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Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 May 2021) | Viewed by 29444

Special Issue Editors


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Guest Editor
Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy
Interests: pediatrics; gastroenterology; chronic inflammation; celiac disease
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Guest Editor
Department of Translational Medical Science, University of Naples, Federico II, 80131 Naples, Italy
Interests: pediatrics; gastroenterology; chronic inflammation; celiac disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ingested food can cause tissue inflammation through different mechanisms. Nutrient surplus, for example,  can trigger intracellular stress signals that potentiate pro-inflammatory signaling. In the intestine and particularly in the enterocytes, nutrients are modulators of various cellular functions and can be involved in tissue immune response and inflammation. An example of an intestinal inflammatory and remodeling response of the intestine to food is the small intestinal lesion in Celiac Disease, induced by gluten—an alimentary protein present in wheat and other cereals.

Celiac Disease (CD) is a frequent disease due to a combination of environmental factors and genetic predisposition. Most of the study on the mechanisms of the disease have focused on the T-cell mediated response to gliadin and little has been investigated on the reason why this response happens only in CD subjects. In this special number we would like to encourage papers that focus both on the the peculiar organoleptic characteristic of gliadin, and wheat proteins in general, and on the costitutive alterations of the CD cells that render them more sensitive to inflammatory agents including viruses, gliadin itself and more in general Western Diet and life stiles. 

We will encourage papers (or reviews) focused on:

  • Gliadin and other wheat proteins: digestibility, permanence in biological fluids, structure, mechanisms of entrance in the cells and also biological activity.
  • Differences between normal and celiacs at any level, from cell structure to biological pathway. Biomarkers of CD.
  • Pro-inflammarory agents that can cooperate or potentiate the gliadin effects on cells, including viruses, diet and other environmental factor
  • Models of CD

We hope that the combination of review and original articles selected for this special number could help to deepen the understanding of CD.

Prof. Dr. Maria Vittoria Barone
Prof. Dr. Salvatore Auricchio
Guest Editors

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Published Papers (7 papers)

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Editorial

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3 pages, 165 KiB  
Editorial
Pro-Inflammatory Nutrient: Focus on Gliadin and Celiac Disease
by Maria Vittoria Barone and Auricchio Salvatore
Int. J. Mol. Sci. 2022, 23(10), 5577; https://doi.org/10.3390/ijms23105577 - 17 May 2022
Cited by 2 | Viewed by 1212
Abstract
Ingested food can cause tissue inflammation through different mechanisms [...] Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)

Research

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16 pages, 2747 KiB  
Article
Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement
by Valentina Discepolo, Giuliana Lania, Maria Leonarda Gertrude Ten Eikelder, Merlin Nanayakkara, Leandra Sepe, Rossella Tufano, Riccardo Troncone, Salvatore Auricchio, Renata Auricchio, Giovanni Paolella and Maria Vittoria Barone
Int. J. Mol. Sci. 2021, 22(5), 2708; https://doi.org/10.3390/ijms22052708 - 8 Mar 2021
Cited by 7 | Viewed by 2424
Abstract
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein [...] Read more.
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls’ DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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21 pages, 3425 KiB  
Article
Pro-Inflammatory Effect of Gliadins and Glutenins Extracted from Different Wheat Cultivars on an In Vitro 3D Intestinal Epithelium Model
by Francesca Truzzi, Camilla Tibaldi, Anne Whittaker, Silvia Dilloo, Enzo Spisni and Giovanni Dinelli
Int. J. Mol. Sci. 2021, 22(1), 172; https://doi.org/10.3390/ijms22010172 - 26 Dec 2020
Cited by 3 | Viewed by 3050
Abstract
There is a need to assess the relationship between improved rheological properties and the immunogenic potential of wheat proteins. The present study aimed to investigate the in vitro effects of total protein extracts from three modern and two landrace Triticum aestivum commercial flour [...] Read more.
There is a need to assess the relationship between improved rheological properties and the immunogenic potential of wheat proteins. The present study aimed to investigate the in vitro effects of total protein extracts from three modern and two landrace Triticum aestivum commercial flour mixes, with significant differences in gluten strength (GS), on cell lines. Cytotoxicity and innate immune responses induced by wheat proteins were investigated using Caco-2 monocultures, two dimensional (2D) Caco-2/U937 co-cultures, and three dimensional (3D) co-cultures simulating the intestinal mucosa with Caco-2 epithelial cells situated above an extra-cellular matrix containing U937 monocytes and L929 fibroblasts. Modern wheat proteins, with increased GS, significantly reduced Caco-2 cell proliferation and vitality in monoculture and 2D co-cultures than landrace proteins. Modern wheat proteins also augmented Caco-2 monolayer disruption and tight junction protein, occludin, redistribution in 3D co-cultures. Release of interleukin-8 into the cell medium and increased U937 monocyte migration in both 2D and 3D co-cultures were similarly apparent. Immuno-activation of migrating U937 cells was evidenced from cluster of differentiation 14 (CD14) staining and CD11b-related differentiation into macrophages. The modern wheat proteins, with gluten polymorphism relatedness and increased GS, were shown to be more cytotoxic and immunogenic than the landrace wheat proteins. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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12 pages, 3286 KiB  
Article
Structural Perspective of Gliadin Peptides Active in Celiac Disease
by Lucia Falcigno, Luisa Calvanese, Mariangela Conte, Merlin Nanayakkara, Maria Vittoria Barone and Gabriella D’Auria
Int. J. Mol. Sci. 2020, 21(23), 9301; https://doi.org/10.3390/ijms21239301 - 6 Dec 2020
Cited by 10 | Viewed by 2710
Abstract
Gluten fragments released in gut of celiac individuals activate the innate or adaptive immune systems. The molecular mechanisms associated with the adaptive response involve a series of immunodominant gluten peptides which are mainly recognized by human leucocyte antigen (HLA)-DQ2.5 and HLA-DQ8. Other peptides, [...] Read more.
Gluten fragments released in gut of celiac individuals activate the innate or adaptive immune systems. The molecular mechanisms associated with the adaptive response involve a series of immunodominant gluten peptides which are mainly recognized by human leucocyte antigen (HLA)-DQ2.5 and HLA-DQ8. Other peptides, such as A-gliadin P31–43, are not recognized by HLA and trigger innate responses by several routes not yet well detailed. Among the gluten fragments known to be active in Celiac disease, here we focus on the properties of all gluten peptides with known tri-dimensional structure either those locked into HLA-DQ complexes whose crystals were X-ray analyzed or characterized in solution as free forms. The aim of this work was to find the structural reasons why some gluten peptides prompt the adaptive immune systems while others do not, by apparently involving just the innate immune routes. We propose that P31–43 is a non-adaptive prompter because it is not a good ligand for HLA-DQ. Even sharing a similar ability to adopt polyproline II structure with the adaptive ones, the way in which the proline residues are located along the sequence disfavors a productive P31–43-HLA-DQ binding. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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Review

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21 pages, 2920 KiB  
Review
Programmed Cell Death in the Small Intestine: Implications for the Pathogenesis of Celiac Disease
by Federico Perez, Carolina Nayme Ruera, Emanuel Miculan, Paula Carasi and Fernando Gabriel Chirdo
Int. J. Mol. Sci. 2021, 22(14), 7426; https://doi.org/10.3390/ijms22147426 - 10 Jul 2021
Cited by 13 | Viewed by 4550
Abstract
The small intestine has a high rate of cell turnover under homeostatic conditions, and this increases further in response to infection or damage. Epithelial cells mostly die by apoptosis, but recent studies indicate that this may also involve pro-inflammatory pathways of programmed cell [...] Read more.
The small intestine has a high rate of cell turnover under homeostatic conditions, and this increases further in response to infection or damage. Epithelial cells mostly die by apoptosis, but recent studies indicate that this may also involve pro-inflammatory pathways of programmed cell death, such as pyroptosis and necroptosis. Celiac disease (CD), the most prevalent immune-based enteropathy, is caused by loss of oral tolerance to peptides derived from wheat, rye, and barley in genetically predisposed individuals. Although cytotoxic cells and gluten-specific CD4+ Th1 cells are the central players in the pathology, inflammatory pathways induced by cell death may participate in driving and sustaining the disease through the release of alarmins. In this review, we summarize the recent literature addressing the role of programmed cell death pathways in the small intestine, describing how these mechanisms may contribute to CD and discussing their potential implications. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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8 pages, 1299 KiB  
Review
A Cumulative Effect of Food and Viruses to Trigger Celiac Disease (CD): A Commentary on the Recent Literature
by Maria Vittoria Barone and Salvatore Auricchio
Int. J. Mol. Sci. 2021, 22(4), 2027; https://doi.org/10.3390/ijms22042027 - 18 Feb 2021
Cited by 9 | Viewed by 3530
Abstract
Celiac disease (CD) is a type of inflammatory chronic disease caused by nutrients such as gliadin that induce a TC (T cell)-mediated response in a partially known genetical background in an environment predisposed to inflammation, including viruses and food. Various experimental and clinical [...] Read more.
Celiac disease (CD) is a type of inflammatory chronic disease caused by nutrients such as gliadin that induce a TC (T cell)-mediated response in a partially known genetical background in an environment predisposed to inflammation, including viruses and food. Various experimental and clinical observations suggest that multiple agents such as viruses and bacteria have some common, inflammatory pathways predisposing individuals to chronic inflammatory diseases including celiac disease (CD). More recently, a Western diet and lifestyle have been linked to tissue inflammation and increase in chronic inflammatory diseases. In CD, the gliadin protein itself has been shown to be able to induce inflammation. A cooperation between viruses and gliadin is present in vitro and in vivo with common mechanisms to induce inflammation. Nutrients could have also a protective effect on CD, and in fact the anti-inflammatory Mediterranean diet has a protective effect on the development of CD in children. The possible impact of these observations on clinical practice is discussed. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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32 pages, 1384 KiB  
Review
Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols
by Charlene B. Van Buiten and Ryan J. Elias
Int. J. Mol. Sci. 2021, 22(2), 595; https://doi.org/10.3390/ijms22020595 - 8 Jan 2021
Cited by 8 | Viewed by 11071
Abstract
Celiac disease is an autoimmune disorder characterized by a heightened immune response to gluten proteins in the diet, leading to gastrointestinal symptoms and mucosal damage localized to the small intestine. Despite its prevalence, the only treatment currently available for celiac disease is complete [...] Read more.
Celiac disease is an autoimmune disorder characterized by a heightened immune response to gluten proteins in the diet, leading to gastrointestinal symptoms and mucosal damage localized to the small intestine. Despite its prevalence, the only treatment currently available for celiac disease is complete avoidance of gluten proteins in the diet. Ongoing clinical trials have focused on targeting the immune response or gluten proteins through methods such as immunosuppression, enhanced protein degradation and protein sequestration. Recent studies suggest that polyphenols may elicit protective effects within the celiac disease milieu by disrupting the enzymatic hydrolysis of gluten proteins, sequestering gluten proteins from recognition by critical receptors in pathogenesis and exerting anti-inflammatory effects on the system as a whole. This review highlights mechanisms by which polyphenols can protect against celiac disease, takes a critical look at recent works and outlines future applications for this potential treatment method. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease)
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