Haptoglobin Polymorphism: A Novel Genetic Risk Factor for Celiac Disease Development and Its Clinical Manifestations

Background: Haptoglobin (Hp) α-chain alleles 1 and 2 account for 3 phenotypes that may influence the course of inflammatory diseases via biologically important differences in their antioxidant, scavenging, and immunomodulatory properties. Hp1-1 genotype results in the production of small dimeric, Hp2-1 linear, and Hp2-2 cyclic polymeric haptoglobin molecules. We investigated the haptoglobin polymorphism in patients with celiac disease and its possible association to the presenting symptoms. Methods: We studied 712 unrelated, biopsy-proven Hungarian celiac patients (357 children, 355 adults; severe malabsorption 32.9%, minor gastrointestinal symptoms 22.8%, iron deficiency anemia 9.4%, dermatitis herpetiformis 15.6%, silent disease 7.2%, other 12.1%) and 384 healthy subjects. We determined haptoglobin phenotypes by gel electrophoresis and assigned corresponding genotypes. Results: Hp2-1 was associated with a significant risk for celiac disease (P = 0.0006, odds ratio [OR] 1.54, 95% CI 1.20–1.98; prevalence 56.9% in patients vs 46.1% in controls). It was also overrepresented among patients with mild symptoms (69.2%) or silent disease (72.5%). Hp2-2 was less frequent in patients than in controls (P = 0.0023), but patients having this phenotype were at an increased risk for severe malabsorption (OR 2.21, 95% CI 1.60–3.07) and accounted for 45.3% of all malabsorption cases. Celiac and dermatitis herpetiformis patients showed similar haptoglobin phenotype distributions. Conclusions: The haptoglobin polymorphism is associated with susceptibility to celiac disease and its clinical presentations. The predominant genotype in the celiac population was Hp2-1, but Hp2-2 predisposed to a more severe clinical course. The phenotype-dependent effect of haptoglobin may result from the molecule’s structural and functional properties

Strong Clonal Relatedness between Serum and Gut IgA despite Different Plasma Cell Origins

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Early recognition of coeliac disease through community pharmacies: A proof of concept study

Setting: 15 community pharmacies in the UK Objective: Proof of concept study to test the use of community pharmacies for active case finding of patients with coeliac disease. Method: Customers accessing over-the counter and prescription medicines indicated in the treatment of possible symptoms of coeliac disease over a six month period were offered a free point of care test. All patients were given advice regarding the test results and those who tested positive were advised to make an appointment with their general practitioner. Patients and pharmacists involved in service provision were asked to complete a satisfaction survey. Pharmacists were additionally invited to undertake interviews to better understand their views on the service. Main outcome measures: Feasibility of service, acceptability to stakeholders and proportion testing positive for coeliac disease. Results: Of the 551 individuals tested, 52 (9.4%) tested positive. 277 (50.3%) were tested for accessing irritable bowel syndrome treatment, 142 (25.8%) due to presenting for diarrhoea. The proportion of patients testing positive with different symptoms or for different treatments were similar. Of 43 customers who returned the satisfaction survey, all would recommend the service to others, believing the community pharmacy to be a suitable location. Community pharmacists believed that it enabled them to improve relationships with their customers and that medical practices were receptive to the service. Conclusion: This proof of concept study has shown that community pharmacies using a point of care test can effectively recognise and refer patients for confirmatory coeliac disease testing with high levels of customer and service provider satisfaction

Transepithelial Transport and Enzymatic Detoxification of Gluten in Gluten-Sensitive Rhesus Macaques

In a previous report, we characterized a condition of gluten sensitivity in juvenile rhesus macaques that is similar in many respects to the human condition of gluten sensitivity, celiac disease. This animal model of gluten sensitivity may therefore be useful toward studying both the pathogenesis and the treatment of celiac disease. Here, we perform two pilot experiments to demonstrate the potential utility of this model for studying intestinal permeability toward an immunotoxic gluten peptide and pharmacological detoxification of gluten in vivo by an oral enzyme drug candidate.Intestinal permeability was investigated in age-matched gluten-sensitive and control macaques by using mass spectrometry to detect and quantify an orally dosed, isotope labeled 33-mer gluten peptide delivered across the intestinal epithelium to the plasma. The protective effect of a therapeutically promising oral protease, EP-B2, was evaluated in a gluten-sensitive macaque by administering a daily gluten challenge with or without EP-B2 supplementation. ELISA-based antibody assays and blinded clinical evaluations of this macaque and of an age-matched control were conducted to assess responses to gluten.Labeled 33-mer peptide was detected in the plasma of a gluten-sensitive macaque, both in remission and during active disease, but not in the plasma of healthy controls. Administration of EP-B2, but not vehicle, prevented clinical relapse in response to a dietary gluten challenge. Unexpectedly, a marked increase in anti-gliadin (IgG and IgA) and anti-transglutaminase (IgG) antibodies was observed during the EP-B2 treatment phase.Gluten-sensitive rhesus macaques may be an attractive resource for investigating important aspects of celiac disease, including enhanced intestinal permeability and pharmacology of oral enzyme drug candidates. Orally dosed EP-B2 exerts a protective effect against ingested gluten. Limited data suggest that enhanced permeability of short gluten peptides generated by gastrically active glutenases may trigger an elevated antibody response, but that these antibodies are not necessarily causative of clinical illness

Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa

<p>Abstract</p> <p>Background</p> <p>Antibody serology is an important tool in the investigation of celiac disease (CD), but does not always correlate with mucosal appearance in the small intestine. Patients with positive CD serology but normal mucosa (Marsh 0) are at increased risk of future CD. In this study we describe a model for identifying and characterizing individuals with normal mucosa but positive CD serology. Such individuals are sometimes referred to as having latent CD.</p> <p>Methods</p> <p>The records of ten Swedish pathology departments were used to identify individuals with biopsies indicating normal duodenal/jejunal mucosa. Using the national personal identification number, these data were linked with CD serology data (antigliadin, antiendomysial and tissue transglutaminase antibodies); and we thereby identified 3,736 individuals with normal mucosa but positive CD serology. Two independent reviewers then manually reviewed their biopsy reports to estimate comorbidity. We also randomly selected 112 individuals for validation through patient chart review.</p> <p>Results</p> <p>The majority of the 3,736 individuals were females (62%). Children (0–15 years) made up 21.4%. The median number of biopsy specimen was 3. Our review of biopsy reports found that other gastrointestinal comorbidity was rare (inflammatory bowel disease: 0.4%; helicobacter pylori infection: 0.2%). Some 22% individuals selected for patient chart review had a relative with CD. The most common symptoms among these individuals were diarrhea (46%) and abdominal pain (45%), while 26% had anemia. Although 27% of the individuals selected for validation had been informed about gluten-free diet, only 13% were adhering to a gluten-free diet at the end of follow-up.</p> <p>Conclusion</p> <p>Individuals with positive CD serology but normal mucosa often have CD-like symptoms and a family history of CD.</p

Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease

<p>Abstract</p> <p>Background</p> <p>Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient.</p> <p>We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration.</p> <p>Methods</p> <p>Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined.</p> <p>Results</p> <p>Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients.</p> <p>Conclusions</p> <p>Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis.</p

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta).Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes.When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function--this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes.A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research