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Raheem MA, Rahim MA, Gul I, Reyad-Ul-Ferdous M, Zhang CY, Yu D, Pandey V, Du K, Wang R, Han S, Han Y, Qin P. COVID-19: Post infection implications in different age groups, mechanism, diagnosis, effective prevention, treatment, and recommendations. Life Sci 2024:122861. [PMID: 38925222 DOI: 10.1016/j.lfs.2024.122861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
SARS-CoV-2 is a highly contagious pathogen that predominantly caused the COVID-19 pandemic. The persistent effects of COVID-19 are defined as an inflammatory or host response to the virus that begins four weeks after initial infection and persists for an undetermined length of time. Chronic effects are more harmful than acute ones thus, this review explored the long-term effects of the virus on various human organs, including the pulmonary, cardiovascular, and neurological, reproductive, gastrointestinal, musculoskeletal, endocrine, and lymphoid systems and found that SARS-CoV-2 adversely affects these organs of older adults. Regarding diagnosis, the RT-PCR is a gold standard method of diagnosing COVID-19; however, it requires specialized equipment and personnel for performing assays and a long time for results production. Therefore, to overcome these limitations, artificial intelligence employed in imaging and microfluidics technologies is the most promising in diagnosing COVID-19. Pharmacological and non-pharmacological strategies are the most effective treatment for reducing the persistent impacts of COVID-19 by providing immunity to post-COVID-19 patients by reducing cytokine release syndrome, improving the T cell response, and increasing the circulation of activated natural killer and CD8 T cells in blood and tissues, which ultimately reduces fever, nausea, fatigue, and muscle weakness and pain. Vaccines such as inactivated viral, live attenuated viral, protein subunit, viral vectored, mRNA, DNA, or nanoparticle vaccines significantly reduce the adverse long-term virus effects in post-COVID-19 patients; however, no vaccine was reported to provide lifetime protection against COVID-19; consequently, protective measures such as physical separation, mask use, and hand cleansing are promising strategies. This review provides a comprehensive knowledge of the persistent effects of COVID-19 on people of varying ages, as well as diagnosis, treatment, vaccination, and future preventative measures against the spread of SARS-CoV-2.
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Affiliation(s)
- Muhammad Akmal Raheem
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Muhammad Ajwad Rahim
- College of Animal Science and Technology, Ahnui Agricultural University, Hefei, PR China
| | - Ijaz Gul
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Md Reyad-Ul-Ferdous
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Can Yang Zhang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Dongmei Yu
- School of Mechanical, Electrical & Information Engineering, Shandong University
| | - Vijay Pandey
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Ke Du
- Department of Chemical and Environmental Engineering, University of California, Riverside, CA, USA
| | - Runming Wang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Sanyang Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Yuxing Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Peiwu Qin
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China.
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Seitz V, Gennermann K, Elezkurtaj S, Groth D, Schaper S, Dröge A, Lachmann N, Berg E, Lenze D, Kühl AA, Husemann C, Kleo K, Horst D, Lennerz V, Hennig S, Hummel M, Schumann M. Specific T-cell receptor beta-rearrangements of gluten-triggered CD8 + T-cells are enriched in celiac disease patients' duodenal mucosa. Clin Immunol 2023; 256:109795. [PMID: 37769786 DOI: 10.1016/j.clim.2023.109795] [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: 07/13/2023] [Revised: 09/12/2023] [Accepted: 09/25/2023] [Indexed: 10/02/2023]
Abstract
Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4+ T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8+ α/β intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRβ-rearrangements derived from gluten-specific CD4+ T-cells and gluten-triggered peripheral blood CD8+ T-cells. We show, that in addition to TCRs from gluten-specific CD4+ T-cells, TCRs of gluten-triggered CD8+ T-cells are significantly enriched in CeD duodenal tissue samples. TCRβ-rearrangements of gluten-triggered CD8+ T-cells were even more expanded in patients than TCRs from gluten-specific CD4+ T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens.
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Affiliation(s)
- V Seitz
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; HS Diagnomics GmbH, Berlin, Germany
| | | | - S Elezkurtaj
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Groth
- Bioinformatics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
| | | | - A Dröge
- HS Diagnomics GmbH, Berlin, Germany
| | - N Lachmann
- Centre for Tumor Medicine, Histocompatibility & Immunogenetics Laboratory, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - E Berg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Lenze
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - A A Kühl
- iPATH.Berlin - Core Unit of the Charité Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - C Husemann
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - K Kleo
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - S Hennig
- HS Diagnomics GmbH, Berlin, Germany
| | - M Hummel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Schumann
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
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Rizzi A, Di Gioacchino M, Gammeri L, Inchingolo R, Chini R, Santilli F, Nucera E, Gangemi S. The Emerging Role of Innate Lymphoid Cells (ILCs) and Alarmins in Celiac Disease: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications. Cells 2023; 12:1910. [PMID: 37508573 PMCID: PMC10378400 DOI: 10.3390/cells12141910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Celiac disease (CD) is an intestinal disease that develops in genetically predisposed individuals and is triggered by the ingestion of gluten. CD was considered a Th1-disease. Today, the role of Th17, IL-21, and IL-17A lymphocytes is well known. Inflammation is regulated by the activity of gluten-specific CD4+ T lymphocytes that produce pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-21, perpetuating the Th1 response. These cytokines determine an inflammatory state of the small intestine, with consequent epithelial infiltration of lymphocytes and an alteration of the architecture of the duodenal mucosa. B cells produce antibodies against tissue transglutaminase and against deamidated gliadin. Although the role of the adaptive immune response is currently known, the evidence about the role of innate immunity cells is still poorly understood. Epithelial damage determines the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Together with the intestinal epithelial cells and the type 1 innate lymphoid cells (ILC1s), alarmins like TSLP, IL-33, and HMGB1 could have a fundamental role in the genesis and maintenance of inflammation. Our study aims to evaluate the evidence in the literature about the role of ILCs and alarmins in celiac disease, evaluating the possible future diagnostic and therapeutic implications.
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Affiliation(s)
- Angela Rizzi
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Mario Di Gioacchino
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
- Center for Advanced Studies and Technology, G. d'Annunzio University, 66100 Chieti, Italy
| | - Luca Gammeri
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
| | - Riccardo Inchingolo
- Pulmonary Medicine Unit, Department of Neurosciences, Sense Organs and Thorax, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Raffaella Chini
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Santilli
- Center for Advanced Studies and Technology, G. d'Annunzio University, 66100 Chieti, Italy
| | - Eleonora Nucera
- UOSD Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
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Romero-Garmendia I. Separation of epithelial and immune cells from biopsy samples. Methods Cell Biol 2023; 179:59-68. [PMID: 37625880 DOI: 10.1016/bs.mcb.2022.12.006] [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] [Indexed: 01/26/2023]
Abstract
Celiac disease (CD) is a chronic and autoimmune disease that develops in genetically predisposed individuals upon exposure to dietary gluten. The availability of the target tissue for research has made it possible to identify alterations in the transcriptome and methylome in the celiac gut. However, gene expression and methylation is highly variable among different cell types, and separation of cellular populations in target tissue must be considered for the understanding of the specific cellular and immune responses to gluten. In this context, a few studies have demonstrated that focusing on an isolated cell population, novel candidate genes involved in the pathogenesis of the disease can be identified. Here, we describe a method to separate epithelial and immune cells from biopsy samples for DNA and RNA isolation. With minor variations, the same technique can be applied to other tissues and cell types.
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Affiliation(s)
- Irati Romero-Garmendia
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
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Ntunzwenimana JC, Boucher G, Paquette J, Gosselin H, Alikashani A, Morin N, Beauchamp C, Thauvette L, Rivard MÈ, Dupuis F, Deschênes S, Foisy S, Latour F, Lavallée G, Daly MJ, Xavier RJ, Charron G, Goyette P, Rioux JD. Functional screen of inflammatory bowel disease genes reveals key epithelial functions. Genome Med 2021; 13:181. [PMID: 34758847 PMCID: PMC8582123 DOI: 10.1186/s13073-021-00996-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/21/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Genetic studies have been tremendously successful in identifying genomic regions associated with a wide variety of phenotypes, although the success of these studies in identifying causal genes, their variants, and their functional impacts has been more limited. METHODS We identified 145 genes from IBD-associated genomic loci having endogenous expression within the intestinal epithelial cell compartment. We evaluated the impact of lentiviral transfer of the open reading frame (ORF) of these IBD genes into the HT-29 intestinal epithelial cell line via transcriptomic analyses. By comparing the genes in which expression was modulated by each ORF, as well as the functions enriched within these gene lists, we identified ORFs with shared impacts and their putative disease-relevant biological functions. RESULTS Analysis of the transcriptomic data for cell lines expressing the ORFs for known causal genes such as HNF4a, IFIH1, and SMAD3 identified functions consistent with what is already known for these genes. These analyses also identified two major clusters of genes: Cluster 1 contained the known IBD causal genes IFIH1, SBNO2, NFKB1, and NOD2, as well as genes from other IBD loci (ZFP36L1, IRF1, GIGYF1, OTUD3, AIRE and PITX1), whereas Cluster 2 contained the known causal gene KSR1 and implicated DUSP16 from another IBD locus. Our analyses highlight how multiple IBD gene candidates can impact on epithelial structure and function, including the protection of the mucosa from intestinal microbiota, and demonstrate that DUSP16 acts a regulator of MAPK activity and contributes to mucosal defense, in part via its regulation of the polymeric immunoglobulin receptor, involved in the protection of the intestinal mucosa from enteric microbiota. CONCLUSIONS This functional screen, based on expressing IBD genes within an appropriate cellular context, in this instance intestinal epithelial cells, resulted in changes to the cell's transcriptome that are relevant to their endogenous biological function(s). This not only helped in identifying likely causal genes within genetic loci but also provided insight into their biological functions. Furthermore, this work has highlighted the central role of intestinal epithelial cells in IBD pathophysiology, providing a scientific rationale for a drug development strategy that targets epithelial functions in addition to the current therapies targeting immune functions.
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Affiliation(s)
- Jessy Carol Ntunzwenimana
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
- Université de Montréal, Montreal, Quebec, Canada
| | - Gabrielle Boucher
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Jean Paquette
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Hugues Gosselin
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Azadeh Alikashani
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Nicolas Morin
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Claudine Beauchamp
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Louise Thauvette
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Marie-Ève Rivard
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Frédérique Dupuis
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Sonia Deschênes
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Sylvain Foisy
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Frédéric Latour
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Geneviève Lavallée
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Mark J Daly
- Massachusetts General Hospital, Boston, MA, USA
- The Broad Institute, Cambridge, MA, USA
| | - Ramnik J Xavier
- Massachusetts General Hospital, Boston, MA, USA
- The Broad Institute, Cambridge, MA, USA
| | - Guy Charron
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - Philippe Goyette
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada
| | - John D Rioux
- Montreal Heart Institute Research Centre, 5000 rue Bélanger, S-6201, Montreal, Quebec, Canada.
- Université de Montréal, Montreal, Quebec, Canada.
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Upadhyay D, Singh A, Das P, Mehtab J, Dattagupta S, Ahuja V, Makharia GK, Jagannathan NR, Sharma U. Abnormalities in metabolic pathways in celiac disease investigated by the metabolic profiling of small intestinal mucosa, blood plasma and urine by NMR spectroscopy. NMR IN BIOMEDICINE 2020; 33:e4305. [PMID: 32394522 DOI: 10.1002/nbm.4305] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 03/06/2020] [Accepted: 03/12/2020] [Indexed: 06/11/2023]
Abstract
Celiac disease (CeD) is an autoimmune enteropathy caused by gluten intake in genetically predisposed individuals. We investigated the metabolism of CeD by metabolic profiling of intestinal mucosa, blood plasma and urine using NMR spectroscopy and multivariate analysis. The metabolic profile of the small intestinal mucosa was compared between patients with CeD (n = 64) and disease controls (DCs, n = 30). The blood plasma and urinary metabolomes of CeD patients were compared with healthy controls (HCs, n = 39). Twelve metabolites (proline (Pro), arginine (Arg), glycine (Gly), histidine (His), glutamate (Glu), aspartate, tryptophan (Trp), fumarate, formate, succinate (Succ), glycerophosphocholine (GPC) and allantoin (Alln)) of intestinal mucosa differentiated CeD from controls. The metabolome of blood plasma with 18 metabolites (Pro, Arg, Gly, alanine, Glu, glutamine, glucose (Glc), lactate (Lac), acetate (Ace), acetoacetate (AcAc), β-hydroxybutyrate (β-OHB), pyruvate (Pyr), Succ, citrate (Cit), choline (Cho), creatine (Cr), phosphocreatine (PCr) and creatinine) and 9 metabolites of urine (Pro, Trp, β-OHB, Pyr, Succ, N-methylnicotinamide (NMN), aminohippurate (AHA), indoxyl sulfate (IS) and Alln) distinguished CeD from HCs. Our data demonstrated changes in nine metabolic pathways. The altered metabolites were associated with increased oxidative stress (Alln), impaired healing and repair mechanisms (Pro, Arg), compromised anti-inflammatory and cytoprotective processes (Gly, His, NMN), altered energy metabolism (Glc, Lac, β-OHB, Ace, AcAc, Pyr, Succ, Cit, Cho, Cr and PCr), impaired membrane metabolism (GPC and Cho) and intestinal dysbiosis (AHA and IS). An orthogonal partial least square discriminant analysis model provided clear differentiation between patients with CeD and controls in all three specimens. A classification model built by combining the distinguishing metabolites of blood plasma and urine samples gave an AUC of 0.99 with 97.7% sensitivity, 93.3% specificity and a predictive accuracy of 95.1%, which was higher than for the models built separately using small intestinal mucosa, blood plasma and urine. In conclusion, a panel of metabolic biomarkers in intestinal biopsies, plasma and urine samples has potential to differentiate CeD from controls and may complement traditional tests to improve the diagnosis of CeD.
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Affiliation(s)
- Deepti Upadhyay
- Department of NMR and MRI Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Alka Singh
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Jiya Mehtab
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Naranamangalam R Jagannathan
- Department of NMR and MRI Facility, All India Institute of Medical Sciences, New Delhi, India
- Department of Radiology, Chettinad Academy of Research & Education, Kelambakkam, Tamil Nadu, India
| | - Uma Sharma
- Department of NMR and MRI Facility, All India Institute of Medical Sciences, New Delhi, India
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Li H, Xu CX, Gong RJ, Chi JS, Liu P, Liu XM. How does Helicobacter pylori cause gastric cancer through connexins: An opinion review. World J Gastroenterol 2019; 25:5220-5232. [PMID: 31558869 PMCID: PMC6761244 DOI: 10.3748/wjg.v25.i35.5220] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/12/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium with a number of virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin A, its pathogenicity island, and lipopolysaccharide, which cause gastrointestinal diseases. Connexins function in gap junctional homeostasis, and their downregulation is closely related to gastric carcinogenesis. Investigations into H. pylori infection and the fine-tuning of connexins in cells or tissues have been reported in previous studies. Therefore, in this review, the potential mechanisms of H. pylori-induced gastric cancer through connexins are summarized in detail.
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Affiliation(s)
- Huan Li
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Can-Xia Xu
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Ren-Jie Gong
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Jing-Shu Chi
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Peng Liu
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Xiao-Ming Liu
- Department of Gastroenterology, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
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8
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Li H, Xu CX, Gong RJ, Chi JS, Liu P, Liu XM. How does Helicobacter pyloricause gastric cancer through connexins: An opinion review. World J Gastroenterol 2019. [DOI: 10.3748/wjg.v25.i355220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Leonard MM, Bai Y, Serena G, Nickerson KP, Camhi S, Sturgeon C, Yan S, Fiorentino MR, Katz A, Nath B, Richter J, Sleeman M, Gurer C, Fasano A. RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis. PLoS One 2019; 14:e0215132. [PMID: 30998704 PMCID: PMC6472737 DOI: 10.1371/journal.pone.0215132] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 03/27/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND & AIMS The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. METHODS We performed whole transcriptome shotgun sequencing of intestinal biopsies in subjects with active and remission CD and non-CD controls. We also performed functional pathway analysis of differentially expressed genes to identify statistically significant pathways that are up or down regulated in subjects with active CD compared to remission CD. RESULTS We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. We identified a unique signature of genes, related to innate immunity, perturbed exclusively in CD irrespective of disease status. Finally, we highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity. CONCLUSIONS Our study confirmed previous findings based on GWAS and immunological studies pertinent to CD pathogenesis and describes novel genes and pathways that with further validation may be found to contribute to the early steps in the pathogenesis of CD, ongoing inflammation, and comorbidities associated with CD.
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Affiliation(s)
- Maureen M. Leonard
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yu Bai
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Gloria Serena
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kourtney P. Nickerson
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Stephanie Camhi
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Craig Sturgeon
- Graduate Program in Life Sciences, University of Maryland, Baltimore, Maryland, United States of America
| | - Shu Yan
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Maria R. Fiorentino
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Aubrey Katz
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Barbara Nath
- Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - James Richter
- Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Matthew Sleeman
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Cagan Gurer
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Alessio Fasano
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
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10
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Hernández-Guerra M, Hadjihambi A, Jalan R. Gap junctions in liver disease: Implications for pathogenesis and therapy. J Hepatol 2019; 70:759-772. [PMID: 30599172 DOI: 10.1016/j.jhep.2018.12.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 12/03/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023]
Abstract
In the normal liver, cells interact closely through gap junctions. By providing a pathway for the trafficking of low molecular mass molecules, these channels contribute to tissue homeostasis and maintenance of hepatic function. Thus, dysfunction of gap junctions affects a wide variety of liver processes, such as differentiation, cell death, inflammation and fibrosis. In fact, dysfunctional gap junctions have been implicated, for more than a decade, in cholestatic disease, hepatic cancer and cirrhosis. Additionally, in recent years there is an increasing body of evidence that these channels are also involved in other relevant and prevalent liver pathological processes, such as non-alcoholic fatty liver disease, acute liver injury and portal hypertension. In parallel to these new clinical implications the available data include controversial observations. Thus, a comprehensive overview is required to better understand the functional complexity of these pores. This paper will review the most recent knowledge concerning gap junction dysfunction, with a special focus on the role of these channels in the pathogenesis of relevant clinical entities and on potential therapeutic targets that are amenable to modification by drugs.
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Affiliation(s)
| | | | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Medical School, London, UK
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11
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Charlesworth RPG, Agnew LL, Scott DR, Andronicos NM. Celiac disease gene expression data can be used to classify biopsies along the Marsh score severity scale. J Gastroenterol Hepatol 2019; 34:169-177. [PMID: 29972865 DOI: 10.1111/jgh.14369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/19/2018] [Accepted: 06/19/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM The diagnosis of celiac disease autoimmune pathology relies on the subjective histological assignment of biopsies into Marsh score categories. It is hypothesized that Marsh score categories have unique gene expression signatures. The aims were as follows: first, to develop a celiac disease quantitative reverse transcription-polymerase chain reaction (RT-PCR) array; second, define gene expression signatures associated with Marsh score categories; and third, develop equations that classify biopsies into Marsh score categories and to monitor the efficacy of patient treatment. METHODS Gene targets for inclusion in the celiac RT-PCR (qRT-PCR) array were identified using systematic analysis of published celiac transcriptomic data. The array was used to assess the gene expression associated with histological changes in duodenal biopsies obtained from adult patients. Finally, Marsh score classification equations were defined using discriminant analysis. RESULTS The array contained 87 genes. The expression of 26 genes were significantly (p < 0.06) associated with the discrete Marsh score categories. As the Marsh score pathology of biopsies increased, there was a progression of innate immune gene expression through adaptive Th1-specific gene expression with a concurrent decrease in intestinal structural gene expression in high Marsh score samples. These 26 genes were used to define classification equations that accounted for 99% of the observed experimental variation and which could classify biopsies into Marsh score categories and monitor patient treatment progression. CONCLUSIONS This proof-of-concept study successfully developed a celiac RT-PCR array and has provided evidence that discriminant equations defined using gene expression data can objectively and accurately classify duodenal biopsies into Marsh score categories.
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Affiliation(s)
- Richard P G Charlesworth
- Discipline of Biomedical Sciences, School of Science and Technology, University of New England, Armidale, New South Wales, Australia
| | - Linda L Agnew
- Discipline of Biomedical Sciences, School of Science and Technology, University of New England, Armidale, New South Wales, Australia
| | - David R Scott
- Hunter New England Area Health Service, Tamworth, New South Wales, Australia
| | - Nicholas M Andronicos
- Discipline of Biomedical Sciences, School of Science and Technology, University of New England, Armidale, New South Wales, Australia
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12
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Bragde H, Jansson U, Fredrikson M, Grodzinsky E, Söderman J. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies. Cell Mol Life Sci 2018; 75:4385-4401. [PMID: 30097691 PMCID: PMC6208765 DOI: 10.1007/s00018-018-2898-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 07/04/2018] [Accepted: 07/19/2018] [Indexed: 12/13/2022]
Abstract
Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n = 20) or without any signs of CD (n = 20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n = 43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.
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Affiliation(s)
- Hanna Bragde
- Laboratory Medicine, Ryhov County Hospital, Building E3 Level 4, 55185, Jönköping, Sweden.
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
| | - Ulf Jansson
- Department of Pediatrics, Ryhov County Hospital, Jönköping, Sweden
| | - Mats Fredrikson
- Department of Clinical and Experimental Medicine and Forum Östergötland, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Ewa Grodzinsky
- Division of Forensic Genetics & Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden
- Department of Medicine and Health, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Jan Söderman
- Laboratory Medicine, Ryhov County Hospital, Building E3 Level 4, 55185, Jönköping, Sweden
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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13
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Benedetti E, Viscido A, Castelli V, Maggiani C, d'Angelo M, Di Giacomo E, Antonosante A, Picarelli A, Frieri G. Mesalazine treatment in organotypic culture of celiac patients: Comparative study with gluten free diet. J Cell Physiol 2018; 233:4383-4390. [PMID: 29030981 DOI: 10.1002/jcp.26217] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/19/2017] [Accepted: 09/29/2017] [Indexed: 12/19/2022]
Abstract
Given the central role of gluten in the pathogenesis of celiac disease (CD), a strict gluten-free diet (GFD) is the only validated treatment able to restore epithelium integrity and eliminate risks of complications. The risk of gluten contamination and the persistence of inflammation, even in patients strictly adhering to GFD, may render this treatment not always effective claiming the necessity of different new solutions. Oxidative and nitrosative stress have been indicated to play a pathophysiological role in CD. Mesalazine (5-ASA), a drug largely used in inflammatory bowel disease, has potent antinflammatory and antioxidant effects. In fact, mesalazine has been shown to decrease in vitro gluten induced cytokine response and it has been used in vivo in some refractory condition. However, its effect has never compared to that of GFD. The present study aimed to address this issue by comparing the ability of mesalazine and GFD in treating gluten-induced inflammation and oxidative stress. These effects were studied on duodenal mucosa biopsy cultures from newly diagnosed CD patients, treated or not in vitro with mesalazine, and CD biopsy cultures from patients on gluten-free diet for at least one year; and a cohort of controls constituted by healty subjects. On these models, the antioxidant cellular defences, the PPARγ, NF-kB and NOS2 proteins levels were studied. This study shows that mesalazine is as effective as GFD in reducing oxidative burst and inducing PPARγ expression; moreover it resulted more effective than GFD in decreasing NF-kB and NOS2 to the levels of controls.
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Affiliation(s)
- Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Angelo Viscido
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Chiara Maggiani
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Erica Di Giacomo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Andrea Antonosante
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Antonio Picarelli
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
| | - Giuseppe Frieri
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
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14
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Immune Response to Rotavirus and Gluten Sensitivity. J Immunol Res 2018; 2018:9419204. [PMID: 29736406 PMCID: PMC5875030 DOI: 10.1155/2018/9419204] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/18/2017] [Accepted: 12/25/2017] [Indexed: 12/21/2022] Open
Abstract
Rotavirus is a double-stranded RNA virus belonging to the family of Reoviridae. The virus is transmitted by the faecal-oral route and infects intestinal cells causing gastroenteritis. Rotaviruses are the main cause of severe acute diarrhoea in children less than 5 years of age worldwide. In our previous work we have shown a link between rotavirus infection and celiac disease. Nonceliac gluten sensitivity (NCGS) is emerging as new clinical entity lacking specific diagnostic biomarkers which has been reported to occur in 6–10% of the population. Clinical manifestations include gastrointestinal and/or extraintestinal symptoms which recede with gluten withdrawal. The pathogenesis of the disease is still unknown. Aim of this work is to clarify some aspects of its pathogenesis using a gene array approach. Our results suggest that NCGS may have an autoimmune origin. This is based both on gene expression data (i.e., TH17-interferon signatures) and on the presence of TH17 cells and of serological markers of autoimmunity in NCGS. Our results also indicate a possible involvement of rotavirus infection in the pathogenesis of nonceliac gluten sensitivity similarly to what we have previously shown in celiac disease.
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15
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Profiling Celiac Disease-Related Transcriptional Changes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 336:149-174. [DOI: 10.1016/bs.ircmb.2017.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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16
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Vorobjova T, Raikkerus H, Kadaja L, Talja I, Uibo O, Heilman K, Uibo R. Circulating Zonulin Correlates with Density of Enteroviruses and Tolerogenic Dendritic Cells in the Small Bowel Mucosa of Celiac Disease Patients. Dig Dis Sci 2017; 62:358-371. [PMID: 27995404 DOI: 10.1007/s10620-016-4403-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/29/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Impaired intestinal integrity, including increased permeability of the small bowel mucosa, has been shown in patients with celiac disease (CD) as well as with type 1 diabetes (T1D). Zonulin (ZO, pre-haptoglobin), a tight junction regulator, plays a particular role in the regulation of intestinal barrier function and in the pathogenesis of the above-mentioned diseases. AIM To investigate whether enteroviruses (EVs) and immunoregulatory cells are associated with intestinal permeability in patients with CD alone and with coexistent T1D. MATERIALS AND METHODS Altogether 80 patients (mean age 10.68 ± 6.69 years) who had undergone small bowel biopsy were studied. Forty patients with functional dyspepsia and normal small bowel mucosa formed the control group. The circulating ZO level in sera was evaluated using ELISA. The densities of EV, FOXP3+ regulatory T cells (Tregs), indoleamine 2,3-dioxygenase (IDO+) dendritic cells (DCs) and glutamic acid dexarboxylase (GAD)65+ cells in small bowel mucosa were investigated by immunohistochemistry. The expression analysis of FOXP3, tight junction protein 1 (TJP1), gap junction (GJA1), IDO and CD103 genes was evaluated by real-time PCR. RESULTS The ZO level was higher in CD patients compared to subjects with a normal small bowel mucosa, particularly in those with Marsh IIIc atrophy (p = 0.01), and correlated with the density of EV (r = 0.63; p = 0.0003) and IDO+ DCs (r = 0.58; p = 0.01) in the small bowel mucosa. The density of GAD65+ epithelial cells was correlated with the density of EV (r = 0.59; p = 0.03) and IDO+ DCs (r = 0.78; p = 0.004) in CD patients. The relative expression of FOXP3 mRNA in the small bowel mucosa tissue was significantly higher in patients with CD, compared to subjects with a normal mucosa, and correlated with the density of EV (r = 0.62; p = 0.017) as well as with the relative expression of IDO mRNA (r = 0.54; p = 0.019). CONCLUSIONS The CD is associated with elevation of the circulating ZO level, the value of which correlates with the density of EV in CD patients with severe atrophic changes in the small bowel mucosa, particularly in cases of concomitant T1D. The CD is also characterized by the close relationship of the density of GAD65+ epithelial cells with the EV, ZO level and IDO+ DCs.
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MESH Headings
- Adolescent
- Antibodies, Viral/immunology
- Antigens, CD/genetics
- Autoantibodies/immunology
- Case-Control Studies
- Celiac Disease/complications
- Celiac Disease/metabolism
- Celiac Disease/pathology
- Celiac Disease/virology
- Child
- Child, Preschool
- Cholera Toxin/blood
- Connexin 43/genetics
- Dendritic Cells/metabolism
- Dendritic Cells/pathology
- Diabetes Mellitus, Type 1/complications
- Enterovirus/immunology
- Enzyme-Linked Immunosorbent Assay
- Female
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- Glutamate Decarboxylase/immunology
- Glutamate Decarboxylase/metabolism
- Haptoglobins
- Humans
- Immunoglobulin A/immunology
- Immunohistochemistry
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Integrin alpha Chains/genetics
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Intestinal Mucosa/virology
- Intestine, Small/metabolism
- Intestine, Small/pathology
- Intestine, Small/virology
- Male
- Permeability
- Protein Precursors
- RNA, Messenger/metabolism
- Real-Time Polymerase Chain Reaction
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
- Zonula Occludens-1 Protein/genetics
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Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014, Tartu, Estonia.
| | - Helerin Raikkerus
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014, Tartu, Estonia
| | - Lumme Kadaja
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Ija Talja
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014, Tartu, Estonia
| | - Oivi Uibo
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Children's Clinic, Tartu University Hospital, Tartu, Estonia
| | - Kaire Heilman
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Tallinn Children's Hospital, Tallinn, Estonia
| | - Raivo Uibo
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014, Tartu, Estonia
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17
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Sala G, Badalamenti S, Ponticelli C. The Renal Connexome and Possible Roles of Connexins in Kidney Diseases. Am J Kidney Dis 2015; 67:677-87. [PMID: 26613807 DOI: 10.1053/j.ajkd.2015.09.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 09/30/2015] [Indexed: 12/21/2022]
Abstract
Connexins are membrane-spanning proteins that allow for the formation of cell-to-cell channels and cell-to-extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment.
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Affiliation(s)
- Gabriele Sala
- Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano (Milano), Italy.
| | - Salvatore Badalamenti
- Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano (Milano), Italy
| | - Claudio Ponticelli
- Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano (Milano), Italy
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18
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Quinn EM, Coleman C, Molloy B, Dominguez Castro P, Cormican P, Trimble V, Mahmud N, McManus R. Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation. PLoS One 2015; 10:e0140049. [PMID: 26444573 PMCID: PMC4596691 DOI: 10.1371/journal.pone.0140049] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/21/2015] [Indexed: 12/16/2022] Open
Abstract
Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P<2.2x10-16) and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; Padjusted = 3.6x10-3) as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P<2.2x10-16) indicating that reduced expression of this master regulator of T cell differentiation promotes a pro-inflammatory response and strongly corroborates genetic evidence that BACH2 plays an important role in CD pathogenesis.
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Affiliation(s)
- Emma M. Quinn
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Ciara Coleman
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Ben Molloy
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Patricia Dominguez Castro
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Paul Cormican
- Animal and Bioscience Research Department, Grange Research Centre, Teagasc, Dunsany, Ireland
| | - Valerie Trimble
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Nasir Mahmud
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
| | - Ross McManus
- Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James’s Hospital, Dublin, 8, Ireland
- * E-mail:
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19
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Maes M, Crespo Yanguas S, Willebrords J, Cogliati B, Vinken M. Connexin and pannexin signaling in gastrointestinal and liver disease. Transl Res 2015; 166:332-43. [PMID: 26051630 PMCID: PMC4570182 DOI: 10.1016/j.trsl.2015.05.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 04/29/2015] [Accepted: 05/08/2015] [Indexed: 12/20/2022]
Abstract
Gap junctions, which mediate intercellular communication, are key players in digestive homeostasis. They are also frequently involved in gastrointestinal and liver pathology. This equally holds true for connexin (Cx) hemichannels, the structural precursors of gap junctions, and pannexin (Panx) channels, Cx-like proteins assembled in a hemichannel configuration. Both Cx hemichannels and Panx channels facilitate extracellular communication and drive a number of deteriorative processes, such as cell death and inflammation. Cxs, Panxs, and their channels underlie a wide spectrum of gastrointestinal and liver diseases, including gastritis and peptic ulcer disease, inflammatory intestinal conditions, acute liver failure, cholestasis, hepatitis and steatosis, liver fibrosis and cirrhosis, infectious gastrointestinal pathologies, and gastrointestinal and liver cancer. This could open promising perspectives for the characterization of new targets and biomarkers for therapeutic and diagnostic clinical purposes in the area of gastroenterology and hepatology.
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Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
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20
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Montén C, Gudjonsdottir AH, Browaldh L, Arnell H, Nilsson S, Agardh D, Naluai ÅT. Genes involved in muscle contractility and nutrient signaling pathways within celiac disease risk loci show differential mRNA expression. BMC MEDICAL GENETICS 2015; 16:44. [PMID: 26123480 PMCID: PMC4630939 DOI: 10.1186/s12881-015-0190-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 06/16/2015] [Indexed: 01/17/2023]
Abstract
Background Risk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development. The aim was to examine expression levels of potential risk genes close to these variants in the small intestine and peripheral blood and also to test if the non-coding variants affect nearby gene expression levels in children with celiac disease. Methods Intestinal biopsy and peripheral blood RNA was isolated from 167 children with celiac disease, 61 with potential celiac disease and 174 disease controls. Transcript levels for 88 target genes, selected from celiac disease risk loci, were analyzed in biopsies of a smaller sample subset by qPCR. Differentially expressed genes (3 from the pilot and 8 previously identified) were further validated in the larger sample collection (n = 402) of both tissues and correlated to nearby celiac disease risk variants. Results All genes were significantly down- or up-regulated in the intestinal mucosa of celiac disease children, NTS being most down-regulated (Fold change 3.6, p < 0.001). In contrast, PPP1R12B isoform C was up-regulated in the celiac disease mucosa (Fold change 1.9, p < 0.001). Allele specific expression of GLS (rs6741418, p = 0.009), INSR (rs7254060, p = 0.003) and NCALD (rs652008, p = 0.005) was also detected in the biopsies. Two genes (APPL2 and NCALD) were differentially expressed in peripheral blood but no allele specific expression was observed in this tissue. Conclusion The differential expression of NTS and PPP1R12B indicate a potential role for smooth muscle contractility and cell proliferation in celiac disease, whereas other genes like GLS, NCALD and INSR suggests involvement of nutrient signaling and energy homeostasis in celiac disease pathogenesis. A disturbance in any of these pathways might contribute to development of childhood celiac disease. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0190-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Caroline Montén
- Diabetes & Celiac Disease Unit, Department of Clinical Sciences, Lund University, Jan Waldenströms gata 35, CRC, 91:10, 202 05, Malmö, Sweden.
| | - Audur H Gudjonsdottir
- Department of Pediatrics, Queen Silvia Children's Hospital, Sahlgrenska Academy, Gothenburg, Sweden.
| | - Lars Browaldh
- Department of Clinical Science & Education, Karolinska Institute Södersjukhuset, Stockholm, Sweden.
| | - Henrik Arnell
- Department of Pediatric Gastroenterology, Hepatology & Nutrition, Karolinska University Hospital, Stockholm, Sweden.
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
| | - Daniel Agardh
- Diabetes & Celiac Disease Unit, Department of Clinical Sciences, Lund University, Jan Waldenströms gata 35, CRC, 91:10, 202 05, Malmö, Sweden.
| | - Åsa Torinsson Naluai
- Department of Medical & Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg, Sweden.
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21
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Maes M, Cogliati B, Crespo Yanguas S, Willebrords J, Vinken M. Roles of connexins and pannexins in digestive homeostasis. Cell Mol Life Sci 2015; 72:2809-21. [PMID: 26084872 DOI: 10.1007/s00018-015-1961-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 06/11/2015] [Indexed: 12/21/2022]
Abstract
Connexin proteins are abundantly present in the digestive system. They primarily form gap junctions, which control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions drive a plethora of gastrointestinal and hepatic functional features, including gastric and gut motility, gastric acid secretion, intestinal innate immune defense, xenobiotic biotransformation, glycogenolysis, bile secretion, ammonia detoxification and plasma protein synthesis. In the last decade, it has become clear that connexin hemichannels, which are the structural precursors of gap junctions, also provide a pathway for cellular communication, namely between the cytosol and the extracellular environment. Although merely pathological functions have been described, some physiological roles have been attributed to connexin hemichannels, in particular in the modulation of colonic motility. This equally holds true for cellular channels composed of pannexins, connexin-like proteins recently identified in the intestine and the liver, which have become acknowledged key players in inflammatory processes and that have been proposed to control colonic motility, secretion and blood flow.
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Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
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22
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Giovanna Z, Marzia D, Claudio L, Puccetti A. Celiac Disease and Rotavirus Infection. INFECTION AND AUTOIMMUNITY 2015:453-464. [DOI: 10.1016/b978-0-444-63269-2.00028-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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23
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Seneff S, Swanson N, Li C. Aluminum and Glyphosate Can Synergistically Induce Pineal Gland Pathology: Connection to Gut Dysbiosis and Neurological Disease. ACTA ACUST UNITED AC 2015. [DOI: 10.4236/as.2015.61005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Dolcino M, Zanoni G, Bason C, Tinazzi E, Boccola E, Valletta E, Contreas G, Lunardi C, Puccetti A. A subset of anti-rotavirus antibodies directed against the viral protein VP7 predicts the onset of celiac disease and induces typical features of the disease in the intestinal epithelial cell line T84. Immunol Res 2014; 56:465-76. [PMID: 23572432 DOI: 10.1007/s12026-013-8420-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Celiac disease (CD) is an autoimmune disorder of the small intestine triggered by environmental factors in genetically predisposed individuals. A strong association between type 1 diabetes (T1DM) and CD has been reported. We have previously shown that rotavirus infection may be involved in the pathogenesis of CD through a mechanism of molecular mimicry. Indeed, we identified a subset of anti-transglutaminase IgA antibodies that recognize the rotavirus viral protein VP7. In this study, we aimed at evaluating whether such antibodies may predict the onset of CD in children affected by T1DM. Moreover, to further analyze the link between rotavirus infection and pathogenesis of CD, we analyzed the effect of anti-rotavirus VP7 antibodies on T84 intestinal epithelial cells using the gene-array technique, complemented by the analysis of molecules secreted in the supernatant of stimulated cells. We found that anti-rotavirus VP7 antibodies are present in the vast majority (81%) of T1DM-CD tested sera, but are detectable also in a fraction (27%) of T1DM children without CD. Moreover, we found that anti-rotavirus VP7 antibodies are present before the CD onset, preceding the detection of anti-tTG and anti-endomysium antibodies. The gene-array analysis showed that purified anti-rotavirus VP7 antibodies modulate genes that are involved in apoptosis, inflammation, and alteration of the epithelial barrier integrity in intestinal epithelial cells, all typical features of CD. Taken together, these new data further support the involvement of rotavirus infection in the pathogenesis of CD and suggest a predictive role of anti-rotavirus VP7 antibodies.
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25
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Carregaro F, Stefanini ACB, Henrique T, Tajara EH. Study of small proline-rich proteins (SPRRs) in health and disease: a review of the literature. Arch Dermatol Res 2013; 305:857-66. [DOI: 10.1007/s00403-013-1415-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 09/11/2013] [Accepted: 09/16/2013] [Indexed: 12/26/2022]
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26
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Parmar A, Greco D, Venäläinen J, Gentile M, Dukes E, Saavalainen P. Gene Expression Profiling of Gliadin Effects on Intestinal Epithelial Cells Suggests Novel Non-Enzymatic Functions of Pepsin and Trypsin. PLoS One 2013; 8:e66307. [PMID: 23824913 PMCID: PMC3688875 DOI: 10.1371/journal.pone.0066307] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 05/03/2013] [Indexed: 01/11/2023] Open
Abstract
Gliadin triggers T-cell mediated immunity in celiac disease, and has cytotoxic effects on enterocytes mediated through obscure mechanisms. In addition, gliadin transport mechanisms, potential cell surface receptors and gliadin-activated downstream signaling pathways are not completely understood. In order to screen for novel downstream gliadin target genes we performed a systematic whole genome expression study on intestinal epithelial cells. Undifferentiated Caco-2 cells were exposed to pepsin- and trypsin- digested gliadin (PT-G), a blank pepsin-trypsin control (PT) and to a synthetic peptide corresponding to gliadin p31-43 peptide for six hours. RNA from four different experiments was used for hybridization on Agilent one color human whole genome DNA microarray chips. The microarray data were analyzed using the Bioconductor package LIMMA. Genes with nominal p<0.01 were considered statistically significant. Compared to the untreated cells 1705, 1755 and 211 probes were affected by PT-G, PT and p31-43 respectively. 46 probes were significantly different between PT and PT-G treated cells. Among the p31-43 peptide affected probes, 10 and 21 probes were affected by PT-G and PT respectively. Only PT-G affected genes could be validated by quantitative real-time polymerase chain reaction. All the genes were, nonetheless, also affected to a comparable level by PT treated negative controls. In conclusion, we could not replicate previously reported direct effects of gliadin peptides on enterocytes. The results rather suggest that certain epitopes derived from pepsin and trypsin may also affect epithelial cell gene transcription. Our study suggests novel non-enzymatic effects of pepsin and trypsin on cells and calls for proper controls in pepsin and trypsin digested gliadin experiments. It is conceivable that gliadin effects on enterocytes are secondary mediated through oxidative stress, NFkB activation and IL-15 up-regulation.
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Affiliation(s)
- Amarjit Parmar
- Research Programs Unit, Immunobiology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Dario Greco
- Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Jarkko Venäläinen
- Department of Pharmacology and Toxicology, University of Eastern Finland, Kuopio, Finland
| | | | - Emma Dukes
- Research Programs Unit, Immunobiology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Päivi Saavalainen
- Research Programs Unit, Immunobiology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland
- * E-mail:
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27
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Luo A, Chen H, Ding F, Zhang Y, Wang M, Xiao Z, Liu Z. Small proline-rich repeat protein 3 enhances the sensitivity of esophageal cancer cells in response to DNA damage-induced apoptosis. Mol Oncol 2013; 7:955-67. [PMID: 23820115 DOI: 10.1016/j.molonc.2013.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 05/28/2013] [Accepted: 05/28/2013] [Indexed: 12/12/2022] Open
Abstract
Small proline-rich repeat protein 3 (SPRR3) has been linked with the altered chemoradiosensitivity, however the underlying molecular mechanisms remain elusive. Here, we report that ectopic overexpression of SPRR3 enhanced the sensitivity of cells in response to DNA damage-induced apoptosis via loss of mitochondrial membrane potential (MMP), and increasing activation of caspase 3 in human esophageal cancer cell lines. Conversely, siRNA knockdown of SPRR3 reduced apoptosis. We found that SPRR3 was localized in mitochondria and interacted with Bcl-2 in vivo, thus facilitating Bax mitochondrial translocation and the subsequent release of cytochrome c, and thereby enhancing cell sensitivity to DNA damage stimuli. In clinical samples, expression of SPRR3 was associated with the pathologic response (P = 0.007 in radiotherapy group, P = 0.035 in preoperative radiotherapy group) and good survival of patients with locally advanced esophageal squamous cell carcinoma (ESCC, P = 0.008). Taken together, our results implicate that SPRR3 might serve as a radiation-sensitive predictor of ESCC.
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Affiliation(s)
- Aiping Luo
- State Key Lab of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, Beijing 100021, PR China
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28
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The last two millennias echo-catastrophes are the driving forces for the potential genetic advantage mechanisms in celiac disease. Med Hypotheses 2011; 77:773-6. [DOI: 10.1016/j.mehy.2011.07.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 07/17/2011] [Indexed: 11/23/2022]
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29
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Koutsoumpas A, Polymeros D, Tsiamoulos Z, Smyk D, Karamanolis G, Triantafyllou K, Rigopoulou EI, Forbes A, Vergani D, Bogdanos DP, Ladas SD. Peculiar antibody reactivity to human connexin 37 and its microbial mimics in patients with Crohn's disease. J Crohns Colitis 2011; 5:101-109. [PMID: 21453878 DOI: 10.1016/j.crohns.2010.10.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 09/30/2010] [Accepted: 10/28/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS We found that pooled Crohn's disease (CD) sera strongly react with a human gap-junction connexin 37 (Cx37) peptide and tested for anti-Cx37 antibody reactivity in sera from CD patients and controls. We also investigated whether peptide-recognition is due to Cx37/microbial molecular mimicry. METHODS The PSI-BLAST program was used for Cx37(121-135)/microbial alignment. Reactivity to biotinylated human Cx37(121-135) and its microbial mimics was determined by ELISA using sera from 44 CD, 30 ulcerative colitis and 28 healthy individuals. RESULTS Anti-Cx37(121-135) reactivity (1/200 dilution) was present in 30/44 (68%) CD cases and persisted at 1/1000 dilution. Database search shows that Cx37(121-135) contains the -ALTAV- motif which is cross-recognized by diabetes-specific phogrin and enteroviral immunity. Testing of 9 Cx37(121-135)-microbial mimics revealed 57-68% reactivity against human enterovirus C, Lactococcus lactis, coxsackie virus A24 and B4. Anti-Cx37(121-135) was inhibited by itself or the microbial mimics. No reactivity was found against the poliovirus, rubella, and Mycobacterium tuberculosis mimics, or the beta cell phogrin autoantigen. Microbial/Cx37 reactivity was not able to differentiate CD patients from UC or healthy controls, in terms of overall prevalence and antibody titres, but microbial mimics were unable to inhibit reactivity to human Cx37 in the majority of the controls. CONCLUSIONS Sera from CD patients react with connexin 37 and cross-react with specific Cx37-mimicking enteroviral peptides. Microbial/self reactivity can be seen in UC and healthy controls. The lack of responses to other Cx37(121-135) microbial mimics and the inability of the reactive microbes to inhibit reactivity to self is intriguing and warrants further investigation.
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Affiliation(s)
- Andreas Koutsoumpas
- Division of Gene and Cell Based Therapy, King's College London School of Medicine at King's College Hospital, London, UK
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Castellanos-Rubio A, Santin I, Martin-Pagola A, Irastorza I, Castaño L, Vitoria JC, Bilbao JR. Long-term and acute effects of gliadin on small intestine of patients on potentially pathogenic networks in celiac disease. Autoimmunity 2010; 43:131-9. [PMID: 19814655 DOI: 10.3109/08916930903225229] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Celiac disease (CD) is a complex, immune-mediated intolerance to gliadin that develops in genetically susceptible individuals. Although the main driving force of the disease is an aberrant autoimmune response, several other pathogenic mechanisms, many still unidentified, are also involved. In order to describe at a network level the alterations provoked by a gliadin insult on the intestinal mucosa of patients, we compared the expression profiles of biopsies from 9 active and 9 treated patients (long-term effects of gliadin), and of 10 biopsies from gluten-free diet treated patients that were incubated in vitro with or without gliadin (acute effects) and integrated significantly altered transcripts into potentially pathogenic biological processes. Using information on Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology terms represented among the differentially expressed genes, we observed important dysfunction in several complex networks, including those related to cell-cell communication, intracellular signaling, ubiquitin-proteasome system, cell cycle/apoptosis and extracellular matrix. The reconstruction of the role of these biological networks in the development of the intestinal lesion in CD provides a comprehensive picture of key events that contribute to the disease, and could point towards novel functional candidates that might be potential therapeutic targets or responsible for genetic susceptibility.
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31
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Cho DH, Jo YK, Roh SA, Na YS, Kim TW, Jang SJ, Kim YS, Kim JC. Upregulation of SPRR3 promotes colorectal tumorigenesis. Mol Med 2010; 16:271-7. [PMID: 20379613 DOI: 10.2119/molmed.2009.00187] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Accepted: 03/16/2010] [Indexed: 11/06/2022] Open
Abstract
Hereditary colorectal cancer develops through a series of well-defined genetic and histological changes. However, elucidation of the canonical pathway based on hereditary colorectal cancer has not provided a clear explanation of the molecular mechanisms of sporadic colorectal cancer. To identify the alterative pathways involved in sporadic colorectal tumorigenesis, we performed gene expression analysis in patients with sporadic colorectal tumors. A comparison analysis of gene expression profiles revealed a pattern of upregulation of small proline rich repeat protein 3 (SPRR3) in tumor samples. SPRR3 has previously been reported to be downregulated in esophageal cancer. However, in the present study, we observed that SPRR3 was strongly upregulated in 31 of 35 samples of sporadic colorectal tumors (88%). We also determined that overexpression of SPRR3 not only accelerates colorectal cancer cell proliferation but also is associated with lymphovascular invasion in colorectal cancer. Moreover, AKT was activated and p53 levels were decreased in cells that overexpressed SPRR3. In contrast to the pattern seen in esophageal cancer, these results suggest that increased expression of SPRR3 is involved in colorectal tumorigenesis.
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Affiliation(s)
- Dong-Hyung Cho
- Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
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Juuti-Uusitalo K, Lindfors K, Mäki M, Patrikainen M, Isola J, Kaukinen K. Inhibition of epithelial growth factor receptor signalling does not preserve epithelial barrier function after in vitro gliadin insult. Scand J Gastroenterol 2010; 44:820-5. [PMID: 19370450 DOI: 10.1080/00365520902898119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE In coeliac disease, small-bowel mucosal permeability is increased in response to gluten consumption. However, the signalling routes leading to such a barrier defect remain obscure. As the epidermal growth factor receptor (EGFR) pathway is up-regulated in untreated coeliac disease, and since this cascade has been related to epithelial hyperpermeability, the aim of this study was to establish whether blocking the EGFR route would restore the barrier after gliadin insult in vitro. MATERIAL AND METHODS Epithelial barrier function was assessed by measuring transepithelial electrical resistance (TER) in Caco-2 epithelial monolayers treated with pepsin trypsin (PT)-digested gliadin with or without monoclonal antibodies against EGFR family members or by inhibitors of the EGFR pathway signalling molecules. Furthermore, tight-junctional integrity was determined by Western blotting and immunofluorescence staining of the tight-junctional protein occludin. RESULTS PT-gliadin significantly reduced TER and the expression of occludin protein. Blocking of the EGFR signalling pathway could not prevent gliadin-triggered damage. In fact, a function-blocking monoclonal antibody against EGFR (ErbB1) actually potentiated the harmful effects of gliadin on TER. CONCLUSIONS The epithelial barrier-disrupting properties of gliadin are independent of the EGFR signalling cascade. However, our results suggest that activation of the EGFR pathway might actually be protective against gliadin-triggered hyperpermeability. Further studies are needed to elucidate the specific gliadin-triggered signalling cascades which lead to increased epithelial permeability in coeliac disease.
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