The autoimmune condition, Celiac Disease (CeD), displays broad clinical symptoms due to gluten exposure. Its genetic association with DQ variants in the human leukocyte antigen (HLA) system has been recognised. Monocyte-derived mature dendritic cells (MoDCs) present gluten peptides through HLA-DQ and co-stimulatory molecules to T lymphocytes, eliciting a cytokine-rich microenvironment. Having access to CeD associated families prevalent in the Czech Republic, this study utilised an in vitro model to investigate their differential monocyte profile. The higher monocyte yields isolated from PBMCs of CeD patients versus control individuals also reflected the greater proportion of dendritic cells derived from these sources following lipopolysaccharide (LPS)/ peptic-tryptic-gliadin (PTG) fragment stimulation. Cell surface markers of CeD monocytes and MoDCs were subsequently profiled. This foremost study identified a novel bio-profile characterised by elevated CD64 and reduced CD33 levels, unique to CD14++ monocytes of CeD patients. Normalisation to LPS stimulation revealed the increased sensitivity of CeD-MoDCs to PTG, as shown by CD86 and HLA-DQ flow cytometric readouts. Enhanced CD86 and HLA-DQ expression in CeD-MoDCs were revealed by confocal microscopy. Analysis highlighted their dominance at the CeD-MoDC membrane in comparison to controls, reflective of superior antigen presentation ability. In conclusion, this investigative study deciphered the monocytes and MoDCs of CeD patients with the identification of a novel bio-profile marker of potential diagnostic value for clinical interpretation. Herein, the characterisation of CD86 and HLA-DQ as activators to stimulants, along with robust membrane assembly reflective of efficient antigen presentation, offers CeD targeted therapeutic avenues worth further exploration.

• Klíčová slova
• CD33, CD64, CD86, MHCDQ, autoimmunity, major histocompatibility complex II, monocyte, monocyte-derived dendritic cells,
• MeSH
• autoimunitní nemoci imunologie   MeSH
• biologické markery metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• celiakie epidemiologie   imunologie   MeSH
• cytotoxické T-lymfocyty imunologie   MeSH
• dendritické buňky imunologie   MeSH
• dospělí MeSH
• gliadin škodlivé účinky   MeSH
• HLA-DQ antigeny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipopolysacharidy MeSH
• mladiství MeSH
• mladý dospělý MeSH
• monocyty metabolismus   MeSH
• náchylnost k nemoci MeSH
• prezentace antigenu imunologie   MeSH
• rodina MeSH
• rodokmen MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• biologické markery MeSH
• CD antigeny MeSH
• gliadin MeSH
• HLA-DQ antigeny MeSH
• lipopolysacharidy MeSH

Immunologically mediated liver diseases belong to the common extraintestinal manifestations of celiac disease. We have reviewed the current literature that addresses the association between celiac disease and liver disorders. We searched relevant articles on MEDLINE/PubMed up to 15 June 2018. The objective of the article is to provide a comprehensive and up-to-date review on the latest hypotheses explaining the pathogenetic relationship between celiac disease and liver injury. Besides the involvement of gut⁻liver axis, tissue transglutaminase antibodies, and impairment of intestinal barrier, we integrate the latest achievements made in elucidation of the role of gut microbiota in celiac disease and liver disorders, that has not yet been sufficiently discussed in the literature in this context. The further objective is to provide a complete clinical overview on the types of liver diseases frequently found in celiac disease. In conclusion, the review highlights the clinical implication, recommend a rational approach for managing elevated transaminases in celiac patients, and underscore the importance of screening for celiac disease in patients with associated liver disease.

• Klíčová slova
• autoimmunity, celiac hepatitis, gut–liver axis, intestinal barrier, liver immunity, non-alcoholic fatty liver disease, tolerance,
• MeSH
• autoimunita * MeSH
• autoimunitní hepatitida dietoterapie   epidemiologie   imunologie   mikrobiologie   MeSH
• autoprotilátky imunologie   MeSH
• bezlepková dieta MeSH
• celiakie dietoterapie   epidemiologie   imunologie   mikrobiologie   MeSH
• dysbióza MeSH
• játra imunologie   mikrobiologie   MeSH
• lidé MeSH
• nealkoholová steatóza jater dietoterapie   epidemiologie   imunologie   mikrobiologie   MeSH
• nedostatek vitaminu D epidemiologie   imunologie   MeSH
• permeabilita MeSH
• prognóza MeSH
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteiny vázající GTP imunologie   MeSH
• rizikové faktory MeSH
• střeva imunologie   MeSH
• střevní mikroflóra MeSH
• střevní sliznice metabolismus   MeSH
• transglutaminasy imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• autoprotilátky MeSH
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteiny vázající GTP MeSH
• transglutaminasy MeSH

Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL-1 cytokine family members IL-1β and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1β and IL-1α and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1β production in celiac PBMC show that PDWGF-induced de novo pro-IL-1β synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL-1β. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1β release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis-associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3(-/-) and ASC(-/-) knockout mice. Moreover, treatment of human PBMC as well as MyD88(-/-) and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)(-/-) BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-κB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1β in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-κB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD.

• MeSH
• adaptorové proteiny vezikulární transportní genetika   imunologie   MeSH
• celiakie MeSH
• dospělí MeSH
• gliadin chemie   imunologie   MeSH
• inflamasomy účinky léků   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• leukocyty mononukleární účinky léků   imunologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   imunologie   MeSH
• myeloidní diferenciační faktor 88 genetika   imunologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• pepsin A MeSH
• peptidové fragmenty farmakologie   MeSH
• primární buněčná kultura MeSH
• protein NLRP3 MeSH
• regulace genové exprese účinky léků   imunologie   MeSH
• signální transdukce účinky léků   genetika   imunologie   MeSH
• toll-like receptor 2 genetika   imunologie   MeSH
• toll-like receptor 4 genetika   imunologie   MeSH
• transportní proteiny genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny vezikulární transportní MeSH
• gliadin MeSH
• inflamasomy MeSH
• interleukin-1beta MeSH
• mitogenem aktivované proteinkinasy MeSH
• MYD88 protein, human MeSH Prohlížeč
• myeloidní diferenciační faktor 88 MeSH
• NLRP3 protein, human MeSH Prohlížeč
• pepsin A MeSH
• peptidové fragmenty MeSH
• protein NLRP3 MeSH
• TICAM1 protein, human MeSH Prohlížeč
• TLR2 protein, human MeSH Prohlížeč
• TLR4 protein, human MeSH Prohlížeč
• toll-like receptor 2 MeSH
• toll-like receptor 4 MeSH
• transportní proteiny MeSH

In genetically predisposed individuals, ingestion of wheat gliadin provokes a T-cell-mediated enteropathy, celiac disease. Gliadin fragments were previously reported to induce phenotypic maturation and Th1 cytokine production by human dendritic cells (DCs) and to boost their capacity to stimulate allogeneic T cells. Here, we monitor the effects of gliadin on migratory capacities of DCs. Using transwell assays, we show that gliadin peptic digest stimulates migration of human DCs and their chemotactic responsiveness to the lymph node-homing chemokines CCL19 and CCL21. The gliadin-induced migration is accompanied by extensive alterations of the cytoskeletal organization, with dissolution of adhesion structures, podosomes, as well as up-regulation of the CC chemokine receptor (CCR) 7 on cell surface and induction of cyclooxygenase (COX)-2 enzyme that mediates prostaglandin E2 (PGE₂) production. Blocking experiments confirmed that gliadin-induced migration is independent of the TLR4 signalling. Moreover, we showed that the α-gliadin-derived 31-43 peptide is an active migration-inducing component of the digest. The migration promoted by gliadin fragments or the 31-43 peptide required activation of p38 mitogen-activated protein kinase (MAPK). As revealed using p38 MAPK inhibitor SB203580, this was responsible for DC cytoskeletal transition, CCR7 up-regulation and PGE₂ production in particular. Taken together, this study provides a new insight into pathogenic features of gliadin fragments by demonstrating their ability to promote DC migration, which is a prerequisite for efficient priming of naive T cells, contributing to celiac disease pathology.

• MeSH
• aktivace enzymů účinky léků   MeSH
• biologické modely MeSH
• chemokin CCL19 farmakologie   MeSH
• chemokin CCL21 farmakologie   MeSH
• chemotaxe účinky léků   MeSH
• cyklooxygenasa 2 metabolismus   MeSH
• cytoskelet účinky léků   metabolismus   MeSH
• dendritické buňky cytologie   účinky léků   enzymologie   MeSH
• dinoproston biosyntéza   MeSH
• gliadin farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém účinky léků   MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• peptidové fragmenty farmakologie   MeSH
• receptory CCR7 metabolismus   MeSH
• upregulace účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CCR7 protein, human MeSH Prohlížeč
• chemokin CCL19 MeSH
• chemokin CCL21 MeSH
• cyklooxygenasa 2 MeSH
• dinoproston MeSH
• gliadin MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• peptidové fragmenty MeSH
• PTGS2 protein, human MeSH Prohlížeč
• receptory CCR7 MeSH

BACKGROUND AND AIMS: Celiac disease (CD) is a chronic inflammatory disorder of the small intestine that is induced by dietary wheat gluten proteins (gliadins) in genetically predisposed individuals. The overgrowth of potentially pathogenic bacteria and infections has been suggested to contribute to CD pathogenesis. We aimed to study the effects of gliadin and various intestinal bacterial strains on mucosal barrier integrity, gliadin translocation, and cytokine production. METHODOLOGY/PRINCIPAL FINDINGS: Changes in gut mucosa were assessed in the intestinal loops of inbred Wistar-AVN rats that were reared under germ-free conditions in the presence of various intestinal bacteria (enterobacteria and bifidobacteria isolated from CD patients and healthy children, respectively) and CD-triggering agents (gliadin and IFN-γ) by histology, scanning electron microscopy, immunofluorescence, and a rat cytokine antibody array. Adhesion of the bacterial strains to the IEC-6 rat cell line was evaluated in vitro. Gliadin fragments alone or together with the proinflammatory cytokine interferon (IFN)-γ significantly decreased the number of goblet cells in the small intestine; this effect was more pronounced in the presence of Escherichia coli CBL2 and Shigella CBD8. Shigella CBD8 and IFN-γ induced the highest mucin secretion and greatest impairment in tight junctions and, consequently, translocation of gliadin fragments into the lamina propria. Shigella CBD8 and E. coli CBL2 strongly adhered to IEC-6 epithelial cells. The number of goblet cells in small intestine increased by the simultaneous incubation of Bifidobacterium bifidum IATA-ES2 with gliadin, IFN-γ and enterobacteria. B. bifidum IATA-ES2 also enhanced the production of chemotactic factors and inhibitors of metalloproteinases, which can contribute to gut mucosal protection. CONCLUSIONS: Our results suggest that the composition of the intestinal microbiota affects the permeability of the intestinal mucosa and, consequently, could be involved in the early stages of CD pathogenesis.

• MeSH
• Bacteria patogenita   MeSH
• bakteriální toxiny farmakologie   MeSH
• Bifidobacterium patogenita   MeSH
• celiakie etiologie   MeSH
• cytokiny biosyntéza   MeSH
• Enterobacteriaceae patogenita   MeSH
• gliadin farmakokinetika   farmakologie   MeSH
• gnotobiologické modely MeSH
• interakce hostitele a patogenu účinky léků   MeSH
• interferon gama farmakologie   MeSH
• krysa rodu Rattus MeSH
• permeabilita MeSH
• pohárkové buňky patologie   MeSH
• střeva mikrobiologie   patologie   MeSH
• střevní sliznice účinky léků   metabolismus   mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bakteriální toxiny MeSH
• cytokiny MeSH
• gliadin MeSH
• interferon gama MeSH