiomac.2023.129174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 12/04/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024]
Abstract
In this study, we aimed to investigate the immunomodulatory effects of polysaccharides from Cyclocarya paliurus leaves after acetylation modification (Ac-CPP0.1) on dendritic cells (DCs) and immunosuppressed mice. In vitro, Ac-CPP0.1 promoted phenotypic and functional maturation of DCs. Specifically, it increased the expression of costimulatory molecules (CD80, CD86, and MHC II) and the secretion of cytokines (TNF-α, IL-6, IL-1β, IL-10, IL-12p70) of DCs. In vivo, Ac-CPP0.1 significantly improved immunosuppression of mice, which was manifested by increased body weight and immune organ index, up-regulated cytokines (IL-4, IL-17, TGF-β3, and TNF-α), and restored short-chain fatty acid (SCFAs) levels of intestinal. The immunoactivation of Ac-CPP0.1 in DCs and in mice is linked to the activation of the TLR4/NF-κB signaling pathway. Furthermore, Ac-CPP0.1 reversed intestinal flora imbalance caused by cyclophosphamide. At the species level, Ac-CPP0.1 increased the abundance of unclassified_Muribaculaceae, unclassified_Desulfovibrio, Bacteroides_acidifaciens and Faecalibaculum_rodentium, decreased the level of Lactobacillus_johnsonii, unclassified_g_Staphylococcus and Staphylococcus_nepalensis. In summary, Ac-CPP0.1 has considerable immunomodulatory potential, which is beneficial to the future utilization and development of Cyclocarya paliurus.
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Affiliation(s)
- Yang Zhang
- Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Meng Zhao
- Key Lab for Agro-product Processing and Quality Control of Nanchang City, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Jing He
- Key Lab for Agro-product Processing and Quality Control of Nanchang City, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Lingli Chen
- Key Lab for Agro-product Processing and Quality Control of Nanchang City, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Wenjun Wang
- Key Lab for Agro-product Processing and Quality Control of Nanchang City, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China.
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Tugizov SM. Molecular Pathogenesis of Human Immunodeficiency Virus-Associated Disease of Oropharyngeal Mucosal Epithelium. Biomedicines 2023; 11:1444. [PMID: 37239115 PMCID: PMC10216750 DOI: 10.3390/biomedicines11051444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/01/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
The oropharyngeal mucosal epithelia have a polarized organization, which is critical for maintaining a highly efficient barrier as well as innate immune functions. In human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) disease, the barrier and innate immune functions of the oral mucosa are impaired via a number of mechanisms. The goal of this review was to discuss the molecular mechanisms of HIV/AIDS-associated changes in the oropharyngeal mucosa and their role in promoting HIV transmission and disease pathogenesis, notably the development of opportunistic infections, including human cytomegalovirus, herpes simplex virus, and Epstein-Barr virus. In addition, the significance of adult and newborn/infant oral mucosa in HIV resistance and transmission was analyzed. HIV/AIDS-associated changes in the oropharyngeal mucosal epithelium and their role in promoting human papillomavirus-positive and negative neoplastic malignancy are also discussed.
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Affiliation(s)
- Sharof M Tugizov
- Department of Medicine, School of Medicine, University of California, San Francisco, CA 94143, USA
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Novel Strategy for Alzheimer’s Disease Treatment through Oral Vaccine Therapy with Amyloid Beta. Biologics 2023. [DOI: 10.3390/biologics3010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Alzheimer’s disease (AD) is a neuropathology characterized by progressive cognitive impairment and dementia. The disease is attributed to senile plaques, which are aggregates of amyloid beta (Aβ) outside nerve cells; neurofibrillary tangles, which are filamentous accumulations of phosphorylated tau in nerve cells; and loss of neurons in the brain tissue. Immunization of an AD mouse model with Aβ-eliminated pre-existing senile plaque amyloids and prevented new accumulation. Furthermore, its effect showed that cognitive function can be improved by passive immunity without side effects, such as lymphocyte infiltration in AD model mice treated with vaccine therapy, indicating the possibility of vaccine therapy for AD. Further, considering the possibility of side effects due to direct administration of Aβ, the practical use of the safe oral vaccine, which expressed Aβ in plants, is expected. Indeed, administration of this oral vaccine to Alzheimer’s model mice reduced Aβ accumulation in the brain. Moreover, almost no expression of inflammatory IgG was observed. Therefore, vaccination prior to Aβ accumulation or at an early stage of accumulation may prevent Aβ from causing AD.
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Stark FC, Akache B, Deschatelets L, Tran A, Stuible M, Durocher Y, McCluskie MJ, Agbayani G, Dudani R, Harrison BA, Renner TM, Makinen SR, Bavananthasivam J, Duque D, Gagne M, Zimmermann J, Zarley CD, Cochrane TR, Handfield M. Intranasal immunization with a proteosome-adjuvanted SARS-CoV-2 spike protein-based vaccine is immunogenic and efficacious in mice and hamsters. Sci Rep 2022; 12:9772. [PMID: 35697917 PMCID: PMC9191540 DOI: 10.1038/s41598-022-13819-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/27/2022] [Indexed: 01/07/2023] Open
Abstract
With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.
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Affiliation(s)
- Felicity C Stark
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Bassel Akache
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada.
| | - Lise Deschatelets
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Anh Tran
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Matthew Stuible
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Yves Durocher
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Michael J McCluskie
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Gerard Agbayani
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Renu Dudani
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Blair A Harrison
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Tyler M Renner
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Shawn R Makinen
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Jegarubee Bavananthasivam
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Diana Duque
- National Research Council Canada, Human Health Therapeutics, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Martin Gagne
- Biodextris Inc., 525 boul. Cartier West, Laval, QC, H7V 3S8, Canada
| | - Joseph Zimmermann
- Inspirevax Inc., 46 rue de Saint-Tropez, Kirkland, QC, H9J 2K6, Canada
| | - C David Zarley
- Oragenics, Inc., 13700 Progress Blvd, Alachua, FL, 32608, USA
- CDZarley LLC., 133 Butternut Dr, Pottstown, PA, 19464, USA
| | - Terrence R Cochrane
- Oragenics, Inc., 13700 Progress Blvd, Alachua, FL, 32608, USA
- BrevisRefero Corporation, 295 Alliance Road Suite 1B/C, Milton, ON, L9T 2X7, Canada
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Wu Y, Lin H, Lu Y, Huang Y, Dasanayaka BP, Ahmed I, Chen G, Chen Y, Li Z. Allergenicity determination of Turbot parvalbumin for safety of fish allergy via dendritic cells, RBL‐2H3 cell and mouse model. Eur Food Res Technol 2021. [DOI: 10.1007/s00217-021-03763-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Oral and nasal probiotic administration for the prevention and alleviation of allergic diseases, asthma and chronic obstructive pulmonary disease. Nutr Res Rev 2020; 34:1-16. [PMID: 32281536 DOI: 10.1017/s0954422420000116] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Interaction between a healthy microbiome and the immune system leads to body homeostasis, as dysbiosis in microbiome content and loss of diversity may result in disease development. Due to the ability of probiotics to help and modify microbiome constitution, probiotics are now widely used for the prevention and treatment of different gastrointestinal, inflammatory, and, more recently, respiratory diseases. In this regard, chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma and allergic rhinitis are among the most common and complicated respiratory diseases with no specific treatment until now. Accordingly, many studies have evaluated the therapeutic efficacy of probiotic administration (mostly via the oral route and much lesser nasal route) on chronic respiratory diseases. We tried to summarise and evaluate these studies to give a perspective of probiotic therapy via both the oral and nasal routes for respiratory infections (in general) and chronic respiratory diseases (specifically). We finally concluded that probiotics might be useful for allergic diseases. For asthmatic patients, probiotics can modulate serum cytokines and IgE and decrease eosinophilia, but with no significant reduction in clinical symptoms. For COPD, only limited studies were found with uncertain clinical efficacy. For intranasal administration, although some studies propose more efficiency than the oral route, more clinical evaluations are warranted.
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Roig J, Saiz ML, Galiano A, Trelis M, Cantalapiedra F, Monteagudo C, Giner E, Giner RM, Recio MC, Bernal D, Sánchez-Madrid F, Marcilla A. Extracellular Vesicles From the Helminth Fasciola hepatica Prevent DSS-Induced Acute Ulcerative Colitis in a T-Lymphocyte Independent Mode. Front Microbiol 2018; 9:1036. [PMID: 29875750 PMCID: PMC5974114 DOI: 10.3389/fmicb.2018.01036] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/01/2018] [Indexed: 12/26/2022] Open
Abstract
The complexity of the pathogenesis of inflammatory bowel disease (ulcerative colitis and Crohn's disease) has led to the quest of empirically drug therapies, combining immunosuppressant agents, biological therapy and modulators of the microbiota. Helminth parasites have been proposed as an alternative treatment of these diseases based on the hygiene hypothesis, but ethical and medical problems arise. Recent reports have proved the utility of parasite materials, mainly excretory/secretory products as therapeutic agents. The identification of extracellular vesicles on those secreted products opens a new field of investigation, since they exert potent immunomodulating effects. To assess the effect of extracellular vesicles produced by helminth parasites to treat ulcerative colitis, we have analyzed whether extracellular vesicles produced by the parasitic helminth Fasciola hepatica can prevent colitis induced by chemical agents in a mouse model. Adult parasites were cultured in vitro and secreted extracellular vesicles were purified and used for immunizing both wild type C57BL/6 and RAG1-/- mice. Control and immunized mice groups were treated with dextran sulfate sodium 7 days after last immunization to promote experimental colitis. The severity of colitis was assessed by disease activity index and histopathological scores. Mucosal cytokine expression was evaluated by ELISA. The activation of NF-kB, COX-2, and MAPK were evaluated by immunoblotting. Administration of extracellular vesicles from F. hepatica ameliorates the pathological symptoms reducing the amount of pro-inflammatory cytokines and interfering with both MAPK and NF-kB pathways. Interestingly, the observed effects do not seem to be mediated by T-cells. Our results indicate that extracellular vesicles from parasitic helminths can modulate immune responses in dextran sulfate sodium (DSS)-induced colitis, exerting a protective effect that should be mediated by other cells distinct from B- and T-lymphocytes.
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Affiliation(s)
- Javier Roig
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Facultad de Ciencias de la Salud, Universidad Europea de Valencia, Burjassot, Spain
| | - Maria L Saiz
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Alicia Galiano
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain
| | - Maria Trelis
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, Universitat de València, Burjassot, Spain
| | - Fernando Cantalapiedra
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Veterinari de Salut Pública, Centre de Salut Pública de Manises, Burjassot, Spain
| | | | - Elisa Giner
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - Rosa M Giner
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - M C Recio
- Departament de Farmacologia, Universitat de València, Burjassot, Spain
| | - Dolores Bernal
- Departament de Bioquímica i Biologia Molecular, Universitat de València, Burjassot, Spain
| | - Francisco Sánchez-Madrid
- Facultad de Ciencias de la Salud, Universidad Europea de Valencia, Burjassot, Spain.,Immunology Service, Hospital de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Antonio Marcilla
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Burjassot, Spain.,Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, Universitat de València, Burjassot, Spain
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Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol 2017; 52:1185-1193. [PMID: 28697651 DOI: 10.1080/00365521.2017.1349173] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gastrointestinal tract (GI tract) is a unique organ inhabited by a range of commensal microbes, while also being exposed to an overwhelming load of antigens in the form of dietary antigens on a daily basis. The GI tract has dual roles in the body, in that it performs digestion and uptake of nutrients while also carrying out the complex and important task of maintaining immune homeostasis, i.e., keeping the balance between the good and the bad. It is equally important that we protect ourselves from reacting against the good, meaning that we stay tolerant to harmless food, commensal bacteria and self-antigens, as well as react with force against the bad, meaning induction of immune responses against harmful microorganisms. This complex task is achieved through the presence of a highly efficient mucosal barrier and a specialized multifaceted immune system, made up of a large population of scattered immune cells and organized lymphoid tissues termed the gut-associated lymphoid tissue (GALT). This review provides an overview of the primary components of the human mucosal immune system and how the immune responses in the GI tract are coordinated and induced.
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Affiliation(s)
- Bani Ahluwalia
- a Department of Microbiology and Immunology , Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden.,b Research Unit , Calmino Group AB , Gothenburg , Sweden
| | - Maria K Magnusson
- a Department of Microbiology and Immunology , Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
| | - Lena Öhman
- a Department of Microbiology and Immunology , Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden.,c Department of Internal Medicine and Clinical Nutrition , Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
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Alkasir R, Li J, Li X, Jin M, Zhu B. Human gut microbiota: the links with dementia development. Protein Cell 2017; 8:90-102. [PMID: 27866330 PMCID: PMC5291774 DOI: 10.1007/s13238-016-0338-6] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 09/28/2016] [Indexed: 02/07/2023] Open
Abstract
Dementia is a comprehensive category of brain diseases that is great enough to affect a person's daily functioning. The most common type of dementia is Alzheimer's disease, which makes most of cases. New researches indicate that gastrointestinal tract microbiota are directly linked to dementia pathogenesis through triggering metabolic diseases and low-grade inflammation progress. A novel strategy is proposed for the management of these disorders and as an adjuvant for psychiatric treatment of dementia and other related diseases through modulation of the microbiota (e.g. with the use of probiotics).
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Affiliation(s)
- Rashad Alkasir
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing Li
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xudong Li
- China-Japan Friendship Hospital, Beijing, 100029, China
| | - Miao Jin
- China-Japan Friendship Hospital, Beijing, 100029, China
| | - Baoli Zhu
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Attainted Hospital College of Medicine, Zhejiang University, Hangzhou, 310058, China.
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12
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Abstract
Dementia is a comprehensive category of brain diseases that is great enough to affect a person's daily functioning. The most common type of dementia is Alzheimer's disease, which makes most of cases. New researches indicate that gastrointestinal tract microbiota are directly linked to dementia pathogenesis through triggering metabolic diseases and low-grade inflammation progress. A novel strategy is proposed for the management of these disorders and as an adjuvant for psychiatric treatment of dementia and other related diseases through modulation of the microbiota (e.g. with the use of probiotics).
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Affiliation(s)
- Rashad Alkasir
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing Li
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xudong Li
- China-Japan Friendship Hospital, Beijing, 100029, China
| | - Miao Jin
- China-Japan Friendship Hospital, Beijing, 100029, China
| | - Baoli Zhu
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Attainted Hospital College of Medicine, Zhejiang University, Hangzhou, 310058, China.
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Park JH, Jeong DY, Peyrin-Biroulet L, Eisenhut M, Shin JI. Insight into the role of TSLP in inflammatory bowel diseases. Autoimmun Rev 2016; 16:55-63. [PMID: 27697608 DOI: 10.1016/j.autrev.2016.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 08/08/2016] [Indexed: 12/22/2022]
Abstract
Proinflammatory cytokines are thought to modulate pathogeneses of various inflammatory bowel diseases (IBDs). Thymic stromal lymphopoietin (TSLP), which has been studied in various allergic diseases such as asthma, atopic dermatitis (AD) and eosinophilic esophagitis (EoE), has been less considered to be involved in IBDs. However, mucosal dendritic cells (DCs) induced by various cytokines including TSLP were reported to cause polarization of T cell toward Th2 response, the differentiation of regulatory T-cell (Treg), and secretion of IgA by B cells. In this review, we discuss the concept that decreased TSLP has the potential to accelerate the development of Th1 response dominant diseases such as the Crohn's disease (CD) while increased TSLP has the potential to lead to a development of Th2 cell dominant diseases such the ulcerative colitis (UC). To examine TSLP's role as a potential determining factor for differentiating UC and CD, we analyzed the effects of other genes regulated by TSLP in regards to the UC and CD pathogeneses using data from online open access resources such as NetPath, GeneMania, and the String database. Our findings indicate that TSLP is a key mediator in the pathogenesis of IBDs and that further studies are needed to evaluate its role.
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Affiliation(s)
| | | | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Luton & Dunstable University Hospital NHS Foundation Trust, Luton, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
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14
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Hetta HF, Mehta MJ, Shata MTM. Gut immune response in the presence of hepatitis C virus infection. World J Immunol 2014; 4:52-62. [DOI: 10.5411/wji.v4.i2.52] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28B genotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
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15
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Abstract
Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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16
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Giordani L, Del Pinto T, Vincentini O, Felli C, Silano M, Viora M. Two wheat decapeptides prevent gliadin-dependent maturation of human dendritic cells. Exp Cell Res 2013; 321:248-54. [PMID: 24262078 DOI: 10.1016/j.yexcr.2013.11.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/07/2013] [Accepted: 11/11/2013] [Indexed: 11/17/2022]
Abstract
Celiac disease (CD) is a small intestinal enteropathy, triggered in susceptible individuals by the ingestion of dietary gluten. Dendritic cells (DC) are instrumental in the generation and regulation of immune responses and oversee intestinal immune homeostasis promoting and maintaining oral tolerance to food antigens. The aim of this study was to monitor the effect of peptic-tryptic digest of gliadin (PT-gliadin) on the maturation of human monocyte-derived DC and the impact of pDAV and pRPQ decapeptides in the modulation of PT-gliadin-induced phenotypic and functional DC maturation. Immature DC (iDC) were challenged in vitro with PT-gliadin. In some experiments iDC were pre-treated with pDAV or pRPQ and after 2h PT-gliadin was added to the cultures. We found that PT-gliadin up-regulates the expression of the maturation markers HLA-DR, CD83, CD80 and CD86. The functional consequence of PT-gliadin treatment of iDC is a significant increase in IL-12, TNF-alpha production as well as in their T cell stimulatory capacity. On the contrary, the digest of zein had no effect on DC maturation. Interestingly, we found that pre-treatment of iDC with pDAV or pRPQ decapeptides significantly prevents the functional maturation of DC induced by PT-gliadin. On the other hand, pDAV and pRPQ did not revert the PT-gliadin-induced phenotypic maturation of DC. Here we report, for the first time, that naturally occurring peptides are able to prevent the gliadin-dependent DC maturation. This finding could have implication for CD, raising the perspective of a potential therapeutic strategy alternative to a gluten free diet.
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Affiliation(s)
- Luciana Giordani
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Tamara Del Pinto
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Olimpia Vincentini
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Cristina Felli
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Marco Silano
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Marina Viora
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
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17
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Alga-produced cholera toxin-Pfs25 fusion proteins as oral vaccines. Appl Environ Microbiol 2013; 79:3917-25. [PMID: 23603678 DOI: 10.1128/aem.00714-13] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Infectious diseases disproportionately affect indigent regions and are the greatest cause of childhood mortality in developing countries. Practical, low-cost vaccines for use in these countries are paramount to reducing disease burdens and concomitant poverty. Algae are a promising low-cost system for producing vaccines that can be orally delivered, thereby avoiding expensive purification and injectable delivery. We engineered the chloroplast of the eukaryotic alga Chlamydomonas reinhardtii to produce a chimeric protein consisting of the 25-kDa Plasmodium falciparum surface protein (Pfs25) fused to the β subunit of the cholera toxin (CtxB) to investigate an alga-based whole-cell oral vaccine. Pfs25 is a promising malaria transmission-blocking vaccine candidate that has been difficult to produce in traditional recombinant systems due to its structurally complex tandem repeats of epidermal growth factor-like domains. The noncatalytic CtxB domain of the cholera holotoxin assembles into a pentameric structure and acts as a mucosal adjuvant by binding GM1 ganglioside receptors on gut epithelial cells. We demonstrate that CtxB-Pfs25 accumulates as a soluble, properly folded and functional protein within algal chloroplasts, and it is stable in freeze-dried alga cells at ambient temperatures. In mice, oral vaccination using freeze-dried algae that produce CtxB-Pfs25 elicited CtxB-specific serum IgG antibodies and both CtxB- and Pfs25-specific secretory IgA antibodies. These data suggest that algae are a promising system for production and oral delivery of vaccine antigens, but as an orally delivered adjuvant, CtxB is best suited for eliciting secretory IgA antibodies for vaccine antigens against pathogens that invade mucosal surfaces using this strategy.
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18
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Campylobacter jejuni-mediated induction of CC and CXC chemokines and chemokine receptors in human dendritic cells. Infect Immun 2012; 80:2929-39. [PMID: 22689814 DOI: 10.1128/iai.00129-12] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Campylobacter jejuni is a leading worldwide bacterial cause of human diarrheal disease. Although the specific molecular mechanisms of C. jejuni pathogenesis have not been characterized in detail, host inflammatory responses are thought to be major contributing factors to the resulting typical acute colitis. The intestinal mucosal chemokine response is particularly important in the initial stages of bacterium-induced gut inflammation. Chemokines attract blood phagocytes and lymphocytes to the site of infection and regulate immune cell maturation and the development of localized lymphoid tissues. The production of chemokines by dendritic cells (DCs) following Campylobacter infection has not yet been analyzed. In the current study, we infected human monocyte-derived DCs with C. jejuni to examine the production of key proinflammatory chemokines and chemokine receptors. The chemokines, including CC families (macrophage inflammatory protein 1α [MIP-1α], MIP-1β, RANTES) and CXC families (growth-related oncogene α [GRO-α], IP-10, and monokine induced by gamma interferon [MIG]), were upregulated in Campylobacter-infected DCs. Chemokine receptors CCR6 and CCR7, with roles in DC trafficking, were also induced in Campylobacter-infected DCs. Further, Campylobacter infection stimulated the phosphorylation of P38, P44/42, and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein kinases (MAPKs) in DCs. NF-κB activation was specifically involved in chemokine induction in DCs infected with C. jejuni. Additionally, STAT3 was significantly increased in Campylobacter-infected DCs compared to that in uninfected DCs. These results suggest that DCs play a significant role in the initiation and modulation of the inflammatory response by enlisting monocytes, neutrophils, and T lymphocytes during human intestinal infection with Campylobacter.
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19
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Geem D, Medina-Contreras O, Kim W, Huang CS, Denning TL. Isolation and characterization of dendritic cells and macrophages from the mouse intestine. J Vis Exp 2012:e4040. [PMID: 22644046 DOI: 10.3791/4040] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Within the intestine reside unique populations of innate and adaptive immune cells that are involved in promoting tolerance towards commensal flora and food antigens while concomitantly remaining poised to mount inflammatory responses toward invasive pathogens. Antigen presenting cells, particularly DCs and macrophages, play critical roles in maintaining intestinal immune homeostasis via their ability to sense and appropriately respond to the microbiota. Efficient isolation of intestinal DCs and macrophages is a critical step in characterizing the phenotype and function of these cells. While many effective methods of isolating intestinal immune cells, including DCs and macrophages, have been described, many rely upon long digestions times that may negatively influence cell surface antigen expression, cell viability, and/or cell yield. Here, we detail a methodology for the rapid isolation of large numbers of viable, intestinal DCs and macrophages. Phenotypic characterization of intestinal DCs and macrophages is carried out by directly staining isolated intestinal cells with specific fluorescence-labeled monoclonal antibodies for multi-color flow cytometric analysis. Furthermore, highly pure DC and macrophage populations are isolated for functional studies utilizing CD11c and CD11b magnetic-activated cell sorting beads followed by cell sorting.
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Affiliation(s)
- Duke Geem
- Department of Pediatrics, Emory University
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20
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Ng SC, Benjamin JL, McCarthy NE, Hedin CRH, Koutsoumpas A, Plamondon S, Price CL, Hart AL, Kamm MA, Forbes A, Knight SC, Lindsay JO, Whelan K, Stagg AJ. Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn's disease. Inflamm Bowel Dis 2011; 17:2027-37. [PMID: 21910165 DOI: 10.1002/ibd.21590] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 10/29/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Altered intestinal dendritic cell (DC) function underlies dysregulated T-cell responses to bacteria in Crohn's disease (CD) but it is unclear whether composition of the intestinal microbiota impacts local DC function. We assessed the relationship between DC function with disease activity and intestinal microbiota in patients with CD. METHODS Surface expression of Toll-like receptor (TLR)-2, TLR-4, and spontaneous intracellular interleukin (IL)-10, IL-12p40, IL-6 production by freshly isolated DC were analyzed by multicolor flow cytometry of cells extracted from rectal tissue of 10 controls and 28 CD patients. Myeloid DC were identified as CD11c(+) HLA-DR(+lin-/dim) cells (lin = anti-CD3, CD14, CD16, CD19, CD34). Intestinal microbiota were analyzed by fluorescent in situ hybridization of fecal samples with oligonucleotide probes targeting 16S rRNA of bifidobacteria, bacteroides-prevotella, C. coccoides-E. rectale, and Faecalibacterium prausnitzii. RESULTS DC from CD produced higher amounts of IL-12p40 and IL-6 than control DC. IL-6(+) DC were associated with the CD Activity Index (r = 0.425; P = 0.024) and serum C-reactive protein (CRP) (r = 0.643; P = 0.004). DC expression of TLR-4 correlated with disease activity. IL-12p40(+) DC correlated with ratio of bacteroides: bifidobacteria (r = 0.535, P = 0.003). IL-10(+) DC correlated with bifidobacteria, and IL-6(+) DC correlated negatively with F. prausnitzii (r = -0.50; P = 0.008). The amount of TLR-4 on DC correlated negatively with the concentration of F. prausnitzii. CONCLUSIONS IL-6 production by intestinal DC is increased in CD and correlates with disease activity and CRP. Bacterially driven local IL-6 production by intestinal DC may overcome regulatory activity, resulting in unopposed effector function and tissue damage. Intestinal DC function may be influenced by the composition of the commensal microbiota.
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Affiliation(s)
- S C Ng
- Antigen Presentation Research Group, Imperial College London, St Mark's Hospital, London, UK
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21
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Abstract
Research has yielded an abundance of vaccine candidates against mucosal infections, but only few mucosal vaccines have been registered for human use. Extensive research is being carried out to identify new and safe adjuvants for mucosal immunization, novel delivery systems, including live vectors and reporter molecules for tissue- and cell-specific targeting of vaccine antigens. If these candidates are to reach those in need, several lessons from clinical and field research carried out under resource-poor settings must be considered. These lessons include the need to develop new vaccines that can be administered topically onto the skin or to the mucosa, without needles or expensive delivery devices. Such topical vaccines must be able to protect all age groups at risk, be safe and effective in immunocompromised people, and be able to contain epidemics following complex emergencies. The anatomical compartmentalization of immune responses imposes constraints on the selection of topical route(s) of vaccine administration and on strategies for measuring these responses, especially in young infants. Thus, the selection of any particular route of immunization is critical when designing and formulating vaccines against organ-specific infections.
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Affiliation(s)
- C Czerkinsky
- International Vaccine Institute, Seoul, South Korea.
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22
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Schirbel A, Fiocchi C. Inflammatory bowel disease: Established and evolving considerations on its etiopathogenesis and therapy. J Dig Dis 2010; 11:266-76. [PMID: 20883422 DOI: 10.1111/j.1751-2980.2010.00449.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Modern studies of inflammatory bowel disease (IBD) pathogenesis have been pursued for about four decades, a period of time where the pace of progress has been steadily increasing. This progress has occurred in parallel with and is largely due to developments in multiple basic scientific disciplines that range from population and social studies, genetics, microbiology, immunology, biochemistry, cellular and molecular biology, and DNA engineering. From this cumulative and constantly expanding knowledge base the fundamental pillars of IBD pathogenesis appear to have been identified and consolidated during the last couple of decades. Presently there is a general consensus among basic IBD investigators that both Crohn's disease (CD) and ulcerative colitis (UC) are the result of the combined effects of four basic components: global changes in the environment, the input of multiple genetic variations, alterations in the intestinal microbiota, and aberrations of innate and adaptive immune responses. There is also agreement on the conclusion that none of these four components can by itself trigger or maintain intestinal inflammation. A combination of various factors, and most likely of all four factors, is probably needed to bring about CD or UC in individual patients, but each patient or set of patients seems to have a different combination of alterations leading to the disease. This would imply that different causes and diverse mechanisms underlie IBD, and this could also explain why every patient displays his or her own clinical manifestations and a personalized response to therapy, and requires tailored approaches with different medications. While we are becoming increasingly aware of the importance of this individual variability, we have only a superficial notion of the reasons why this occurs, as hinted by the uniqueness of the genetic background and of the gut flora in each person. So, we are apparently facing the paradox of having to deal with the tremendous complexity of the mechanisms responsible for chronic intestinal inflammation in the setting of each patient's individuality in the response to this biological complexity. This obviously poses considerable challenges to reaching a full understanding of IBD pathogenesis, but being aware of the difficulties is the first step in finding answers to them.
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Affiliation(s)
- Anja Schirbel
- Department of Hepatology and Gastroenterology, Charité- Universitätsmedizin, Berlin, Germany
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23
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Abstract
Oral vaccines offer significant advantages over needle-based vaccines for achieving universal childhood vaccination goals. The expression of vaccine antigens in transgenic plants has the potential to provide a convenient, safe approach for oral vaccination and thus a feasible alternative to traditional parenteral vaccines. Many developments in the field have ushered in improvements such as enhanced protein antigen expression for the use of plants as factories for vaccine production, and facilitated studies pertaining to immunogenicity of candidate vaccines. Oral delivery of plant-based vaccines offers the benefit of antigen protection within the harsh intestinal environment. Within the gut, mucosal immune cells are poised to respond to pathogens, but can also be exploited to elicit protective immune responses to oral vaccines. Inclusion of mucosal adjuvants during immunization with the vaccine antigen has been an important step towards the success of plant-based vaccines. This review discusses the mechanisms that control mucosal immune responses and highlights some of the studies and the results achieved following immunization with transgenic plants.
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Affiliation(s)
- Amit A Lugade
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
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24
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Ochiel DO, Ghosh M, Fahey JV, Guyre PM, Wira CR. Human uterine epithelial cell secretions regulate dendritic cell differentiation and responses to TLR ligands. J Leukoc Biol 2010; 88:435-44. [PMID: 20385795 DOI: 10.1189/jlb.1009700] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The balance between immunity and tolerance in the endometrium is governed by dynamic interactions of UEC and immune cells including DC. In this study, we tested the hypothesis that soluble immune mediators secreted by UEC modulate the differentiation and functions of human DC. We found that DC differentiated with CM from polarized UEC (i.e., CM-DC) expressed significantly lower surface CD86. Upon activation with LPS or PIC, the expression of CD80, CD86, and CD83 was decreased significantly on CM-DC relative to Con-DC. Further, mRNA for TLR3, TLR4, and TLR5 was decreased significantly in CM-DC relative to Con-DC. As a functional read-out of the effect of CM on DC, we determined the following parameters: First, analysis of cytokine production showed that when compared with Con-DC, CM-DC responded to LPS or PIC stimulation with enhanced IL-10 production but undetectable IL-12p70 secretion. Second, RT-PCR analysis showed that CM-DC significantly expressed higher mRNA for IDO, an immune tolerance-promoting enzyme. Lastly, in a MLR assay, CM-DC induced significantly lower allogeneic proliferative responses compared with Con-DC. These findings indicate collectively that epithelial cells confer a tolerogenic phenotype to DC in the endometrium. Our results suggest novel cellular and molecular mechanisms for the regulation of adaptive immunity within the FRT.
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Affiliation(s)
- Daniel O Ochiel
- Department of Physiology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
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25
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Atkins D, Furuta GT. Mucosal immunology, eosinophilic esophagitis, and other intestinal inflammatory diseases. J Allergy Clin Immunol 2010; 125:S255-61. [PMID: 20176262 DOI: 10.1016/j.jaci.2009.11.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 11/16/2009] [Accepted: 11/23/2009] [Indexed: 02/08/2023]
Abstract
The gastrointestinal mucosa constitutes the largest host-environment interface of the body. It uses both innate and adaptive immune mechanisms to provide protection from the diverse onslaught of foods, microbes, and other ingested products. The innate immune system is genetically encoded and evolutionarily ancient, possesses no memory, and lacks diversity. In contrast, the adaptive immune system is quite diverse, develops memory, and undergoes expansion after stimulation. The gastrointestinal mucosa is charged with the difficult task of mounting protective responses against invading microorganisms while simultaneously maintaining an overall state of nonresponsiveness or tolerance to innocuous substances, such as commensal bacteria and food antigens. Perturbation or malfunction of these complex protective mechanisms results in diseases, such as inflammatory bowel diseases, celiac disease, or eosinophilic gastrointestinal diseases.
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Affiliation(s)
- Dan Atkins
- Department of Pediatrics, National Jewish Health, Denver, Aurora, Colo., USA
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26
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Abstract
The intestine is subjected to a barrage of insults from food, bacterial flora, and pathogens. Despite this constant antigenic challenge, the mucosal tissues lining the intestinal tract remain largely under control. The mechanisms regulating the homeostatic balance in the gut have been investigated for many years by many groups, but the precise nature of the regulatory control remains elusive. In this review, we provide an overview of pathways proposed to be involved in dampening the inflammatory response and maintaining the homeostatic balance in the intestine, and how these pathways may be disrupted in ulcerative colitis and Crohn's disease.
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27
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Vannucci L, Stepankova R, Grobarova V, Kozakova H, Rossmann P, Klimesova K, Benson V, Sima P, Fiserova A, Tlaskalova-Hogenova H. Colorectal carcinoma: Importance of colonic environment for anti-cancer response and systemic immunity. J Immunotoxicol 2010; 6:217-26. [PMID: 19908940 DOI: 10.3109/15476910903334343] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The intestinal environment is considered to play an important role both in colorectal tumor development and in the evolution and modulation of mucosal immunity. Studies in animals reared in germ-free (GF, without any intestinal microflora) versus conventional (CV, with regular microflora in bowel) conditions can aid in clarifying the influence of bacteria on carcinogenesis and anti-cancer immune responses in situ. The lower incidence of colon cancers and better immunological parameters in GF animals versus CV ones after chemically-induced carcinogenesis raises questions about specific characteristics of the immunological networks in each respective condition. Different levels of tolerance/regulatory mechanisms in the GF versus CV animals may influence the development of immune responses not only at the level of mucosal, but also at the systemic, immunity. We hypothesize that GF animals can better recognize and respond to evolving neoplasias in the bowel as a consequence of their less-tolerogenic immunity (i.e., due to their more limited exposure to antigens to become tolerated against at the intestinal level). In this paper, we review the role of bacteria in modulating gut environment and mucosal immunity, their importance in cancer development, and aspects of immune regulation (both at local and systemic level) that can be modified by bacterial microflora. Lastly, the use of GF animals in comparison with conventionally-raised animals is proposed as a suitable and potent model for understanding the inflammatory network and its effect on cancer immunity especially during colorectal cancer development.
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Affiliation(s)
- Luca Vannucci
- Laboratory of Natural Cell Immunity, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
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28
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Strauch UG, Grunwald N, Obermeier F, Gürster S, Rath HC. Loss of CD103 + intestinal dendritic cells during colonic inflammation. World J Gastroenterol 2010; 16:21-9. [PMID: 20039445 PMCID: PMC2799913 DOI: 10.3748/wjg.v16.i1.21] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [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 investigate possible differences in dendritic cells (DC) within intestinal tissue of mice before and after induction of colitis.
METHODS: Mucosal DC derived from intestinal tissue, as well as from mesenteric lymph nodes and spleen, were analyzed by fluorescence activated cell sorting (FACS) analysis. Supernatants of these cells were analyzed for secretion of different pro- and anti-inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed on cryosections of mucosal tissue derived from animals with colitis as well as from healthy mice.
RESULTS: It was shown that DC derived from healthy intestinal lamina propria (LP) represented an immature phenotype as characterized by low-level expression of costimulatory cytokines. In contrast to DC from spleen and mesenteric lymph nodes (MLN) that secreted proinflammatory cytokines, LP-DC produced high levels of the anti-inflammatory cytokine IL-10. After induction of murine colitis in a CD4+CD62L+ transfer model or in chronic dextran sulfate sodium-colitis, a marked increase of activated CD80+ DC could be observed within the inflamed colonic tissue. Interestingly, in contrast to splenic DC, a significant population of DC within MLN and colonic LP expressed the mucosal integrin CD103 which was lost during colitis.
CONCLUSION: The constitutive secretion of anti-inflammatory cytokines by immature DC within the intestinal LP might regulate the homeostatic balance between mucosal immunity and tolerance. CD103+ DC could mediate this important function.
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29
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Czerkinsky C, Holmgren J. Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues. Curr Top Microbiol Immunol 2010; 354:1-18. [PMID: 21053117 DOI: 10.1007/82_2010_112] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The mucosal immune system exhibits a high degree of anatomic compartmentalization related to the migratory patterns of lymphocytes activated at different mucosal sites. The selective localization of mucosal lymphocytes to specific tissues is governed by cellular "homing" and chemokine receptors in conjunction with tissue-specific addressins and epithelial cell-derived chemokines that are differentially expressed in "effector" tissues. The compartmentalization of mucosal immune responses imposes constraints on the selection of vaccine administration route. Traditional routes of mucosal immunization include oral and nasal routes. Other routes for inducing mucosal immunity include the rectal, vaginal, sublingual, and transcutaneous routes. Sublingual administration is a new approach that results in induction of mucosal and systemic T cell and antibody responses with an exceptionally broad dissemination to different mucosae, including the gastrointestinal and respiratory tracts, and the genital mucosa. Here, we discuss how sublingual and different routes of immunization can be used to generate immune responses in the desired mucosal tissue(s).
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Affiliation(s)
- C Czerkinsky
- International Vaccine Institute, Seoul, South Korea.
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30
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Rescigno M, Di Sabatino A. Dendritic cells in intestinal homeostasis and disease. J Clin Invest 2009; 119:2441-50. [PMID: 19729841 DOI: 10.1172/jci39134] [Citation(s) in RCA: 243] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
DCs are specialized APCs that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs, which induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. Several subsets of mucosal DCs have been described that display unique functions, dictated in part by the local microenvironment. In this review, we summarize the distinct subtypes of DCs and their distribution in the gut; examine how DC dysfunction contributes to intestinal disease development, including inflammatory bowel disease and celiac disease; and discuss manipulation of DCs for therapy.
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Affiliation(s)
- Maria Rescigno
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
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31
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Sánchez-Fayos Calabuig P, Martín Relloso MJ, Porres Cubero JC. [Multifactorial etiology and pathogenic factors in inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2009; 32:633-52. [PMID: 19647892 DOI: 10.1016/j.gastrohep.2009.02.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2008] [Accepted: 02/13/2009] [Indexed: 01/06/2023]
Abstract
All the currently available evidence suggests that the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), involve a conflict between the immune system of the intestinal mucosa and intraluminal antigens, mainly the intestinal microflora, which are normally tolerated by the immune system. This conflict is modulated by numerous environmental factors and a clear polygenetic predisposition. The present article reviews the behavior of all the etiologic circumstances (microbial, genetic and environmental) and subsequently analyzes the possible pathogenic factors in which the etiologies can be found, namely: dysfunction of the intestinal epithelium, innate immune system alterations, and distortion of the cellular and humoral arms of the acquired immune system. The role of tissue ischemia in CD and expression of "extraintestinal inflammatory metastases", both in CD and UC, are briefly discussed. Finally, the view that IBD may be a spectrum of pathological processes provoked by distinct etiopathogenic factors and the possible biological significance of the growing incidence of this disease in the western world, coinciding with the decline in infectious diseases in this geographical area, are discussed.
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Borchers AT, Selmi C, Meyers FJ, Keen CL, Gershwin ME. Probiotics and immunity. J Gastroenterol 2009; 44:26-46. [PMID: 19159071 DOI: 10.1007/s00535-008-2296-0] [Citation(s) in RCA: 307] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 09/03/2008] [Indexed: 02/04/2023]
Abstract
Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.
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Affiliation(s)
- Andrea T Borchers
- Department of Nutrition, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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Qualls JE, Tuna H, Kaplan AM, Cohen DA. Suppression of experimental colitis in mice by CD11c+ dendritic cells. Inflamm Bowel Dis 2009; 15:236-47. [PMID: 18839426 DOI: 10.1002/ibd.20733] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The innate immune system serves a critical role in homeostasis of the gastrointestinal (GI) tract. Both macrophages (MØs) and dendritic cells (DCs) have been shown to have pathogenic roles in animal models of inflammatory bowel disease. However, studies by several labs have established that resident MØs and DCs within the normal GI tract maintain an immunosuppressive phenotype compared to that seen in other peripheral sites. Recent studies by our lab demonstrated that the depletion of both MØs and DCs before the initiation of dextran sodium sulfate (DSS)-induced colitis resulted in exacerbation of disease, partly caused by increased neutrophil influx. METHODS/RESULTS In this current report, DSS-induced colitis was shown to be significantly more severe when DCs were selectively depleted in mice as indicated by changes in weight loss, stool consistency, rectal bleeding, and histopathology. In contrast to enhanced colitis in MØ/DC-depleted mice, which was associated with increased neutrophil influx, increased colitis in DC-depleted mice was not associated with an increase in neutrophils in the colon, as shown by CXCL1 chemokine levels and myeloperoxidase (MPO) activity. However, increased IL-6 gene and protein expression in colon tissues correlated positively with increased colitis severity in DC-depleted mice compared to colitis in DC-intact mice. CONCLUSIONS This study demonstrates that resident DCs can suppress the severity of acute DSS colitis and that regulation of IL-6 production may contribute to DC-mediated control of intestinal inflammation.
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Affiliation(s)
- Joseph E Qualls
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, College of Medicine, Lexington, Kentucky 40536-0084, USA
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Lee JY, Kim H, Cha MY, Park HG, Kim YJ, Kim IY, Kim JM. Clostridium difficile toxin A promotes dendritic cell maturation and chemokine CXCL2 expression through p38, IKK, and the NF-kappaB signaling pathway. J Mol Med (Berl) 2008; 87:169-80. [PMID: 18985311 DOI: 10.1007/s00109-008-0415-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Revised: 10/13/2008] [Accepted: 10/20/2008] [Indexed: 12/22/2022]
Abstract
Clostridium difficile toxin A causes acute colitis associated with intense infiltrating neutrophils. Although dendritic cells (DCs) play an important role in the regulation of inflammation, little is known about the effects of toxin A on the maturation and neutrophil-attracting chemokine expression in DCs. This study investigated whether C. difficile toxin A could influence the maturation of mouse bone-marrow-derived DCs and chemokine CXCL2 expression. Toxin A increased the DC maturation which was closely related to CXCL2 upregulation. Concurrently, toxin A activated the signals of p65/p50 nuclear factor kappa B (NF-kappaB) heterodimers and phospho-I kappa B kinase (IKK) in DCs. The increased DC maturation, CXCL2 expression, and neutrophil chemoattraction were significantly downregulated in the NF-kappaB knockout mice. In addition, toxin A activated the phosphorylated signals of mitogen-activated protein kinases (MAPKs), such as ERK, p38, and JNK. Of all three MAPK signals, p38 MAPK was significantly related to DC maturation. Thus, suppression of p38 activity using SB203580 and siRNA transfection resulted in the significant reduction of IKK activity, DC maturation, and CXCL2 upregulation by toxin A. These results suggest that p38 MAPK may lead to the activation of IKK and NF-kappaB signaling, resulting in enhanced DC maturation and CXCL2 expression in response to C. difficile toxin A stimulation.
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Affiliation(s)
- Jin Young Lee
- Department of Microbiology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-791, South Korea
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Fiocchi C. What is "physiological" intestinal inflammation and how does it differ from "pathological" inflammation? Inflamm Bowel Dis 2008; 14 Suppl 2:S77-8. [PMID: 18816772 DOI: 10.1002/ibd.20618] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Claudio Fiocchi
- Departments of Pathobiology and Gastroenterology & Hepatology, Cleveland Clinic Foundation, Ohio, USA
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Braun J, Wei B. Body traffic: ecology, genetics, and immunity in inflammatory bowel disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2008; 2:401-29. [PMID: 18039105 DOI: 10.1146/annurev.pathol.1.110304.100128] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The abundant bacteria and other microbial residents of the human intestine play important roles in nutrient absorption, energy metabolism, and defense against microbial pathogens. The mutually beneficial relationship of host and commensal microbiota represents an ancient and major coevolution in composition and mutual regulation of the human mucosa and the resident microbial community. Inflammatory bowel disease (IBD) is a set of chronic, relapsing inflammatory intestinal diseases in which rules of normal host-microbial interaction have been violated. This review considers the components of this host-microbial mutualism and the ways in which it is undermined by pathogenic microbial traits and by host immune and epithelial functions that confer to them susceptibility in patients with IBD. Recent advances in understanding the genetics of IBD and the immunology of host-microbial interaction are opening new strategies for treatments that target host susceptibility, candidate microbial pathogens, and intestinal ecology.
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Affiliation(s)
- Jonathan Braun
- David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
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Abstract
One of the major tasks of the mucosal immune system is to discriminate between dangerous and harmless antigens that are encountered daily at mucosal sites. In the gastrointestinal tract, immune cells have to tolerate food antigens and commensal microbes but at the same time have to induce a prompt response against invasive pathogens, when needed. In this issue of the European Journal of Immunology, it is shown that intestinal dendritic cell (DC) populations can be distinguished based on the expression level of Toll-like receptors (TLR) and on the response of these TLR to their microbial ligands. DC either do not express TLR or they express them but respond in a non-inflammatory mode. In this commentary, these findings are discussed in the context of available knowledge on lamina propria DC.
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Affiliation(s)
- Maria Rescigno
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
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Valdez Y, Diehl GE, Vallance BA, Grassl GA, Guttman JA, Brown NF, Rosenberger CM, Littman DR, Gros P, Finlay BB. Nramp1 expression by dendritic cells modulates inflammatory responses during Salmonella Typhimurium infection. Cell Microbiol 2008; 10:1646-61. [PMID: 18397382 PMCID: PMC3051341 DOI: 10.1111/j.1462-5822.2008.01155.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Host resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) is mediated by natural resistance-associated macrophage protein 1 (Nramp1/Slc11a1). Nramp1 is critical to host defence, as mice lacking Nramp1 fail to control bacterial replication and succumb to low doses of S. Typhimurium. Despite this crucial role, the mechanisms underlying Nramp1's protective effects are unclear. Dendritic cells (DCs) that sample the intestinal lumen are among the first cells encountered by S. Typhimurium following oral infection and act as a conduit for S. Typhimurium to cross the intestinal epithelial barrier. We report that DCs, including intestinal, splenic and bone marrow-derived DCs (BMDCs), express Nramp1 protein. In the small intestine, Nramp1 expression is greater in a subset of DCs (CD11c(+)CD103(-)) characterized by the elevated expression of pro-inflammatory cytokines in response to bacterial products. While Nramp1 expression did not affect S. Typhimurium replication in BMDCs, infected Nramp1+/+ BMDCs and intestinal CD11c(+)CD103(-) DCs secreted more inflammatory cytokines (IL-6, IL-12 and TNF-alpha) than Nramp1-/-, suggesting that Nramp1 expression may promote a more rapid inflammatory response following infection. Collectively, these findings reveal a new role for DCs and Nramp1 in modulating the host inflammatory response to S. Typhimurium.
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Affiliation(s)
- Yanet Valdez
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3
- Department of Microbiology and Immunology, University of British Columbia
| | - Gretchen E. Diehl
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, United States of America
| | - Bruce A. Vallance
- Division of Gastroenterology, BC Children’s Hospital, Vancouver, British Columbia, Canada
| | - Guntram A. Grassl
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3
| | - Julian A. Guttman
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3
- Simon Fraser University, Department of Biological Sciences, Burnaby, BC V5A 1S6
| | - Nat F. Brown
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3
| | | | - Dan R. Littman
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, United States of America
- Howard Hughes Medical Institute, Departments of Microbiology and Pathology, New York University School of Medicine, New York, New York, United States of America
| | - Philippe Gros
- Department of Biochemistry, Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada H3A 2T5
| | - B. Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3
- Department of Microbiology and Immunology, University of British Columbia
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40
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Abstract
The immune system faces a considerable challenge in its efforts to maintain tissue homeostasis in the intestinal mucosa. It is constantly confronted with a large array of antigens, and has to prevent the dissemination and proliferation of potentially harmful agents while sparing the vital structures of the intestine from immune-mediated destruction. Complex interactions between the highly adapted effector cells and mechanisms of the innate and adaptive immune system generally prevent the luminal microflora from penetrating the intestinal mucosa and from spreading systemically. Non-haematopoietic cells critically contribute to the maintenance of local tissue homeostasis in an antigen-rich environment by producing protective factors (e.g. production of mucus by goblet cells, or secretion of microbicidal defensins by Paneth cells) and also through interactions with the adaptive and innate immune system (such as the production of chemotactic factors that lead to the selective recruitment of immune cell subsets). The complexity of the regulatory mechanisms that control the local immune response to luminal antigens is also reflected in the observation that mutations in immunologically relevant genes often lead to the development of uncontrolled inflammatory reactions in the microbially colonized intestine of experimental animals.
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Affiliation(s)
- Mirjam Schenk
- Institute of Pathology, University of Bern, Bern, Switzerland
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Barclay AR, Morrison DJ, Weaver LT. What is the role of the metabolic activity of the gut microbiota in inflammatory bowel disease? Probing for answers with stable isotopes. J Pediatr Gastroenterol Nutr 2008; 46:486-95. [PMID: 18493202 DOI: 10.1097/mpg.0b013e3181615b3a] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pathogenesis of inflammatory bowel disease remains obscure. However, there has been increasing interest in the role of the gut microbiota, focusing in particular on the "unculturable majority" of luminal and mucosal bacteria, which until recently have been difficult to study owing to the technical challenges of identification and elucidating function. Bacterial components and metabolites have been implicated in signalling to host immune systems and regulating inflammatory responses. Although the rapid expansion in techniques of molecular microbiology has increased our understanding of bacterial diversity, the tools to assess bacterial metabolic activity, and to link the 2, lag behind. Stable isotope probing is a powerful technique to link the metabolic activity and diversity of "unculturable" bacteria through isotopic labelling of biomarkers such as DNA and RNA. Progression of current stable isotope probing methodology with high-resolution oligonucleotide 16s rRNA probe technology and high precision liquid chromatographic isotope ratio mass spectrometry may facilitate application in human microbial ecology. Progress towards stable isotope probing use in vivo, in concert with other advances in bacterial metabolome analysis, will lead to the development of a dynamic picture of the metabolic activity and diversity of intestinal bacteria in inflammatory bowel disease. Such insights will, over time, lead to fuller understanding of inflammatory bowel disease pathogenesis and the development of targeted therapies to reverse the "dysbiosis" that precedes disease relapse.
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Affiliation(s)
- Andrew R Barclay
- Department of Child Health, Division of Developmental Medicine, University of Glasgow, UK.
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Kadaoui KA, Corthésy B. Secretory IgA mediates bacterial translocation to dendritic cells in mouse Peyer's patches with restriction to mucosal compartment. THE JOURNAL OF IMMUNOLOGY 2008; 179:7751-7. [PMID: 18025221 DOI: 10.4049/jimmunol.179.11.7751] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In addition to fulfilling its function of immune exclusion at mucosal surfaces, secretory IgA (SIgA) Ab exhibits the striking feature to adhere selectively to M cells in the mouse and human intestinal Peyer's patches (PPs). Subsequent uptake drives the SIgA Ab to dendritic cells (DCs), which become partially activated. Using freshly isolated mouse DCs, we found that the interaction with SIgA was tissue and DC subtype dependent. Only DCs isolated from PPs and mesenteric lymph nodes interacted with the Ab. CD11c(+)CD11b(+) DCs internalized SIgA, while CD11c(+)CD19(+) DCs only bound SIgA on their surface, and no interaction occurred with CD11c(+)CD8alpha(+) DCs. We next examined whether SIgA could deliver a sizeable cargo to PP DCs in vivo by administering SIgA-Shigella flexneri immune complexes into a mouse ligated intestinal loop containing a PP. We found that such immune complexes entered the PPs and were internalized by subepithelial dome PP DCs, in contrast to S. flexneri alone that did not penetrate the intestinal epithelium in mice. Dissemination of intraepithelial S. flexneri delivered as immune complexes was limited to PPs and mesenteric lymph nodes. We propose that preexisting SIgA Abs associated with microbes contribute to mucosal defense by eliciting responses that prevent overreaction while maintaining productive immunity.
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Affiliation(s)
- Khalil A Kadaoui
- R&D Laboratory of the Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon, Switzerland
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Sublingual vaccination with influenza virus protects mice against lethal viral infection. Proc Natl Acad Sci U S A 2008; 105:1644-9. [PMID: 18227512 DOI: 10.1073/pnas.0708684105] [Citation(s) in RCA: 161] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We assessed whether the sublingual (s.l.) route would be an effective means of delivering vaccines against influenza virus in mice by using either formalin-inactivated or live influenza A/PR/8 virus (H1N1). Sublingual administration of inactivated influenza virus given on two occasions induced both systemic and mucosal antibody responses and conferred protection against a lethal intranasal (i.n.) challenge with influenza virus. Coadministration of a mucosal adjuvant (mCTA-LTB) enhanced these responses and resulted in complete protection against respiratory viral challenge. In addition, s.l. administration of formalin-inactivated A/PR/8 plus mCTA-LTB induced systemic expansion of IFN-gamma-secreting T cells and virus-specific cytotoxic T lymphocyte responses. Importantly, a single s.l. administration of live A/PR/8 virus was not pathogenic and induced protection mediated by both acquired and innate immunity. Moreover, s.l. administration of live A/PR/8 virus conferred heterosubtypic protection against respiratory challenge with H3N2 virus. Unlike the i.n. route, the A/PR/8 virus, whether live or inactivated, did not migrate to or replicate in the CNS after s.l. administration. Based on these promising findings, we propose that the s.l. mucosal route offers an attractive alternative to mucosal routes for administering influenza vaccines.
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Akesson CP, McL Press C, Espenes A, Aleksandersen M. Phenotypic characterisation of intestinal dendritic cells in sheep. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2008; 32:837-849. [PMID: 18222542 DOI: 10.1016/j.dci.2007.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2007] [Revised: 11/26/2007] [Accepted: 12/06/2007] [Indexed: 05/25/2023]
Abstract
The present study was undertaken to identify dendritic cells (DCs) in the ileum and rectum of lambs and adult sheep. The distribution of these cells in four different intestinal compartments, i.e. lamina propria, lymphoid follicles, domes and interfollicular areas was assessed, and the presence of these cells in lambs and adult sheep was compared. Specimens were examined by using a number of potential DC markers (CD11c, CD205, MHC class II (MHCII), CD1b and CD209) in immunohistochemical and multicolour immunofluorescent procedures. The ovine ileal and rectal mucosa contain many CD11c+/CD205+ cells with a dendritic morphology, and the majority of these cells co-expressed MHCII. These double-positive cells were also labelled with the CD209 antibody in the lamina propria and interfollicular regions. Only very few cells expressed CD1b. In conclusion, a major DC population in ileum and rectum of sheep co-expressed the CD11c, CD205 and MHCII molecules. The CD209 antibody appeared to be a novel marker for a subpopulation of ovine intestinal DCs.
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Affiliation(s)
- Caroline Piercey Akesson
- Department of Basic Sciences and Aquatic Medicine, Norwegian College of Veterinary Science, P.O. Box 8146 Dep., 0033 Oslo, Norway.
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Rescigno M, Mileti E. Interactions between Epithelial Cells and Dendritic Cells in Bacterial Handling. Biosci Microflora 2008. [DOI: 10.12938/bifidus.27.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Berndt BE, Zhang M, Chen GH, Huffnagle GB, Kao JY. The role of dendritic cells in the development of acute dextran sulfate sodium colitis. THE JOURNAL OF IMMUNOLOGY 2007; 179:6255-62. [PMID: 17947701 DOI: 10.4049/jimmunol.179.9.6255] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Dendritic cells (DCs) are essential mediators of the host immune response to surrounding microbes. In this study, we investigate the role of DCs in the pathogenesis of a widely used colitis model, dextran sulfate sodium-induced colitis. The effect of dextran sulfate sodium on the production of proinflammatory cytokines and chemokines by bone marrow-derived DCs (BM-DCs) was analyzed. BM-DCs were adoptively transferred into C57BL/6 mice or DCs were ablated using transgenic CD11c-DTR/GFP mice before treatment with 5% dextran sulfate sodium in drinking water. We found that dextran sulfate sodium induced production of proinflammatory cytokines (IL-12 and TNF-alpha) and chemokines (KC, MIP-1alpha, MIP-2, and MCP-1) by DCs. Adoptive transfer of BM-DCs exacerbated dextran sulfate sodium colitis while ablation of DCs attenuated the colitis. We conclude that DCs are critical in the development of acute dextran sulfate sodium colitis and may serve a key role in immune balance of the gut mucosa.
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Di Sabatino A, Pickard KM, Gordon JN, Salvati V, Mazzarella G, Beattie RM, Vossenkaemper A, Rovedatti L, Leakey NAB, Croft NM, Troncone R, Corazza GR, Stagg AJ, Monteleone G, MacDonald TT. Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease. Gastroenterology 2007; 133:1175-1187. [PMID: 17919493 DOI: 10.1053/j.gastro.2007.08.018] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2006] [Accepted: 06/14/2007] [Indexed: 02/02/2023]
Abstract
BACKGROUND & AIMS Dendritic cells (DCs) play a crucial role in immune responses by controlling the extent and type of T-cell response to antigen. Celiac disease is a condition in which T-cell immunity to gluten plays an important pathogenic role, yet information on DCs is scant. We examined mucosal DCs in celiac disease in terms of phenotype, activation/maturation state, cytokine production, and function. METHODS Mucosal DCs from 48 celiacs and 30 controls were investigated by flow cytometry. In situ distribution of DCs was analyzed by confocal microscopy. Interferon (IFN)-alfa, interleukin (IL)-4, IL-5, IL-12p35, IL-12p40, IL-18, IL-23p19, IL-27, and transforming growth factor-beta transcripts were measured by real-time reverse-transcription polymerase chain reaction in sorted DCs. DC expression of IL-6, IL-12p40, and IL-10 was assessed by intracellular cytokine staining. The effect of IFN-alfa and IL-18 blockade on the gluten-induced IFN-gamma response in celiac biopsy specimens grown ex vivo also was investigated. RESULTS Mucosal DCs were increased in untreated, but not treated, celiacs. The majority of them were plasmacytoid with higher levels of maturation (CD83) and activation (CD80/CD86) markers. Higher transcripts of Th1 relevant cytokines, such as IFN-alfa, IL-18, and IL-23p19, were produced by celiac DCs, but because IL-12p40 was undetectable, a role for IL-23 is unlikely. Intracellular cytokine staining of celiac DCs showed higher IL-6, but lower IL-10 expression, and confirmed the lack of IL-12p40. Blocking IFN-alfa inhibited IFN-gamma transcripts in ex vivo organ culture of celiac biopsy specimens challenged with gluten. CONCLUSIONS These data suggest that IFN-alfa-producing DCs contribute to the Th1 response in celiac disease.
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Affiliation(s)
- Antonio Di Sabatino
- Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom
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Zeuthen LH, Fink LN, Frokiaer H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-beta. Immunology 2007; 123:197-208. [PMID: 17655740 PMCID: PMC2433297 DOI: 10.1111/j.1365-2567.2007.02687.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Humans and other mammals coexist with a diverse array of microbes colonizing the intestine, termed the microflora. The relationship is symbiotic, with the microbes benefiting from a stable environment and nutrient supply, and the host gaining competitive exclusion of pathogens and continuously maintenance of the gut immune homeostasis. Here we report novel crosstalk mechanisms between the human enterocyte cell line, Caco2, and underlying human monocyte-derived DC in a transwell model where Gram-positive (G+) commensals prevent Toll-like receptor-4 (TLR4)-dependent Escherichia coli-induced semimaturation in a TLR2-dependent fashion. These findings add to our understanding of the hypo-responsiveness of the gut epithelium towards the microflora. Gut DC posses a more tolerogenic phenotype than conventional DC. Here we show that Caco2 spent medium (SM) induces tolerogenic DC with lower expression of maturation markers, interleukin (IL)-12p70, and tumour necrosis factor-alpha when matured with G+ and Gram-negative (G-) commensals, while IL-10 production is enhanced in DC upon encountering G+ commensals and reduced upon encountering G- bacteria. The Caco2 SM-induced tolerogenic phenotype is also seen in DC priming of naive T cells with elevated levels of transforming growth factor-beta (TGF-beta) and markedly reduced levels of bacteria-induced interferon-gamma production. Caco2 cell production of IL-8, thymic stromal lymphopoietin (TSLP) and TGF-beta increases upon microbial stimulation in a strain dependent manner. TSLP and TGF-beta co-operate in inducing the tolerogenic DC phenotype but other mediators might be involved.
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Affiliation(s)
- Louise Hjerrild Zeuthen
- BioCentrum-DTU, Nutritional Immunology Group, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
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Bimczok D, Rau H, Wundrack N, Naumann M, Rothkötter HJ, McCullough K, Summerfield A. Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells. Vet Res 2007; 38:597-612. [PMID: 17565907 DOI: 10.1051/vetres:2007020] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 02/16/2007] [Indexed: 01/02/2023] Open
Abstract
Cholera toxin (Ctx) is a powerful mucosal adjuvant with potential applications for oral vaccination of swine. Dendritic cells (DC) play a key role in the decision between immunity and tolerance, and are likely target cells for mediating Ctx functions in vivo. Therefore, we examined the capacity of Ctx to enhance stimulatory activity of porcine monocyte-derived DC (MoDC). Ctx promoted the development of a semi-mature DC phenotype, with decreased levels of MHC class II and CD40, but increased CD80/86 expression. These changes were associated with activation of extracellular signal-regulated kinase (ERK), but not NFkappaB or c-Jun N-terminal kinase (JNK). Functionally, Ctx-priming greatly diminished T cell stimulatory capacity both in antigen-specific and superantigen-induced proliferation assays. The lower proliferation rate was not due to increased apoptosis of either DC or T cells. Ctx suppressed TNFalpha secretion by MoDC, but induced IL-10 production. The observed effects on T cell proliferation could only be partially mimicked by IL-10 alone. However, addition of recombinant TNFalpha to co-cultures of Ctx-primed MoDC and lymphocytes restored lymphocyte proliferation in a concentration-dependent manner. Ctx-primed DC were not actively tolerogenic, since they could not suppress proliferative T cell reactions induced by untreated DC.
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Affiliation(s)
- Diane Bimczok
- Institute of Anatomy, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
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Corthésy B. Roundtrip ticket for secretory IgA: role in mucosal homeostasis? THE JOURNAL OF IMMUNOLOGY 2007; 178:27-32. [PMID: 17182536 DOI: 10.4049/jimmunol.178.1.27] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
An important activity of mucosal surfaces is the production of Ab referred to as secretory IgA (SIgA). SIgA serves as the first line of defense against microorganisms through a mechanism called immune exclusion. In addition, SIgA adheres selectively to M cells in intestinal Peyer's patches, thus mediating the transepithelial transport of the Ab molecule from the intestinal lumen to underlying gut-associated organized lymphoid tissue. In Peyer's patches, SIgA binds and is internalized by dendritic cells in the subepithelial dome region. When used as carrier for Ags in oral immunization, SIgA induces mucosal and systemic responses associated with production of anti-inflammatory cytokines and limits activation of dendritic cells. In terms of humoral immunity at mucosal surfaces, SIgA appears thus to combine properties of a neutralizing agent (immune exclusion) and of a mucosal immunopotentiator inducing effector immune responses in a noninflammatory context favorable to preserve local homeostasis of the gastrointestinal tract.
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Affiliation(s)
- Blaise Corthésy
- R&D Laboratory of the Division of Immunology and Allergy, State University Hospital (Centré Hospitalìer Universitaire Vandois), Rue du Bugnon, BH 19-650, 1011 Lausanne, Switzerland.
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