Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.
- MeSH
- ameloblasty metabolismus MeSH
- amelogenesis imperfecta * komplikace imunologie MeSH
- antigeny imunologie metabolismus MeSH
- autoimunitní polyglandulární syndromy * komplikace imunologie MeSH
- autoprotilátky * imunologie MeSH
- celiakie * komplikace imunologie MeSH
- imunoglobulin A imunologie MeSH
- lidé MeSH
- protein AIRE nedostatek MeSH
- proteiny imunologie metabolismus MeSH
- střeva imunologie metabolismus MeSH
- zubní sklovina imunologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AIRE protein, human MeSH Prohlížeč
- antigeny MeSH
- autoprotilátky * MeSH
- imunoglobulin A MeSH
- protein AIRE MeSH
- proteiny MeSH
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
INTRODUCTION: To test whether parechovirus and anellovirus, frequent enteric viruses, were associated with subsequent celiac disease (CD). We hypothesized that children who later developed CD would have increased frequency of parechovirus infections before transglutaminase 2 (TG2) antibody development. Anellovirus testing was exploratory, as a potential marker of immune status. METHODS: Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk of CD (carrying the human leukocyte antigen genotype DR4-DQ8/DR3-DQ2, recruited throughout Norway during 2001-2007). We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually, to determine when TG2 antibodies developed. Of 220 genetically at-risk children tested, 25 were diagnosed with CD (cases; ESPGHAN 2012 criteria) and matched for follow-up time, birthdate, and county of residence with 2 randomly selected children free from CD (controls) from the cohort. Viruses were quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time polymerase chain reaction methods. RESULTS: Parechovirus was detected in 222 of 2,005 stool samples (11.1%) and was more frequent in samples from cases before developing TG2 antibodies (adjusted odds ratio 1.67, 95% confidence interval 1.14-2.45, P = 0.01). The odds ratio was higher when a sample was positive for both parechovirus and enterovirus (adjusted odds ratio 4.73, 95% confidence interval 1.26-17.67, P = 0.02). Anellovirus was detected in 1,540 of 1,829 samples (84.2%), but did not differ significantly between case and control subjects. DISCUSSION: Early-life parechovirus infections were associated with development of CD in genetically at-risk children.
- MeSH
- autoimunita * MeSH
- autoprotilátky krev MeSH
- celiakie diagnóza imunologie virologie MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- následné studie MeSH
- Parechovirus imunologie MeSH
- pikornavirové infekce diagnóza imunologie virologie MeSH
- předškolní dítě MeSH
- protilátky virové imunologie MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- věkové faktory MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- autoprotilátky MeSH
- protilátky virové MeSH
A therapeutic gluten-free diet often has nutritional limitations. Nutritional qualities such as high protein content, the presence of biologically active and beneficial substances (fiber, beta-glucans, polyunsaturated fatty acids, essential amino acids, antioxidants, vitamins, and minerals), and tolerance by the majority of celiac patients make oat popular for use in gluten-free diet. The health risk of long-time consumption of oat by celiac patients is a matter of debate. The introduction of oat into the diet is only recommended for celiac patients in remission. Furthermore, not every variety of oat is also appropriate for a gluten-free diet. The risk of sensitization and an adverse immunologically mediated reaction is a real threat in some celiac patients. Several unsolved issues still exist which include the following: (1) determination of the susceptibility markers for the subgroup of celiac patients who are at risk because they do not tolerate dietary oat, (2) identification of suitable varieties of oat and estimating the safe dose of oat for the diet, and (3) optimization of methods for detecting the gliadin contamination in raw oat used in a gluten-free diet.
- Klíčová slova
- amylase/trypsin inhibitors, celiac disease, gluten-free diet, gluten-free oat, oat,
- MeSH
- bezlepková dieta * škodlivé účinky MeSH
- celiakie diagnóza dietoterapie imunologie MeSH
- gliadin škodlivé účinky imunologie MeSH
- hodnocení rizik MeSH
- jedlá semena * škodlivé účinky klasifikace imunologie MeSH
- klinické rozhodování MeSH
- kontaminace potravin MeSH
- lidé MeSH
- nutriční hodnota MeSH
- oves * škodlivé účinky klasifikace imunologie MeSH
- výběr pacientů MeSH
- výživové doporučené dávky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- gliadin MeSH
Celiac disease is a very common autoimmune disorder caused by the ingestion of dietary gluten products in genetically susceptible persons. Its global prevalence is estimated around 1 %. However, the most cases are not diagnosed. Clinical presentation is widely variable with the involvement of various human systems. Besides a clinical picture (that is often non characteristic), the diagnosis is based on positivity of serological testing (tissue transglutaminase autoantibodies) and histological evaluation of small intestinal mucosa. The article presents a rational diagnostic approach to celiac disease. Key words: celiac disease - Marsh classification - tissue transglutaminase autoantibodies - villous atrophy.
- Klíčová slova
- celiac disease - Marsh classification - tissue transglutaminase autoantibodies - villous atrophy,
- MeSH
- autoprotilátky MeSH
- celiakie * diagnóza imunologie MeSH
- duodenum MeSH
- gluteny MeSH
- lidé MeSH
- střevní sliznice MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- autoprotilátky MeSH
- gluteny MeSH
The alcohol-soluble fraction of wheat gluten (gliadins) induces in genetically susceptible individuals immunologically mediated celiac disease (CLD). However, gliadins and related cereal proteins are not unique foodstuff targets of CLD patients´ immune system. Non-gluten wheat alpha-amylase inhibitor 0.19 (AAI 0.19) has been found to be capable of activating human monocyte-derived dendritic cells and inducing pro-inflammatory status in intestinal mucosa of patients with celiac disease (CLD). The possible contribution of this reactivity in incomplete remission of CLD patients on a gluten-free diet (GFD) is matter of contention. In an attempt to characterize the antigenicity of AAI 0.19 in patients with active CLD, patients on a GFD and healthy controls we developed ELISA employing wheat recombinant AAI 0.19. Using this test we revealed a significant (P<0.001) elevation of IgA anti-AAI 0.19 antibodies (Ab) in patients with active CLD (12 out of 30 patients were seropositive) but also in CLD patients on a GFD (15/46), in contrast to healthy controls (2/59). Anti-AAI 0.19 IgG Ab levels were increased (P<0.001) only in patients with active CLD (14/30) in contrast to the controls. Interestingly, the levels of anti-AAI 0.19 IgG Ab were decreased in CLD patients on a GFD (P<0.001, 1/46) compared to the controls (1/59). Notably, 20 out of 30 patients with active CLD were positive either for IgA or for IgG anti-AAI 0.19 Ab. Thus, the majority of CLD patients developed a robust IgA and IgG Ab response against AAI 0.19. These findings may contribute to the broadening of the knowledge about CLD pathogenesis.
- MeSH
- celiakie krev diagnóza imunologie MeSH
- dospělí MeSH
- imunoglobulin A krev imunologie MeSH
- imunoglobulin G krev imunologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- protilátky anti-idiotypické krev imunologie MeSH
- rostlinné proteiny * imunologie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- imunoglobulin A MeSH
- imunoglobulin G MeSH
- protilátky anti-idiotypické MeSH
- rostlinné proteiny * MeSH
- WDAI-3 protein, Triticum aestivum MeSH Prohlížeč
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
BACKGROUND & AIMS: The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. METHODS: We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. RESULTS: Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00). CONCLUSIONS: Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.
- Klíčová slova
- Autoimmunity, ESPGHAN, Nonbiopsy Approach, ProCeDE Study,
- MeSH
- autoprotilátky krev MeSH
- biologické markery krev MeSH
- biopsie MeSH
- celiakie krev diagnóza genetika imunologie MeSH
- diagnostické techniky molekulární MeSH
- dítě MeSH
- HLA-DQ antigeny genetika imunologie MeSH
- imunoglobulin A krev MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- prediktivní hodnota testů MeSH
- předškolní dítě MeSH
- prognóza MeSH
- prospektivní studie MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP imunologie MeSH
- reprodukovatelnost výsledků MeSH
- sérologické testy MeSH
- tenké střevo imunologie patologie MeSH
- transglutaminasy imunologie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- validační studie MeSH
- Geografické názvy
- Evropa MeSH
- Střední východ MeSH
- Názvy látek
- autoprotilátky MeSH
- biologické markery MeSH
- HLA-DQ antigeny MeSH
- HLA-DQ2 antigen MeSH Prohlížeč
- HLA-DQ8 antigen MeSH Prohlížeč
- imunoglobulin A MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP MeSH
- transglutaminasy MeSH
Celiac disease is triggered by partially digested gluten proteins. Enzyme therapies that complete protein digestion in vivo could support a gluten-free diet, but the barrier to completeness is high. Current options require enzyme amounts on the same order as the protein meal itself. In this study, we evaluated proteolytic components of the carnivorous pitcher plant (Nepenthes spp.) for use in this context. Remarkably low doses enhance gliadin solubilization rates, and degrade gliadin slurries within the pH and temporal constraints of human gastric digestion. Potencies in excess of 1200:1 (substrate-to-enzyme) are achieved. Digestion generates small peptides through nepenthesin and neprosin, the latter a novel enzyme defining a previously-unknown class of prolyl endoprotease. The digests also exhibit reduced TG2 conversion rates in the immunogenic regions of gliadin, providing a twin mechanism for evading T-cell recognition. When sensitized and dosed with enzyme-treated gliadin, NOD/DQ8 mice did not show intestinal inflammation, when compared to mice challenged with only pepsin-treated gliadin. The low enzyme load needed for effective digestion suggests that gluten detoxification can be achieved in a meal setting, using metered dosing based on meal size. We demonstrate this by showing efficient antigen processing at total substrate-to-enzyme ratios exceeding 12,000:1.
- MeSH
- bezlepková dieta * MeSH
- celiakie enzymologie imunologie terapie MeSH
- Drosophila metabolismus MeSH
- enzymoterapie * MeSH
- gliadin metabolismus MeSH
- gluteny metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- myši inbrední NOD MeSH
- myši MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP metabolismus MeSH
- proteolýza MeSH
- transglutaminasy metabolismus MeSH
- zánět imunologie metabolismus prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- gliadin MeSH
- gluteny MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP MeSH
- transglutaminasy MeSH
Celiac disease (CD) is an autoimmune enteropathy initiated and sustained by the ingestion of gluten in genetically susceptible individuals. It is caused by a dysregulated immune response toward both dietary antigens, the gluten proteins of wheat, rye, and barley, and autoantigens, the enzyme tissue transglutaminase (TG2). The small intestine is the target organ. Although routine immunochemical protocols for a laboratory diagnosis of CD are available, faster, easier-to-use, and cheaper analytical devices for CD diagnosis are currently unavailable. This review focuses on biosensors, consisting of a physicochemical transducer and a bioreceptor, as promising analytical tools for diagnosis of CD and other diseases. Examples of recently developed biosensors as well as expectations for future lines of research and development in this field are presented.
- Klíčová slova
- Antibody, Biosensors, Celiac disease, Diagnosis, ELISA, Immunochemistry,
- MeSH
- biosenzitivní techniky metody MeSH
- celiakie diagnóza imunologie MeSH
- elektrochemické techniky MeSH
- gliadin imunologie MeSH
- imunohistochemie MeSH
- lidé MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP imunologie MeSH
- protilátky metabolismus MeSH
- transglutaminasy imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- gliadin MeSH
- protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
- proteiny vázající GTP MeSH
- protilátky MeSH
- transglutaminasy MeSH
