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Talipova D, Smagulova A, Poddighe D. Toll-like Receptors and Celiac Disease. Int J Mol Sci 2022; 24:265. [PMID: 36613709 PMCID: PMC9820541 DOI: 10.3390/ijms24010265] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/10/2022] [Accepted: 12/13/2022] [Indexed: 12/28/2022] Open
Abstract
Celiac disease (CD) is an immune-mediated disorder triggered by dietary gluten intake in some genetically predisposed individuals; however, the additional non-HLA-related genetic factors implicated in CD immunopathogenesis are not well-defined. The role of the innate immune system in autoimmunity has emerged in the last few years. Genetic polymorphisms of some pattern-recognition receptors, including toll-like receptors (TLRs), have been associated with several autoimmune disorders. In this review, we summarize and discuss the evidence from basic research and clinical studies as regards the potential role of TLRs in CD immunopathogenesis. The evidence supporting the role of TLRs in CD immunopathogenesis is limited, especially in terms of basic research. However, differences in the expression and activation of TLRs between active CD patients from one side, and controls and treated CD patients from the other side, have been described in some clinical studies. Therefore, TLRs may be part of those non-HLA-related genetic factors implicated in CD etiopathogenesis, considering their potential role in the interaction between the host immune system and some environmental factors (including viral infections and gut microbiota), which are included in the list of candidate agents potentially contributing to the determination of CD risk in genetically predisposed individuals exposed to dietary gluten intake. Further basic research and clinical studies focused on TLRs in the context of CD and other gluten-related disorders are needed.
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Affiliation(s)
- Diana Talipova
- Department of Medicine, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan
| | - Aiganym Smagulova
- Department of Medicine, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan
| | - Dimitri Poddighe
- Department of Medicine, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan
- Clinical Academic Department of Pediatrics, National Research Center for Maternal and Child Health, University Medical Center, Astana 010000, Kazakhstan
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2
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Functional implications of the CpG island methylation in the pathogenesis of celiac disease. Mol Biol Rep 2022; 49:10051-10064. [PMID: 35633417 DOI: 10.1007/s11033-022-07585-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
Investigation of gene-environment cross talk through epigenetic modifications led to better understanding of the number of complex diseases. Clinical heterogeneity and differential treatment response often contributed by the epigenetic signatures which could be personal. DNA methylation at CpG islands presents a critical nuclear process as a result of gene-environment interactions. These CpG islands are frequently present near the promoter sequence of genes and get differentially methylated under specific environmental conditions. Technical advancements facilitate in high throughput screening of differentially methylated CpG islands. Recent epigenetic studies unraveled several CD susceptibility genes expressed in peripheral blood lymphocytes (PBLs), duodenal mucosa, lamina and epithelial cells that are influenced by differentially methylated CpG islands. Here we highlighted these susceptibility genes; classify these genes based on cellular functions and tissue of expression. We further discussed how these genes interacts with each other to influence critical pathways like NF-κB signaling pathway, IL-17 signaling cascade, RIG-I like receptor signaling pathway, NOD-like receptor pathways among several others. This review also shed light on how gut microbiota may lead to the differential methylation of CpG islands of CD susceptibility genes. Large scale epigenetic studies followed by estimation of heritability of these CpG methylation and polygenic risk score estimation of these genes would prioritize potentially druggable targets for better therapeutics. In vivo studies are warranted to unravel further cellular responses to CpG methylation.
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Rojas L, Grüttner J, Ma’ayeh S, Xu F, Svärd SG. Dual RNA Sequencing Reveals Key Events When Different Giardia Life Cycle Stages Interact With Human Intestinal Epithelial Cells In Vitro. Front Cell Infect Microbiol 2022; 12:862211. [PMID: 35573800 PMCID: PMC9094438 DOI: 10.3389/fcimb.2022.862211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/31/2022] [Indexed: 12/02/2022] Open
Abstract
Giardia intestinalis is a protozoan parasite causing diarrheal disease, giardiasis, after extracellular infection of humans and other mammals’ intestinal epithelial cells (IECs) of the upper small intestine. The parasite has two main life cycle stages: replicative trophozoites and transmissive cysts. Differentiating parasites (encysting cells) and trophozoites have recently been shown to be present in the same regions of the upper small intestine, whereas most mature cysts are found further down in the intestinal system. To learn more about host-parasite interactions during Giardia infections, we used an in vitro model of the parasite’s interaction with host IECs (differentiated Caco-2 cells) and Giardia WB trophozoites, early encysting cells (7 h), and cysts. Dual RNA sequencing (Dual RNAseq) was used to identify differentially expressed genes (DEGs) in both Giardia and the IECs, which might relate to establishing infection and disease induction. In the human cells, the largest gene expression changes were found in immune and MAPK signaling, transcriptional regulation, apoptosis, cholesterol metabolism and oxidative stress. The different life cycle stages of Giardia induced a core of similar DEGs but at different levels and there are many life cycle stage-specific DEGs. The metabolic protein PCK1, the transcription factors HES7, HEY1 and JUN, the peptide hormone CCK and the mucins MUC2 and MUC5A are up-regulated in the IECs by trophozoites but not cysts. Cysts specifically induce the chemokines CCL4L2, CCL5 and CXCL5, the signaling protein TRKA and the anti-bacterial protein WFDC12. The parasite, in turn, up-regulated a large number of hypothetical genes, high cysteine membrane proteins (HCMPs) and oxidative stress response genes. Early encysting cells have unique DEGs compared to trophozoites (e.g. several uniquely up-regulated HCMPs) and interaction of these cells with IECs affected the encystation process. Our data show that different life cycle stages of Giardia induce different gene expression responses in the host cells and that the IECs in turn differentially affect the gene expression in trophozoites and early encysting cells. This life cycle stage-specific host-parasite cross-talk is an important aspect to consider during further studies of Giardia’s molecular pathogenesis.
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Affiliation(s)
- Laura Rojas
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Jana Grüttner
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | | | - Feifei Xu
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Staffan G. Svärd
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
- SciLifeLab, Uppsala University, Uppsala, Sweden
- *Correspondence: Staffan G. Svärd,
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Ghasiyari H, Rostami-Nejad M, Amani D, Rostami K, Pourhoseingholi MA, Asadzadeh-Aghdaei H, Zali MR. Diverse Profiles of Toll-Like Receptors 2, 4, 7, and 9 mRNA in Peripheral Blood and Biopsy Specimens of Patients with Celiac Disease. J Immunol Res 2018; 2018:7587095. [PMID: 30057921 PMCID: PMC6051003 DOI: 10.1155/2018/7587095] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 04/21/2018] [Accepted: 05/28/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Both adaptive and innate immunity are involved in the development of celiac disease (CD). Altered Toll-like receptors (TLR) expression and activation may be partially responsible for the inflammation and subsequently crypt hyperplasia, but the main driver for inflammation is gliadin-reactive T-cells. Therefore, the aim of this study was to investigate the TLRs 2, 4, 7, and 9 gene expressions in both peripheral blood and intestinal mucosa of patients with celiac disease compared to healthy control (HC). MATERIAL AND METHODS Blood samples from 120 confirmed active CD patients and 120 age- and sex-matched healthy volunteers served as control group were collected during 2015-2016. Also, 20 biopsy specimens from the study group were randomly collected. Total RNA was isolated using a standard commercial kit. The mRNA expression of TLRs was quantified by relative qPCR with β2 microglobulin (β2m) as a reference gene. RESULTS TLR4 (P = 0.01) and TLR9 (P = 0.02) mRNA were significantly elevated in blood samples from CD patients compared to the healthy controls. Moreover, TLR2 (P = 0.03) and TLR4 (P = 0.0003) expression level was increased in CD biopsy specimens compared to controls, whereas expression of TLR9 mRNA was significantly decreased in CD patients. There was no significant difference in the expression of TLR7 in biopsy and blood specimens. CONCLUSIONS The alteration of TLR4 and TLR9 expression in the blood and biopsy samples of patients with CD supports the critical role of the innate immune system in the pathogenesis of this disease. Upregulation of TLR4 and TLR9 suggests the contribution of gut microbiota or dysregulation of the immune response to commensal flora in small bowel mucosa in celiac patients.
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Affiliation(s)
- Haniye Ghasiyari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davar Amani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamran Rostami
- Department of Gastroenterology, Milton Keynes University Hospital, Milton Keynes, UK
| | - Mohamad Amin Pourhoseingholi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Rostami-Nejad M, Hejazi SH, Peña AS, Asadzadeh-Aghdaei H, Rostami K, Volta U, Zali MR. Contributions of HLA haplotypes, IL8 level and Toxoplasma gondii infection in defining celiac disease's phenotypes. BMC Gastroenterol 2018; 18:66. [PMID: 29776388 PMCID: PMC5960085 DOI: 10.1186/s12876-018-0796-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 05/08/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND It is not clear why some patients with coeliac disease (CD) present with severe symptoms and small intestinal mucosal damages while others present with milder symptoms and no frank enteropathy. There is no study to assess the associated factors with mild/severe symptoms and enteropathy. The terminologies like latent, silent and potential are difficult to use and are unrepresentative. In the present study we describe coeliac disease's phenotypes based on HLA haplotypes, IL8 production and past infection with Toxoplasma gondii (T. gondii) infection. METHODS In this case-control study, sera originating from 150 healthy subjects and 150 patients diagnosed with CD during the years 2013-14 were analyzed for the presence of antibodies specific T. gondii of the IgG and IgM subclasses. The level of IL8 were measured and HLA-DQ2 and HLA-DQ8 alleles were genotyped. The correlation between these parameters and the damages in intestinal mucosal were assessed using an accepted histopathological classification. RESULTS High levels of IgG antibodies against T. gondii were found in the sera of control group compared to the CD group (52.6% vs. 39.4%, P = 0.02). Mean serum levels of IL8 was significantly higher in CD patients compared with control (P ≤ 0.05). By comparing the level of anti- T. gondii IgG and mucosal damage in celiac disease, we found a significant relationship between the severity of mucosal damages and anti- T. gondii IgG level (P = 0.02). No correlation was detected between Toxoplasma gondii infection and types of HLA (P > 0.05). However, patients with severely abnormal histology carried HLA-DQ2 risk alleles (92 patients (61%)) more often than the controls and those with mild histological abnormalities. CONCLUSIONS CD patients with severe histological changes had more often Toxoplasma gondii infection than those affected with mild histological features. This suggests that CD's phenotypes are correlated to additional factors like infections and to particular HLA DQ2 alleles that may need additional investigations and potentially will require additional treatment.
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Affiliation(s)
- Mohammad Rostami-Nejad
- Celiac Disease Department, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Hejazi
- Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical sciences, Isfahan, Iran
| | - Amado Salvador Peña
- Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, Vrije Universiteit Medical Center (VUmc), Amsterdam, the Netherlands
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamran Rostami
- Department of Gastroenterology, Milton Keynes University Hospital, Milton Keynes, UK
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Mohammad Reza Zali
- Celiac Disease Department, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Lerner A, Arleevskaya M, Schmiedl A, Matthias T. Microbes and Viruses Are Bugging the Gut in Celiac Disease. Are They Friends or Foes? Front Microbiol 2017; 8:1392. [PMID: 28824555 PMCID: PMC5539691 DOI: 10.3389/fmicb.2017.01392] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 07/10/2017] [Indexed: 12/17/2022] Open
Abstract
The links between microorganisms/viruses and autoimmunity are complex and multidirectional. A huge number of studies demonstrated the triggering impact of microbes and viruses as the major environmental factors on the autoimmune and inflammatory diseases. However, growing evidences suggest that infectious agents can also play a protective role or even abrogate these processes. This protective crosstalk between microbes/viruses and us might represent a mutual beneficial equilibrium relationship between two cohabiting ecosystems. The protective pathways might involve post-translational modification of proteins, decreased intestinal permeability, Th1 to Th2 immune shift, induction of apoptosis, auto-aggressive cells relocation from the target organ, immunosuppressive extracellular vesicles and down regulation of auto-reactive cells by the microbial derived proteins. Our analysis demonstrates that the interaction of the microorganisms/viruses and celiac disease (CD) is always a set of multidirectional processes. A deeper inquiry into the CD interplay with Herpes viruses and Helicobacter pylori demonstrates that the role of these infections, suggested to be potential CD protectors, is not as controversial as for the other infectious agents. The outcome of these interactions might be due to a balance between these multidirectional processes.
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Affiliation(s)
- Aaron Lerner
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of TechnologyHaifa, Israel
- Department of Research, AESKU.KIPP InstituteWendelsheim, Germany
| | - Marina Arleevskaya
- Central Research Laboratory, Kazan State Medical Academy KazanKazan, Russia
| | - Andreas Schmiedl
- Department of Research, AESKU.KIPP InstituteWendelsheim, Germany
| | - Torsten Matthias
- Department of Research, AESKU.KIPP InstituteWendelsheim, Germany
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7
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Pellegrini S, Sordi V, Bolla AM, Saita D, Ferrarese R, Canducci F, Clementi M, Invernizzi F, Mariani A, Bonfanti R, Barera G, Testoni PA, Doglioni C, Bosi E, Piemonti L. Duodenal Mucosa of Patients With Type 1 Diabetes Shows Distinctive Inflammatory Profile and Microbiota. J Clin Endocrinol Metab 2017; 102:1468-1477. [PMID: 28324102 DOI: 10.1210/jc.2016-3222] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 11/29/2016] [Indexed: 02/04/2023]
Abstract
CONTEXT Increasing evidences suggest a correlation between gut and type 1 diabetes (T1D). OBJECTIVE The objective of this study is to evaluate the gut inflammatory profile and microbiota in patients with T1D compared with healthy control (CTRL) subjects and patients with celiac disease (CD) as gut inflammatory disease controls. DESIGN/SETTING/PARTICIPANTS The inflammatory status and microbiome composition were evaluated in biopsies of the duodenal mucosa of patients with T1D (n = 19), in patients with CD (n = 19), and CTRL subjects (n = 16) recruited at San Raffaele Scientific Institute, in Milan, Italy, between 2009 and 2015. MAIN OUTCOME MEASURES Inflammation was evaluated by gene expression study and immunohistochemistry. Microbiome composition was analyzed by 16S ribosomal RNA gene sequencing. RESULTS An increased expression of CCL13, CCL19, CCL22, CCR2, COX2, IL4R, CD68, PTX3, TNFα, and VEGFA was observed in patients with T1D compared with CTRL subjects and patients with CD. Immunohistochemical analysis confirmed T1D-specific inflammatory status compared with healthy and CD control tissues, mainly characterized by the increase of the monocyte/macrophage lineage infiltration. The T1D duodenal mucosal microbiome results were different from the other groups, with an increase in Firmicutes and Firmicutes/Bacteroidetes ratio and a reduction in Proteobacteria and Bacteroidetes. The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in the duodenum. CONCLUSIONS This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.
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MESH Headings
- Adolescent
- Adult
- Aged
- Antigens, CD/genetics
- Antigens, CD/immunology
- Antigens, Differentiation, Myelomonocytic/genetics
- Antigens, Differentiation, Myelomonocytic/immunology
- C-Reactive Protein/genetics
- C-Reactive Protein/immunology
- Case-Control Studies
- Celiac Disease/immunology
- Celiac Disease/microbiology
- Chemokine CCL19/genetics
- Chemokine CCL19/immunology
- Chemokine CCL22/genetics
- Chemokine CCL22/immunology
- Child
- Child, Preschool
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/immunology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/microbiology
- Duodenum/immunology
- Duodenum/microbiology
- Female
- Gastrointestinal Microbiome/genetics
- Humans
- Infant
- Interleukin-4 Receptor alpha Subunit/genetics
- Interleukin-4 Receptor alpha Subunit/immunology
- Intestinal Mucosa/immunology
- Intestinal Mucosa/microbiology
- Male
- Middle Aged
- Monocyte Chemoattractant Proteins/genetics
- Monocyte Chemoattractant Proteins/immunology
- RNA, Ribosomal, 16S/genetics
- Real-Time Polymerase Chain Reaction
- Receptors, CCR2/genetics
- Receptors, CCR2/immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Serum Amyloid P-Component/genetics
- Serum Amyloid P-Component/immunology
- Transcriptome
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/immunology
- Young Adult
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Affiliation(s)
- Silvia Pellegrini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Andrea Mario Bolla
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Diego Saita
- Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Roberto Ferrarese
- Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Filippo Canducci
- Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Department of Biotechnology and Life Sciences, University of Insubria, Varese 21100, Italy
| | - Massimo Clementi
- Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- University "Vita-Salute" San Raffaele, Milan 20132, Italy
| | - Francesca Invernizzi
- Pathology Department, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Alberto Mariani
- Gastroenterology and Digestive Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Riccardo Bonfanti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Pediatrics and Neonatal Disease Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Graziano Barera
- Pediatrics and Neonatal Disease Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Pier Alberto Testoni
- Gastroenterology and Digestive Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- University "Vita-Salute" San Raffaele, Milan 20132, Italy
| | - Claudio Doglioni
- Pathology Department, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- University "Vita-Salute" San Raffaele, Milan 20132, Italy
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- University "Vita-Salute" San Raffaele, Milan 20132, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- University "Vita-Salute" San Raffaele, Milan 20132, Italy
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Serena G, Yan S, Camhi S, Patel S, Lima RS, Sapone A, Leonard MM, Mukherjee R, Nath BJ, Lammers KM, Fasano A. Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease. Clin Exp Immunol 2017; 187:490-506. [PMID: 27936497 DOI: 10.1111/cei.12911] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 11/16/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022] Open
Abstract
Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg ) are CD4+ CD25++ forkhead box protein 3 (FoxP3+ ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.
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Affiliation(s)
- G Serena
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - S Yan
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - S Camhi
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - S Patel
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - R S Lima
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - A Sapone
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - M M Leonard
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - R Mukherjee
- Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - B J Nath
- Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - K M Lammers
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA
| | - A Fasano
- Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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9
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Losurdo G, Giorgio F, Piscitelli D, Montenegro L, Covelli C, Fiore MG, Giangaspero A, Iannone A, Principi M, Amoruso A, Barone M, Di Leo A, Ierardi E. May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis? World J Gastroenterol 2016; 22:8017-8025. [PMID: 27672296 PMCID: PMC5028815 DOI: 10.3748/wjg.v22.i35.8017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME). METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni's test. The χ(2) test was used for categorical variables. Pearson's test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS. RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels (6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD88 levels similarly to non gluten-related causes of DL (7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count (15-25 and more than 25/100 enterocytes) strongly correlated with mRNA levels of all tested molecules (P < 0.0001). CONCLUSION Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of tTG and IFNγ mRNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. MyD88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value.
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Pohjanen VM, Koivurova OP, Huhta H, Helminen O, Mäkinen JM, Karhukorpi JM, Joensuu T, Koistinen PO, Valtonen JM, Niemelä SE, Karttunen RA, Karttunen TJ. Toll-Like Receptor 4 Wild Type Homozygozity of Polymorphisms +896 and +1196 Is Associated with High Gastrin Serum Levels and Peptic Ulcer Risk. PLoS One 2015; 10:e0131553. [PMID: 26161647 PMCID: PMC4498789 DOI: 10.1371/journal.pone.0131553] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 06/03/2015] [Indexed: 01/14/2023] Open
Abstract
Toll-like receptor 4 is a part of the innate immune system and recognizes Helicobacter pylori lipopolysaccharide. The goal of this study was to analyze the role of Toll-like receptor 4 polymorphisms +896 (rs4986790) and +1196 (rs4986791) in the pathogenesis of Helicobacter pylori related gastroduodenal diseases in relation to gastric secretion and inflammation. Toll-like receptor 4 polymorphisms, serum gastrin-17 and pepsinogen I and II concentrations were determined, and gastroscopies with histopathological analyses were performed to 216 dyspeptic patients. As genotype controls, 179 controls and 61 gastric cancer patients were studied. In our study, the Toll-like receptor 4 +896 and +1196 polymorphisms were in total linkage disequilibrium. The homozygous wild types displayed higher gastrin-17 serum concentrations than the mutants (p = 0.001) and this effect was independent of Helicobacter pylori. The homozygous wild types also displayed an increased risk for peptic ulcers (OR: 4.390). Toll-like receptor 4 genotypes did not show any association with Helicobacter pylori positivity or the features of gastric inflammation. Toll-like receptor 4 expression was seen in gastrin and somatostatin expressing cells of antral mucosa by immunohistochemistry. Our results suggest a role for Toll-like receptor 4 in gastric acid regulation and that the Toll-like receptor 4 +896 and +1196 wild type homozygozity increases peptic ulcer risk via gastrin secretion.
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Affiliation(s)
- Vesa-Matti Pohjanen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | | | - Heikki Huhta
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Olli Helminen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Johanna M. Mäkinen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jari M. Karhukorpi
- Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Oulu, Finland
- Eastern Finland Laboratory Centre Joint Authority Enterprise (ISLAB), Joensuu, Finland
| | - Tapio Joensuu
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- Department of Internal Medicine, Pietarsaari City Hospital, Pietarsaari, Finland
| | | | | | - Seppo E. Niemelä
- Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
| | - Riitta A. Karttunen
- Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Oulu, Finland
| | - Tuomo J. Karttunen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- * E-mail:
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Abstract
Wheat-related disorders have become a growing area of clinical and scientific interest and can be categorized broadly as: autoimmune-mediated; allergic; and non-autoimmune/non-allergic conditions. Non-celiac gluten sensitivity (NCGS) and non-celiac wheat sensitivity (NCWS) present on this spectrum as disorders associated with adverse gastrointestinal and extra-intestinal manifestations following exposure to gluten and/or other wheat-related constituents. NCGS/NCWS is increasingly considered in patients with unexplained symptoms after the exclusions of celiac disease and wheat allergy. As objective diagnostic data and specific biomarkers are lacking, response to a gluten-free/wheat-free diet can confirm the presence of NCGS/NCWS. An association with irritable bowel syndrome has been detected, and the effects of other food components, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, may contribute. Our organization and synthesis of extant knowledge pertaining to wheat-related disorders may advance current practice and research efforts toward an improved understanding of NCGS/NCWS as an evolving clinical entity.
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Affiliation(s)
- Renée M Marchioni Beery
- Division of Gastroenterology and Hepatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1845, USA
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Pagliari D, Urgesi R, Frosali S, Riccioni ME, Newton EE, Landolfi R, Pandolfi F, Cianci R. The Interaction among Microbiota, Immunity, and Genetic and Dietary Factors Is the Condicio Sine Qua Non Celiac Disease Can Develop. J Immunol Res 2015; 2015:123653. [PMID: 26090475 PMCID: PMC4451297 DOI: 10.1155/2015/123653] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 10/14/2014] [Indexed: 12/24/2022] Open
Abstract
Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.
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Affiliation(s)
- D. Pagliari
- Institute of Internal Medicine, Catholic University, 00168 Rome, Italy
| | - R. Urgesi
- Gastroenterology and Digestive Endoscopy Unit, Belcolle Hospital, 01100 Viterbo, Italy
| | - S. Frosali
- Institute of Internal Medicine, Catholic University, 00168 Rome, Italy
| | - M. E. Riccioni
- Digestive Endoscopy Unit, Catholic University, 00168 Rome, Italy
| | | | - R. Landolfi
- Institute of Internal Medicine, Catholic University, 00168 Rome, Italy
| | - F. Pandolfi
- Institute of Internal Medicine, Catholic University, 00168 Rome, Italy
| | - R. Cianci
- Institute of Internal Medicine, Catholic University, 00168 Rome, Italy
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Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr 2014; 33:39-54. [PMID: 24533607 DOI: 10.1080/07315724.2014.869996] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND A significant percentage of the general population report problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA), because they test negative both for CD-specific serology and histopathology and for immunoglobulin E (IgE)-mediated assays. Most patients report both gastrointestinal and nongastrointestinal symptoms, and all report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS). AIM We attempt to define the current pathogenic, clinical, and diagnostic criteria of this "new" disease, to provide a practical view that might be useful to evaluate, diagnose, and manage NCGS patients. METHODS We reviewed the international literature through PubMed and Medline, using the search terms "wheat (hyper)sensitivity," "wheat allergy," "wheat intolerance," "gluten (hyper)sensitivity," and "gluten intolerance," and we discuss current knowledge about NCGS. RESULTS It has been demonstrated that patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. NCGS diagnosis can be reached only by excluding CD and WA. Recent evidence shows that a personal history of food allergy in infancy, coexistent atopy, positive for immunoglobulin G (IgG) antigliadin antibodies and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. CONCLUSIONS Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroups. Key teaching points: • Most patients report both gastrointestinal and nongastrointestinal symptoms, and all agree that there is an improvement of symptoms on a gluten-free diet. • NCGS diagnosis can be reached only by excluding celiac disease and wheat allergy. • Patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. • A personal history of food allergy in infancy, coexistent atopy, positive IgG antigliadin antibodies (AGA) and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. • Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroup.
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Affiliation(s)
- Pasquale Mansueto
- a Internal Medicine, University Hospital of Palermo , Palermo , ITALY
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Moossavi S. Gliadin is an uncatalogued Toll-like receptor ligand. JOURNAL OF MEDICAL HYPOTHESES AND IDEAS 2014. [DOI: 10.1016/j.jmhi.2013.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Interleukin-21-mediated TLR4 activation in celiac disease. Dig Dis Sci 2013; 58:2425. [PMID: 23828138 DOI: 10.1007/s10620-013-2738-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 05/29/2013] [Indexed: 12/09/2022]
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