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Intracellular Localization of Microbial Transglutaminase and Its Influence on the Transport of Gliadin in Enterocytes.
Stricker, S, de Laffolie, J, Rudloff, S, Komorowski, L, Zimmer, KP
Journal of pediatric gastroenterology and nutrition. 2019;(3):e43-e50
Abstract
OBJECTIVE Celiac disease (CD) is a systemic inflammatory disorder, characterized by the destruction of duodenal epithelium. The CD8 T cells involved are associated with cross-presentation. In addition to other factors, the rising prevalence of CD might be induced by microbial transglutaminase (mTG) an enzyme frequently used in food production that shares enzymatic and antigenic properties of tissue transglutaminase (TG2), the autoantigen in CD. We hypothesized that mTG and gliadin are transported into the endoplasmic reticulum (ER), indicating cross-presentation of both antigens. METHODS Apical incubation of duodenal biopsies from CD and control patients was performed with mTG alone or with mTG and simultaneously with Frazer's fraction. Evaluation was carried out by immunofluorescence and electron microscopy. RESULTS Approximately 6% to 9% of the intracellular mTG and gliadin were transported to the ER of enterocytes. RACE cells (Rapid uptake of Antigen into the Cytosol of Enterocytes) displayed an enhanced antigen uptake into a dilated ER. mTG strongly localized at the basolateral membrane and the lamina propria. CONCLUSIONS mTG and gliadin are transported to the ER of enterocytes and to a greater extent to the ER of RACE cells, suggesting cross-presentation of exogenous antigens. The strong localization of mTG at the basolateral membrane and the lamina propria may also indicate a potential antigenic interaction with cells of the immune system. Since mTG may not only been taken up with food stuffs but could also be released by bacteria within the intestinal microbiota, further investigations are needed regarding the role of mTG in CD pathogenesis.
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Celiac Disease: Updates on Pathology and Differential Diagnosis.
Dai, Y, Zhang, Q, Olofson, AM, Jhala, N, Liu, X
Advances in anatomic pathology. 2019;(5):292-312
Abstract
Celiac disease is a gluten-triggered immune-mediated disorder, characterized by inflammation of the enteric mucosa following lymphocytic infiltration and eventually resulting in villous blunting. There have been many developments in refining diagnostic laboratory tests for celiac disease in the last decade. Biopsy-sparing diagnostic guidelines have been proposed and validated in a few recent prospective studies. However, despite these developments, histologic evaluation of duodenal mucosa remains one of the most essential diagnostic tools as it helps in the diagnosis of celiac disease in individuals who do not fulfill the biopsy-sparing diagnostic criteria and in those not responding to a gluten-free diet. Histologic evaluation also allows for the assessment of mucosal recovery after treatment and in the identification of concurrent intestinal diseases. Therefore, pathologists should be familiar with the histologic spectrum of celiac disease and need to be aware of other disorders with similar symptoms and histopathology that may mimic celiac disease. This review aims to provide pathologists with updates on celiac laboratory testing, biopsy-sparing diagnostic criteria, histopathology, complications, and differential diagnoses of celiac disease.
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Case report on pathogenetic link between gluten and IgA nephropathy.
Costa, S, Currò, G, Pellegrino, S, Lucanto, MC, Tuccari, G, Ieni, A, Visalli, G, Magazzù, G, Santoro, D
BMC gastroenterology. 2018;(1):64
Abstract
BACKGROUND A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time. CASE PRESENTATION A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology. CONCLUSIONS Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.
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What a practitioner needs to know about celiac disease?
Garg, K, Gupta, RK
Indian journal of pediatrics. 2015;(2):145-51
Abstract
Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals and is characterized by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes and enteropathy. CD is triggered by wheat gluten and related prolamines in barley and rye. Worldwide, the disease affects approximately 1 % of the general population. Clinical features of CD vary considerably. Intestinal symptoms are more common in young children. In older children extra intestinal manifestations affecting almost all organs are seen. IgA tTG antibody, upper GI endoscopy with histological analysis of multiple biopsies of the duodenum and in selected cases HLA DQ2 and DQ8 positivity and endomysial antibodies (EMA) are needed for diagnosis. Currently, the only treatment for CD is a life-long gluten-free diet (GFD). Strict avoidance of wheat, rye, barley and their derivatives will result in intestinal healing and relief of symptoms for the majority of individuals with CD. The GFD is simple in principle, however, completely eliminating all foods and ingredients containing wheat, rye, barley, and most commercial oats can be very challenging. Newly diagnosed CD children should undergo testing and treatment for micronutrient deficiencies specially iron, folic acid, vitamin D, and vitamin B12. Long-term monitoring and follow up of patients with CD is necessary.
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Differential NF-kappaB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance.
van Baarlen, P, Troost, FJ, van Hemert, S, van der Meer, C, de Vos, WM, de Groot, PJ, Hooiveld, GJ, Brummer, RJ, Kleerebezem, M
Proceedings of the National Academy of Sciences of the United States of America. 2009;(7):2371-6
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Abstract
How do we acquire immune tolerance against food microorganisms and commensal bacteria that constitute the intestinal microbiota? We investigated this by stimulating the immune system of adults with commensal Lactobacillus plantarum bacteria. We studied the in vivo human responses to L. plantarum in a randomized double-blind placebo-controlled cross-over study. Healthy adults ingested preparations of living and heat-killed L. plantarum bacteria. Biopsies were taken from the intestinal duodenal mucosa and altered expression profiles were analyzed using whole-genome microarrays and by biological pathway reconstructions. Expression profiles of human mucosa displayed striking differences in modulation of NF-kappaB-dependent pathways, notably after consumption of living L. plantarum bacteria in different growth phases. Our in vivo study identified mucosal gene expression patterns and cellular pathways that correlated with the establishment of immune tolerance in healthy adults.
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Nuclear factor kappa B is activated in small intestinal mucosa of celiac patients.
Maiuri, MC, De Stefano, D, Mele, G, Fecarotta, S, Greco, L, Troncone, R, Carnuccio, R
Journal of molecular medicine (Berlin, Germany). 2003;(6):373-9
Abstract
NF-kappa B regulates inflammatory and immune response by increasing the expression of specific genes. In celiac disease proinflammatory cytokines, adhesion molecules, and enzymes whose gene expression is known to be regulated by NF-kappa B are involved. This study investigated the activation of NF-kappa B in inflamed mucosa from patients with untreated celiac disease. Biopsy specimens from control, untreated, and treated patients were subjected to molecular biology analysis. NF-kappa B activation was evaluated by electrophoretic mobility shift assay. NF-kappa B related subunit protein level, and inducible nitric oxide synthase and cyclo-oxygenase 2 protein expression was analyzed by western blot. Both NF-kappa B/DNA binding activity and p50/p65 nuclear levels were higher in biopsy specimens from untreated patients than in those from treated patients and controls. The degradation of I kappa B beta in the cytosol and the reappearance in the nucleus indicated a persistent NF-kappa B activation in celiac disease. NF-kappa B activity was maintained in cultured biopsy specimens up to 6 h and decreased at 24 h, and then the addition of peptic-tryptic digest of gliadin caused the recovery of NF-kappa B activity at 6 h. NF-kappa B/DNA binding activity was correlated with inducible nitric oxide synthase and cyclo-oxygenase-2 protein expression. These results show for the first time that NF-kappa B is activated in the inflamed mucosa of celiac patients and suggest that it may represent a molecular target for the modulation of inflammatory response in celiac disease.
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Do you still need a biopsy to diagnose celiac disease?
Guandalini, S, Gupta, P
Current gastroenterology reports. 2001;(5):385-91
Abstract
Celiac disease is a common and permanent condition caused by an abnormal immune response to ingested gluten in genetically susceptible individuals. Its proper diagnosis is very important even in patients presenting with mild symptoms because severe and debilitating complications may occur in celiac patients not following a strict gluten-free diet. In the past several years, important progress has been made not only in our understanding of the pathogenesis of this condition but also in the availability of tools to screen it. Antigliadin antibodies, once largely used for this purpose, have been basically replaced by the more costly but far more accurate antiendomysium antibodies. More recently, the enzyme-linked immunosorbent assay (ELISA), which measures the antibodies directed against the autoantigen responsible for the disease (tissue transglutaminase), has also been developed and tested as a screening tool. Currently, however, the poor positive predictive value of this test does not allow practitioners to diagnose celiac disease without the duodenal biopsy showing the typical morphologic changes.