Intestine Of Celiac Disease Patients Research Articles

Reduced frequency of circulating regulatory T cells and their related immunosuppressive mediators in treated celiac patients.

Regulatory T cells (Tregs) have an important role in the control of the immune responses. This study aimed to compare the frequency of peripheral blood (PB) CD4+ CD25+ FoxP3+ Treg cells and PB and duodenal expression levels of pro- and anti-inflammatory mediators in treated celiac disease (CD) patients and healthy controls. Duodenal biopsy specimens and PB samples were collected from 60 treated CD patients and 60 controls. Flow cytometry analysis was conducted on peripheral blood mononuclear cell (PBMC) specimens and relative PB and duodenal mRNA expression levels of CD25, forkhead box P3 (Foxp3), interleukin (IL)-10 and granzyme B (GrzB) were evaluated using quantitative real-time PCR. The levels of serum IL-10 and IL-6 were tested with sandwich enzyme-linked immunosorbent assay kits. p values < 0.05 were considered significant. Flow cytometry analysis showed a significant decrease in the number of Tregs in CD patients' PBMC specimens (p = 0.012). CD25 and Foxp3 PB mRNA expressions were also lower in CD patients without reaching the significance level (p > 0.05). IL-10PB mRNA and protein expression did not differ between the groups (p > 0.05), and GrzBPB expression was significantly reduced in CD patients (p = 0.001). In duodenal specimens of CD patients, while significantly increased CD25, Foxp3 mRNA expression (p = 0.01 and 0.001, respectively) and decreased IL-10 mRNA expression (p = 0.02) were observed, GrzB mRNA expression did not differ between groups (p > 0.05). Moreover, a high serum level of IL-6 was observed in CD patients (p = 0.001). Despite following the gluten free diet, there may still be residual inflammation in the intestine of CD patients. Accordingly, finding a therapeutic approach based on strengthening the function of Treg cells in CD might be helpful.

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease.

Celiac disease (CD) is a common intestinal inflammatory disease involving both a genetic background and environmental triggers. The ingestion of gluten, a proteic component of several cereals, represents the main hexogen factor implied in CD onset that involves concomitant innate and adaptive immune responses to gluten. Immunogenicity of some gluten sequences are strongly enhanced as the consequence of the deamidation of specific glutamine residues by type 2 transglutaminase (TG2), a ubiquitous enzyme whose expression is up-regulated in the intestine of CD patients. A short gluten sequence resistant to intestinal proteases, the α-gliadin peptide 31-43, seems to modulate TG2 function in the gut; on the other hand, the enzyme can affect the biological activity of this peptide. In addition, an intense auto-immune response towards TG2 is a hallmark of CD. Auto-antibodies exert a range of biological effects on several cells, effects that in part overlap with those induced by peptide 31-43. In this review, we delineate a scenario in which TG2, anti-TG2 antibodies and peptide 31-43 closely relate to each other, thus synergistically participating in CD starting and progression.

Analysis of IL17A and IL21 Expression in the Small Intestine of Celiac Disease Patients and Correlation with Circulating Thioredoxin Level

Th17 cells and their related cytokines play an important role in the pathogenesis of celiac disease (CD), and thioredoxin (Trx) is an extracellular TG2 activity regulator. This study evaluated Trx serum levels and the expression levels of IL17A, IL21, and Trx genes in biopsies of treated (gluten-free diet) and naïve (untreated) CD patients compared with healthy individuals. Duodenal biopsies were collected from treated CD patients (n = 60), healthy controls (n = 60), and eight newly diagnosed celiac patients. IL17A, IL21, and Trx gene expression was assessed by quantitative polymerase chain reaction (qPCR) and compared with serum Trx levels assessed by enzyme-linked immunosorbent assay (ELISA). Expression levels of the IL21 and Trx genes were not significantly modulated in the CD group compared to the control group, whereas the IL17A gene in CD patients was transcribed at significantly higher levels among the CD group. Serum concentrations of Trx were significantly increased in treated CD patients compared to the control group. We observed that IL17A gene is more highly expressed in duodenal biopsies of CD patients than controls, and that the serum levels of Trx are significantly higher in treated CD patients than controls. Therefore, the expression levels of these genes and gene products, respectively, could potentially be used as diagnostic biomarkers for CD patients, although more studies are needed to unravel the underlying molecular mechanisms.

An undigested gliadin peptide activates innate immunity and proliferative signaling in enterocytes: the role in celiac disease

On ingestion of gliadin, the major protein component of wheat and other cereals, the celiac intestine is characterized by the proliferation of crypt enterocytes with an inversion of the differentiation/proliferation program. Gliadins and A-gliadin peptide P31-43, in particular, act as growth factors for crypt enterocytes in patients with celiac disease (CD). The effects of gliadin on crypt enterocyte proliferation and activation of innate immunity are mediated by epidermal growth factors (EGFs) and innate immunity mediators [interleukin 15 (IL15)]. The aim of this study was to determine the molecular basis of proliferation and innate immune response to gliadin peptides in enterocytes. The CaCo-2 cell line was used to study EGF-, IL15-, and P31-43-induced proliferation. Silencing messenger RNAs and blocking EGF receptor and IL15 antibodies have been used to study proliferation in CaCo-2 cells and intestinal biopsy samples from patients with CD and control subjects. In the CaCo-2 cell model, IL15 and EGF cooperated to induce proliferation in intestinal epithelial cells at both the transcriptional and posttranscriptional levels, and the respective receptors interacted to activate each other's signaling. In addition, the effects of the P31-43 peptide on CaCo-2 cell proliferation and downstream signaling were mediated by cooperation between EGF and IL15. The increased crypt enterocyte proliferation in intestinal biopsy samples from patients with CD was reduced by EGF receptor and IL15 blocking antibodies only when used in combination. EGF receptor/IL15R-α cooperation regulates intestinal epithelial cell proliferation induced by EGF, IL15, and the gliadin peptide P31-43. Increased proliferation of crypt enterocytes in the intestine of CD patients is mediated by EGF/IL15 cooperation.

Celiac disease: how complicated can it get?

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.

Interleukin 18 maintains a long-standing inflammation in coeliac disease patients

Dietary gluten induces an early response in the intestine of coeliac disease patients (CD), within a few hours, and this is driven by high levels of proinflammatory cytokines, including IFNgamma and IL-15, as has been thoroughly shown by gluten stimulation of biopsy explants. Our aim was to identify the immune mediators involved in the long-standing inflammation in untreated CD patients at diagnosis. mRNA and protein levels of TNFalpha, IL-12(p35), IL-12(p40), IL-15, IL-18 and IL-23(p19) were quantified in biopsies from active CD patients, CD patients on a gluten-free diet (GFD), healthy controls, and patients with non-CD inflammation and mild histological changes in the intestine. Biopsies from CD patients on a GFD were also stimulated in vitro with gliadin, and protein expression of IL-15 and IL-18 was analysed. Levels of IL-12 and IL-23 mRNA are nearly absent, and TNFalpha levels remain unchanged among different groups. Both the active and inactive forms of IL-18 protein have been found in all samples from active CD, and protein expression was only localized within the crypts. Levels of IL-15 mRNA remain unchanged, and protein expression, localized within the lamina propria, is found in a small number of samples. In vitro stimulation with gluten induces the expression of IL-15 and IL-18. In active CD, the early response following gluten intake characterized by high IFNgamma levels is driven by IL-18, and probably IL-15, and this alternates with periods of long-standing inflammation with moderate IFNgamma levels, maintained by IL-18 alone.

Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients

Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several genome screens have been successful in identifying susceptibility loci in celiac disease, the only genetic contributors identified so far are the human leukocyte antigen (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of celiac disease is the activation of a T-helper 1 immune response, when the antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4+ T-cells. Recently, new insights into the activation of an innate immune response have also been described. It is generally accepted that the immune response triggers destruction of the mucosa in the small intestine of celiac disease patients. Hence, the activation of a detrimental immune response in the intestine of celiac disease patients appears to be key in the initiation and progression of the disease. This review summarizes the immunologic pathways that have been studied in celiac disease thus far, and will point to new potential candidate genes and pathways involved in the etiopathogenesis of celiac disease, which should lead to novel alternatives for diagnosis and treatment.

Dietary proteins and mechanisms of gastrointestinal diseases: gliadin as a model.

Dietary proteins and mechanisms of gastrointestinal diseases: gliadin as a model.

HLA restriction patterns of gliadin- and astrovirus-specific CD4+ T cells isolated in parallel from the small intestine of celiac disease patients.

Celiac disease is a common HLA-DQ2-associated enteropathy caused by an abnormal T-cell-mediated immune response to ingested wheat gliadin proteins. We have previously isolated in situ activated mucosal T cells from celiac disease patients and demonstrated that these T cells were gliadin specific and predominantly DQ2 restricted. In contrast to this, gliadin-specific T cells isolated from peripheral blood display a variable HLA restriction pattern, thereby indicating that the skewed DQ restriction of T cells resident in the celiac lesions could be dictated by a preference for DQ-mediated antigen presentation in the mucosa of CD patients. To address this, we analyzed the HLA restriction of T cells recognizing astrovirus, a common gastroentetitis virus, isolated from intestinal mucosa of six celiac disease patients. As an internal control, gliadin-specific T cells were isolated and analyzed in parallel. The gliadin-specific mucosal T cells were marked in their DQ2 restriction, whereas the parallel astrovirus-specific T cells were predominantly restricted by DR molecules. Our data indicate that the repertoire of T cells present in celiac lesions is determined by the priming antigen(s) and not by a skewing in the expression of functional HLA class II isotypes in the disease affected small intestinal mucosa.

Cœliac disease 40 years gluten-free

History of coeliac disease. Dicke and the origin of the gluten-free diet.- HLA and coeliac disease, a finnish family study.- Adenovirus 12 and coeliac disease.- Gliadin peptides: their effect on the gut mucosa.- HLA-DR-DP and -DQ antigens in coeliac disease.- A cis- or transassociated DQ heterodimer predisposes to the gluten sensitive enteropathy seen in coeliac disease and dermatitis herpetiformis.- Nonhuman primates as animal models for coeliac disease: approach and feasibility.- T-cell subpopulations in intestinal mucosa.- Persistent increase of intra-epithelial T-cell receptor ? ? cells in coeliac disease.- T-cell subpopulations in coeliac disease longterm follow up with a gluten containing diet.- Intraepithelial T-cells of the TcR?/?+CD8- and V?1+ phenotypes are strikingly increased in coeliac disease.- Intestinalg amma/delta receptor bearing T lymphocytes are increased in coeliac disease and dermatitis herpetiformis.- Detecting gluten and related prolamins in food.- Gluten-free products, the Dutch experience.- The quest for gliadin limits and tolerance.- The incidence of coeliac disease and changes in gluten consumption.- Cath-up growth in 60 children with coeliac disease.- Clinical features of adult coeliac disease in Italy.- Associated diseases in children with coeliac disease.- Coeliac disease and autoimmune enteropathy.- Coeliac disease, malignancy and the effect of gluten free diet.- Dermatitis Herpetiformis: coeliac disease of the skin.- Latent coeliac disease.- Small intestinal biopsy.- High incidence of atypical forms of coeliac disease in a pediatric case study.- Coeliac disease in The Netherlands.- IGA reticulin antibody binding to human jejunum in sera of children with coeliac disease: the possible autoantibody of gluten sensitive enteropathy.- Evidence for a dominant gene mechanism in coeliac disease.- Crypt intraepithelial lymphocytes number is a sensitive index of dietary compliance in teenager coeliacs.- Upper G.I. damages seen at endoscopy in children with coeliac disease.- HLA class II contribution to coeliac disease -a family study-.- Diabetes-related immunologic markers in children coeliac disease.- HLA antigens and phenotypes associated with severe immunoglobulin - a deficiency in coeliac disease paediatric patients.- DR3 and DR7 -negative coeliac disease- a clinically relevant entity?.- Intestinal expression of HLA-DQ alleles associated to coeliac disease.- Is persistent adenovirus 12 (Ad12) infection involved in coeliac disease?.- Negative humoral response to adenovirus 12 in coeliac disease.- Characterization of ? ? TCR in T cell clones from small intestine of coeliac disease patients.- Characterization of intestinal ? ? and ?? T-cell receptor positive cells in coeliac disease.- Intercellular adhesion molecule-1 expression in coeliac disease.- Coeliac disease in Cyprus.- Coeliac disease in saudi children.- The spectrum of gluten intolerance in a defined paediatric population.- The reasons of malnutrition in children with coeliac disease.- Nervous system involvement in paediatric coeliac patients.- Coeliac disease and epilepsy with posterior cerebral calcifications: a causal association.- Genetic and immunological markers in children with dermatitis herpetiformis.- The clinical use of the gliadin antibody test.- Serum antigliadin antibodies during gluten challenge.- IgG-subclass antibodies to food antigens in patients with coeliac disease.- Isolation and characterization of wheat proteins with antibody reactivity against serum of a patient with coeliac disease.- Specific IgA-gliadin antibody as a marker of relapse in coeliac children on gluten challenge.- Gluten and dermatitis herpetiformis clinical observations in 5 active DH patients on an elemental diet.- Serum transglutaminase in the follow-up of coeliac disease.- Methods for measurement of gluten in foodstuffs.- Identification of coeliac-active peptides using a novel in vitro test for cellular immunity.- Unresponsive subtotal villous atrophy, ulcerative jejunitis: treatment with omeprazole.- Acknowledgements.