[Dosaging of proton pumps inhibitors].
Explore the source record for details and available documents.
Antacids↗
Biomedical subjects
Knut E A Lundin
Publications and source records attributed to Knut E A Lundin.
HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.
Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, alpha-gliadin AJ133612 and gamma-gliadin M36999. For alpha-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For gamma-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some gamma-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.
Amino Acid Sequence↗
[New Swedish specialty structure].
Explore the source record for details and available documents.
Humans↗
A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells.
BACKGROUND & AIMS: Celiac disease is a chronic inflammation of the duodenal mucosa driven by gluten-reactive T cells restricted by the disease-associated HLA-DQ2 molecule. The mechanisms that regulate the activation of mucosal T cells are, however, understood poorly. The aim of this study was to identify the antigen-presenting cells that are responsible for the activation of gluten-reactive T cells in the celiac lesion. METHODS: Intestinal biopsy specimens obtained from untreated and treated celiac patients and normal controls were either snap-frozen directly or incubated for 24 hours with or without gluten peptides. Cryosections were subjected to multicolor immunofluorescence applying monoclonal antibodies to a range of antigen-presenting cell markers. Macrophages and dendritic cells were isolated from enzymatically digested small intestinal biopsies of untreated patients and incubated with gluten-reactive T-cell clones to measure their antigen-presenting capacity. RESULTS: HLA-DQ2+ cells in the normal duodenal mucosa consisted of 2 distinct cell populations: about 80% were CD68+ DC-lysosome intercellular adhesion molecule-3-grabbing nonintegrin+ macrophages and 20% were CD11c+ dendritic cells. Importantly, the CD11c+ dendritic cells accumulated in the celiac lesion and revealed an activated phenotype expressing CD86 and DC-specific-associated membrane protein. Moreover, when isolated from challenged biopsy specimens, the CD11c+ dendritic cells efficiently activated gluten-reactive T cells. CONCLUSIONS: Our results suggest that a unique subset of dendritic cells are responsible for local activation of gluten-reactive T cells in the celiac lesion.
Adolescent↗
Gluten-free diet--what is toxic?
The cornerstone of treatment of coeliac disease is a gluten-free diet devoid of proteins from wheat, rye, barley and related cereals. Oats are tolerated by most patients with coeliac disease but are not totally innocent. There are considerable differences between individual patients with respect to clinical and mucosal responses to gluten challenge. In vitro and in vivo testing has identified synthetic peptides that are toxic to the coeliac small intestinal mucosa. This toxicity overlaps at least partly to the known epitopes that are recognised by small intestinal T-cells. However, the clinical significance of several of these epitopes is unclear, as is the maximum level of gluten intake that can be recommended to be safe for patients with coeliac disease. Future efforts may lead to better understanding of the disease processes as well as possible new therapeutic options.
Celiac Disease↗
Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease.
BACKGROUND & AIMS: Patients with celiac disease (CD) who do not improve or exhibit villous atrophy on a gluten-free diet may have type 1 refractory CD (RCD) with a polyclonal mucosal T-cell infiltrate, or type 2 RCD with a monoclonal infiltrate, also termed cryptic T-cell lymphoma. Both conditions are difficult to treat. Here we describe the effects of a nonimmunogenic elemental diet on clinical symptoms and mucosal immunopathology in type 1 RCD. METHODS: Ten CD patients on a strict gluten-free diet were diagnosed with type 1 RCD after extensive clinical evaluation in a tertiary referral hospital. A 4-week amino-acid-based liquid elemental diet regimen was given with no other treatment, except in 1 patient who also received methotrexate. Duodenal biopsy specimens were obtained before and after treatment for histologic assessment, immunophenotyping of intraepithelial lymphocytes, T-cell receptor clonality, mucosal interleukin (IL)-15 expression, flow-cytometric analysis of interferon (IFN)-gamma-secreting T cells, and whole biopsy specimen IFN-gamma messenger RNA determination. RESULTS: Nine patients completed the treatment; however, 1 patient did not tolerate the diet. Histologic improvement and reduced epithelial IL-15 were seen in 8 patients, whereas IFN-gamma-secreting mucosal T cells and IFN-gamma messenger RNA levels decreased in 4 and 7 patients, respectively. Clinical improvement was noted in 6 patients, with 1 patient showing normalization of hypoalbuminemia. Three patients could discontinue their total parenteral nutrition. CONCLUSIONS: Persistent mucosal IFN-gamma and IL-15 production often occurs in type 1 RCD despite conventional treatment. Elemental diet is a therapeutic option that can provide long-term immunopathologic and clinical improvement of this difficult condition.
Adult↗
Mapping of gluten T-cell epitopes in the bread wheat ancestors: implications for celiac disease.
BACKGROUND AND AIMS: Celiac disease is a prevalent disorder characterized by a chronic intestinal inflammation driven by HLA-DQ2 or -DQ8-restricted T cells specific for ingested wheat gluten peptides. The dominant T-cell responses are to epitopes that cluster within a stable 33mer fragment formed by physiologic digestion of distinct alpha-gliadins. Celiac disease is treated by excluding all gluten proteins from the diet. Conceivably, a diet based on baking-quality gluten from a wheat species that expresses no or few T-cell stimulatory gluten peptides should be equally well tolerated by the celiac patients and, importantly, also be beneficial for disease prevention. METHODS: To identify baking quality, harmless wheat, we followed the evolution of the wheat back to the species that most likely have contributed the AA, BB, and DD genomes to the bread wheat. Gluten were extracted from a large collection of these ancient wheat species and screened for T-cell stimulatory gluten peptides. RESULTS: Distinct differences in the intestinal T-cell responses to the diploid species were identified. Interestingly, we found that the fragments identical or equivalent to the immunodominant 33mer fragment are encoded by alpha-gliadin genes on the wheat chromosome 6D and thus absent from gluten of diploid einkorn (AA) and even certain cultivars of the tetraploid (AABB) pasta wheat. CONCLUSIONS: These findings have implications for celiac disease because they raise the prospect of identifying or producing by breeding wheat species with low or absent levels of harmful gluten proteins.
Amino Acid Sequence↗
Commentary: transient coeliac disease back on stage again?
Explore the source record for details and available documents.
Autoantibodies↗
The molecular basis for oat intolerance in patients with celiac disease.
BACKGROUND: Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. METHODS AND FINDINGS: We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine-->glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation. CONCLUSIONS: We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable.
Atrophy↗
[Cardiology as an engine for internal medicine].
Explore the source record for details and available documents.
Cardiology↗
[Coeliac disease--new clinical findings and diagnostic tools].
Coeliac disease is a disorder characterised by intolerance to wheat gluten and related proteins from rye and barley, ingestion of which leads to a harmful immune activation in the small intestinal mucosa. The symptoms are often vague and do not suggest an intestinal disorder. The diagnosis is often easy once the question is raised; it requires a combination of serological tests and small intestinal biopsies. Coeliac disease can also exist with a normal serology. The trend in many countries is to require less pronounced mucosal abnormalities than previously for the diagnosis.
Antibodies↗
[Disease mechanisms in coeliac disease].
Coeliac disease is a chronic inflammatory disorder that is caused by an inappropriate immune response in the gut to wheat gluten and similar proteins of barley and rye. The disease has a multifactorial aetiology involving multiple genes and environmental factors. In recent years we have gained new knowledge of the molecular basis of this disorder; this paper gives an overview of the current understanding of the pathogenesis of coeliac disease.
Celiac Disease↗
[Dietary treatment of coeliac disease and dermatitis herpetiformis].
Life-long gluten-free diet is the established therapy for coeliac disease and dermatitis herpetiformis. Diet therapy allows the intestinal mucosa to recover, improves nutrient malabsorption, osteoporosis and a weakened general condition. A gluten-free diet is without wheat, rye and barley and related products. Oats tested free of contamination by other cereals has recently been allowed for adult coeliac patients, but concern still remains regarding its general safety. Gluten-free flour mixes contain more starch and less proteins, vitamins, minerals and fibre compared to regular flour. Recently some questions have been raised as to the nutritional quality of the gluten-free diet. Successful therapy with gluten-free diet requires motivation and dietary counselling, including knowledge of the nutritional value of foods, labelling of prepackaged foods and practical training in cooking. The local chapters of the Norwegian Coeliac Society are active partners, as are the clinical nutritionists that work in most major hospitals. The physician making the diagnosis has a duty to see to it that all coeliac patients get adequate dietary counselling and management.
Adult↗
Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease.
BACKGROUND & AIMS: The chronic, small intestinal inflammation that defines celiac disease is initiated by a HLA-DQ2 restricted T-cell response to ingested gluten peptides after their in vivo deamidation by tissue transglutaminase (TG2). To date, celiac disease can only be treated by a lifelong abstinence from foods that contain wheat, rye, or barley; better therapeutic options are hence needed. An attractive target would be to identify nontoxic wheat cultivars or components thereof with intact baking qualities. Because these qualities are mainly determined by the high molecular weight (HMW) glutenin proteins of gluten, it is critical to know if these proteins are toxic or, more specifically, if they will trigger the activation of T cells in the celiac lesion. METHODS: Different, highly purified HMW glutenins were isolated from wheat cultivars or expressed as recombinant proteins. The proteins were first tested for recognition by a large panel of gluten-specific T-cell lines established from celiac lesions and then applied during ex vivo challenges of celiac biopsies to allow for a direct identification of HMW specific T cells. RESULTS: Intestinal T-cell responses to TG2-deamidated HMW glutenins but not the corresponding native proteins were detectable in 9 of the 22 adult and childhood celiac disease patients tested. CONCLUSIONS: T cells within celiac lesions frequently recognize deamidated HMW glutenin proteins. This finding questions the possibility of implementing these proteins in novel food items destined to be nontoxic for celiac disease patients.
Adult↗
Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues.
BACKGROUND & AIMS: Celiac disease is a gluten-induced enteropathy that shows a strong association with HLA-DQ2 and -DQ8. Gluten-specific T cells, invariably restricted by DQ2 or DQ8, can be isolated from celiac lesions. Such gut-derived T cells have a preference for recognition of gluten that has been specifically deamidated by tissue transglutaminase. Only a few gliadin T-cell epitopes have been identified by earlier work. The aim of this study was to perform a systematic characterization of DQ2-restricted T-cell epitopes in alpha- and gamma-gliadins. METHODS: Epitopes were identified by mass spectrometry analysis of peptide fragments of recombinant gliadins and by use of synthetic peptides. RESULTS: We identified several new gamma-gliadin epitopes and an additional alpha-gliadin epitope. Interestingly, these and the previously identified epitopes are not randomly scattered across the gliadins but cluster in regions of the proteins with high content of proline residues. CONCLUSIONS: Several DQ2-restricted T-cell epitopes exist in gliadin that are located in regions rich in proline. This likely reflects epitope selection at the levels of digestive and antigen-presenting cell processing, transglutaminase-mediated deamidation, and/or peptide binding to DQ2.
Amino Acid Sequence↗