Coeliac disease: dissecting a complex inflammatory disorder

The disease mechanisms of complex inflammatory disorders are difficult to define because of extensive interactions between genetic and environmental factors. Coeliac disease is a typical complex inflammatory disorder, but this disease is unusual in that crucial genetic and environmental factors have been identified. This knowledge has allowed functional studies of the predisposing HLA molecules, the identification of antigenic epitopes and detailed studies of disease-relevant T cells in coeliac disease. This dissection of the pathogenic mechanisms of coeliac disease has uncovered principles that are relevant to other chronic inflammatory diseases.     

Coeliac disease in Type 1 diabetes from 1990 to 2009: higher incidence in young children after longer diabetes duration

Diabet. Med. 29, e286-e289 (2012) ABSTRACT: Aims To determine the incidence of coeliac disease in young people with Type?1 diabetes and to examine the effect of age at diabetes onset and disease duration. Methods This was a clinic-based observational cohort study of 4379 people aged ≤?18?years (49% male) between 1990 and 2009 from Sydney, Australia. Screening for coeliac disease was performed at diagnosis and 1-2?yearly using anti-endomysial and/or anti-tissue transglutaminase immunoglobulin?A (IgA) antibodies. Coeliac disease was diagnosed by small bowel biopsy based on Marsh score ≥?III. Results Coeliac disease was confirmed by biopsy in 185; of these, 61 (33%) were endomysial or tissue transglutaminase IgA antibody-positive at diabetes diagnosis. Mean age at diabetes onset was 6.6?±?4.0 vs. 8.4?±?4.1?years in those without coeliac disease (P?相似文献   

The pathogenesis of coeliac disease

Coeliac disease is a chronic enteropathy caused by intolerance to gluten proteins. The true prevalence of this condition is greater than previously thought, with increasing numbers of 'silent' cases being diagnosed. Untreated coeliac disease is associated with significant morbidity and increased mortality. There have been a number of advances in our understanding of the pathogenesis of coeliac disease, in particular the mechanisms whereby gluten epitopes are processed, become modified by tissue transglutaminase (tTG) and then interact with HLA restricted T cells. An improved understanding of the immune response to gluten is likely to lead to the development of novel strategies for the treatment of coeliac disease.     

A genetic perspective on coeliac disease

Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune-related. Over 50% of the disease-associated single nucleotide polymorphisms are correlated with gene expression. Most of the coeliac disease-associated regions are shared with other immune-related diseases, as well as with metabolic, haematological or neurological traits, or cancer. We review recent progress in the genetics of coeliac disease and describe the pathways these genes are in, the functional consequences of the associated markers on gene expression and the genes shared between coeliac disease and other traits.     

CD69 expression on alpha-gliadin-specific T cells in coeliac disease

Coeliac disease (CD) is a T-cell mediated immunological disease of the small intestine which is triggered in susceptible individuals by ingestion of gluten. The pathogenic mechanism of coeliac disease, and the role that alpha-gliadin specific T cells play in mucosal lesions and their involvement in peripheral blood is not yet explained at all. Previous studies have reported proliferative response to alpha-gliadin measured with the classic assay of 3HTdR incorporation. We analysed the activation antigen CD69 on T cells from CD patients and normal individuals following stimulation with alpha-gliadin and different antigens (tetanus toxoid, peptides unrelated to gliadin and PHA). CD69 coexpression with T cell CD3+ and proliferation marker Ki67 was evaluated with time. CD69 coexpression with T cell CD3+, CD4+ and CD8+ was also evaluated. It was found that peripheral blood mononuclear cells (PBMC) of coeliac patients increased their percentage of CD69 positive T cells when stimulated with alpha-gliadin, in comparison with cells from controls. Significant T cell activation was found only in subjects not treated with the gluten free diet; a positive response was found also in two coeliac patients with selective IgA deficiency, anti-endomisium negative, without circulating IgA anti alpha-gliadin or anti-tissue transglutaminase antibodies. The CD69 expression after stimulation was compared with the standard method of 3HTdR incorporation. Our data show that CD69 expression is useful to asses a specific T cell response to alpha-gliadin in coeliac disease. in a very short time. Moreover, the method allows to investigate T cell response at the lymphocyte subsets level, which represents a useful tool in the diagnosis of coeliac disease.     

Persistent Changes in Circulating and Intestinal γδ T Cell Subsets,Invariant Natural Killer T Cells and Mucosal-Associated Invariant T Cells in Children and Adults with Coeliac Disease

Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56⁺ T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.     

Epidemiology of coeliac disease in children in one Croatian county: the cumulative incidence over ten-year period and the way of clinical presentation (Part I)

Coeliac disease is a permanent intolerance to gluten, producing small-intestinal lesions. Its incidence in European countries varies from 1:400 to 1:2000, while there are no such epidemiological data for Croatia. Therefore, we investigated the incidence of coeliac disease for ten-year period in one well-defined region. Also, data concerning age at diagnosis and symptoms at the disease onset were collected. The cumulative incidence was 1.9:1000 life-births. The disease presented typically in more than 60% of cases. In 65% of patients, symptoms appeared during the first 2 years of life, while, when diagnosed, 45% were below 2 years. Also, it was shown that coeliac disease presented significantly later in children diagnosed during the last five years (p < 0.05). In conclusion, coeliac disease in Croatia is more frequent than previously suspected. It presents early, mostly with classical symptoms, although a tendency towards later ages of diagnosis was observed during the last few years.     

Genetic associations and immunopathogenesis of coeliac disease.

Coeliac disease is the most common disorder with malabsorption of the small instestine, caused by the gluten fraction of cereals in genetically predisposed individuals. Gluten peptides are efficiently presented by coeliac disease-specific HLA-DQ2- and HLA-DQ8-positive antigen-presenting cells, and thus drive the antigen-presenting cells, predominantly in the connective tissue of the lamina propria. The studying of the recently explored autoantibodies against tissue transglutaminase brought us further in the understanding of the pathophysiology of coeliac disease. The spreading of reliable serologic methods modified our knowledge on the clinical picture and prevalence of the disease. Long-standing untreated coeliac disease, even if clinically silent, predisposes for other autoimmune diseases. Therefore, population screening for immunoglobulin A antibodies to tissue transglutaminase seems justified.     

The use of Cellomics to study enterocyte cytoskeletal proteins in coeliac disease patients

Coeliac disease is characterised by inflammation of small intestinal mucosa accompanied by abnormal villous architecture. It is now accepted that some patients with positive coeliac serology tests may have minor mucosal lesions that may not be apparent on routine histopathological analysis. The aim of the study was to perform detailed examination of enterocyte morphology and cytoskeletal structures using a high content analysis technology. Duodenal biopsies from 14 untreated and 10 treated coeliac patients and from 20 non-coeliac controls were examined. Tissue sections from six patients (study group subjects) before and after the development of gluten-sensitive enteropathy were also investigated. Immunohistochemical studies were performed on paraffin-embedded sections using an anti-α-tubulin antibody. Significant differences in enterocyte morphology and intracellular cytoskeletal structures were demonstrated in patients with proven coeliac disease and in the study group subjects. These changes were present in study group biopsies before evidence of enteropathy, as assessed by routine microscopy. This is the first study to demonstrate detailed characteristics of enterocyte morphology in coeliac patients using a high content analysis approach. The use of this technology allows a quantitative analysis of enterocyte intracellular structures from routine biopsy material and permits detection of subtle changes that precede the characteristic histological lesion.     

A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease?

Coeliac disease is an autoimmune-mediated disorder with both innate and adaptive immune components. The disease is triggered by dietary gluten, which provokes the development of a massive immune reaction leading to the destruction of the small-intestinal mucosal morphology and intestinal dysfunction. Besides the typical small-bowel symptoms extraintestinal manifestations may also arise in a subset of coeliac disease patients. In addition, gluten evokes the production of antibodies mainly targeting deamidated gluten peptides or transglutaminase 2. Although coeliac disease has traditionally been regarded as a T cell-mediated disorder, this review discusses the role of the gluten-induced disease-specific anti-transglutaminase 2-autoantibodies in the pathogenesis of the disease.     

Differences between the fecal microbiota of coeliac infants and healthy controls

Coeliac disease (CD) is an immune-mediated enteropathy with a multifactorial aetiology, characterized by chronic inflammation of the small intestinal mucosa. Although evidence suggests that the gut microbiota contributes to other chronic inflammatory disorders, its possible role in CD has not been determined. In this study, the composition of the fecal microbiota of coeliac children and age-matched controls was investigated by culture-dependent and -independent methodologies, using fluorescent in situ hybridization (FISH). The levels of Bacteroides, Clostridium and Staphylococcus were significantly higher (p < 0.05) in fecal samples from coeliac patients than in healthy subjects when analysed by culture methods. The numbers of Bacteroides-Prevotella, Clostridium histolyticum, Eubacterium rectale-C. coccoides, Atopobium, and sulfate reducing bacterial groups were also significantly higher (p < 0.05) in fecal samples from coeliac infants when analysed by FISH. The counts of Bifidobacterium tended to be higher in healthy controls by the two type of analysis but the differences were not significant. This is the first report on the identification of the specific bacterial groups responsible for alterations in the intestinal microecology of children with active CD. The bacterial pattern detected in coeliac patients, correlates with the epidemiological data and metabolic deviations associated with CD, and involve bacterial groups link to other chronic inflammatory disorders.     

Coeliac disease in children and adolescents with type 1 diabetes mellitus: to screen or not, to treat or not?

Coeliac disease is more prevalent in individuals with type 1 diabetes mellitus than in the normal population. It often presents in an atypical or silent form. Specific autoantibodies are found in almost all cases. Untreated coeliac disease may be associated with long-term health risks, so screening and early treatment with a gluten-free diet seem to be justified. However, extended follow-up is needed to document the clinical benefits of screening and treatment in diabetic patients.     

Differences in faecal bacterial communities in coeliac and healthy children as detected by PCR and denaturing gradient gel electrophoresis

Coeliac disease (CD) is a chronic inflammatory disorder of the small intestinal mucosa. Scientific evidence supports a role of the gut microbiota in chronic inflammatory disorders; yet information is not specifically available for CD. In this study, a comparative denaturing gradient gel electrophoresis analysis of faecal samples from coeliac children and age-matched controls was carried out. The diversity of the faecal microbiota was significantly higher in coeliac children than in healthy controls. The presence of the species Lactobacillus curvatus, Leuconostoc mesenteroides and Leuconostoc carnosum was characteristic of coeliac patients, while that of the Lactobacillus casei group was characteristic of healthy controls. The Bifidobacterium population showed a significantly higher species diversity in healthy children than in coeliacs. In healthy children, this population was characterized by the presence of Bifidobacterium adolescentis. Overall, the results highlighted the need for further characterization of the microbiota in coeliac patients, and suggested a potential role of probiotics and/or prebiotics in restoring their gut microbial balance.     

Coeliac disease in primary care: case finding study

ObjectivesTo provide evidence of underdiagnosis of coeliac disease and to describe the main presenting symptoms of coeliac disease in primary care.DesignCase finding in a primary care setting by testing for coeliac disease by using the endomysial antibody test.SettingNine surgeries in and around a market town in central England, serving a population of 70 000.ParticipantsFirst 1000 patients screened from October 1996 to October 1997.ResultsThe 30 patients (out of 1000 samples) with positive results on the endomysial antibody test all had histological confirmation on small intestine biopsy. The commonest mode of presentation (15/30) was anaemia of varying severity. Most patients (25/30) presented with non-gastrointestinal symptoms. Specificity of the endomysial antibody test was 30/30.ConclusionsUnderdiagnosis and misdiagnosis of coeliac disease are common in general practice and often result in protracted and unnecessary morbidity. Serological screening in primary care will uncover a large proportion of patients with this condition and should be made widely available and publicised. Coeliac disease should be considered in patients who have anaemia or are tired all the time, especially when there is a family history of the disease.

Key messages

• General practitioners currently see many people with undiagnosed coeliac disease
• The most likely presentation is a combination of microcytic anaemia, past or present, a family history of the disease, and feeling tired all the time
• Estimations of endomysial antibody and IgA are reliable diagnostic tools
• The prevalence of coeliac disease in Britain is higher than the accepted figure of 1:1000 population
• Increased awareness of the extra intestinal manifestations of coeliac disease, coupled with a low threshold for serological testing, will uncover a large portion of undiagnosed coeliac disease

     

Unusually High Incidence of Paediatric Coeliac Disease in Sweden during the Period 1973 – 2013

Objective

The prevalence of coeliac disease in Sweden during the “epidemic period” (1984−1996) was one of the highest in the world. The aim of this study was to assess the coeliac disease incidence in our region over the 41-year period, and how diagnostic activity and diagnostic accuracy were affected by the introduction of antibody testing. We also looked into how patients with mild enteropathy were evaluated.

Methods

In the county of Östergötland in Sweden, 2790 paediatric patients were investigated for suspected coeliac disease between 1973 and 2013. Notes were scrutinised for data on sex, age, histopathological reports and final diagnosis. For comparative purposes this period was divided into three sub-periods (1973−1983, 1984−1996 and 1997−2013) named pre-epidemic, epidemic and post-epidemic.

Results

Coeliac disease diagnosis was received by 1,030 patients. The peak incidence rate, 301 cases/100,000 in 1994 for the age group 0−1.9 years is the highest figure ever reported. The other age groups, 2−4.9, 5−14.9, and 15−17.9 years, also had high incidence rates. After the 1984−1996 “epidemic period” the incidence decreased for the youngest group but continued to increase for the other groups. The cumulative incidence at 18 years-of-age for children born during the epidemic reached 14 cases/1000 births, the highest figure hitherto reported. Diagnostic activity differed significantly between the three sub-periods (p<0.001) increasing gradually from 1984 and reaching a peak value of 0.87 in 2012. Cases of mild enteropathy were more frequently regarded as non-coeliac disease cases, decreasing significantly in the “post-epidemic” period (p<0.001).

Conclusions

The incidence rate and cumulative incidence of coeliac disease were possibly the highest ever reported. Changes in diagnostic activity and accuracy could not be attributed to the introduction of new antibody tests, possibly because of other changes e.g. variations in the symptoms at presentation and improved knowledge of the disease among parents and health professionals.     

The Global Burden of Childhood Coeliac Disease: A Neglected Component of Diarrhoeal Mortality?

Objectives

Coeliac disease has emerged as an increasingly recognised public health problem over the last half-century, and is now coming to be seen as a global phenomenon, despite a profound lack of globally representative epidemiological data. Since children with coeliac disease commonly present with chronic diarrhoea and malnutrition, diagnosis is often overlooked, particularly in poorer settings where children often fail to thrive and water-borne infectious diarrhoeas are common. This is the first attempt to make global estimates of the burden of coeliac disease in childhood.

Methods

We built a relatively crude model of childhood coeliac disease, incorporating estimates of population prevalence, probability of non-diagnosis, and likelihood of mortality among the undiagnosed across all countries from 1970 to 2010, based around the few available data. All our assumptions are stated in the paper and the model is available as a supplementary file.

Findings

Our model suggests that in 2010 there were around 2.2 million children under 5 years of age living with coeliac disease. Among these children there could be 42,000 deaths related to coeliac disease annually. In 2008, deaths related to coeliac disease probably accounted for approximately 4% of all childhood diarrhoeal mortality.

Conclusions

Although coeliac disease may only account for a small proportion of diarrhoeal mortality, these deaths are not preventable by applying normal diarrhoea treatment guidelines, which may even involve gluten-based food supplements. As other causes of diarrhoeal mortality decline, coeliac disease will become a proportionately increasing problem unless consideration is given to trying gluten-free diets for children with chronic diarrhoea and malnutrition.     

Gluten-free diet impact on leptin levels in asymptomatic coeliac adolescents: one year of follow-up

Coeliac disease, daily more frequently diagnosed in our population, involves many organs also in oligosymptomatic patients and with an adequate nutritional regime. Possible endocrine implications include failure to thrive, pubertal delay and reproduction diseases due to deregulation of GH, FSH and LH secretion. Leptin, an adipose tissue hormone, can be decreased as well and its deficiency could be related to growth and puberty anomalies. We studied 14 asymptomatic coeliac patients in peripubertal age (7.5-13.8 years) and tested their leptin levels in order to correlate them with endocrine and anthropometric data. Before the diet was started leptinaemia (M+/-DS) was: 4.94+/-5.53 ng/ml. In 10/14 patients (71%) leptinaemia was相似文献   

Immune Response to Gluten in Adult Coeliac Disease

Cultures of mesenteric node lymphocytes obtained from two adult coeliac disease patients were stimulated by gluten fraction III. No stimulation was observed in cultures of axillary node lymphocytes from one of these patients, of mesenteric node lymphocytes from the two patients with other diseases or of peripheral blood lymphocytes from adult coeliacs and normal subjects. Peripheral blood lymphocytes of two of the six adult coeliac patients responded poorly to phytohaemagglutin alone, but this was probably owing to technical factors. In a further six adult coeliacs skin tests to gluten fraction III were negative. It is suggested that delayed hypersensitivity to gluten is likely to have a secondary pathogenic role in adult coeliac disease.     

Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma.

Features that might distinguish uncomplicated coeliac disease from enteropathy associated T cell lymphoma were investigated. Of 76 patients with coeliac disease, 71 (93%) had raised levels of alpha gliadin antibody and all responded clinically and histologically to treatment with a gluten free diet. In contrast, none of 16 patients with enteropathy associated T cell lymphoma had raised levels of alpha gliadin antibody, and treatment with a gluten free diet resulted in histological improvement in one and transient clinical improvement in six patients. The ratio of women to men was 2.2:1 in the group with coeliac disease and 1:1.6 in the patients with enteropathy associated T cell lymphoma. Thus patients with enteropathy associated T cell lymphoma do not display a humoral immune response to wheat protein (alpha gliadin), rarely respond to a gluten free diet, and are often men. Patients with uncomplicated coeliac disease usually have raised levels of alpha gliadin antibody, always respond to a gluten free diet, and are frequently women. These findings suggest the presence of two separate forms of enteropathy: one is benign and sensitive to wheat protein whereas the other runs a malignant course.     

Parathyroid adenoma with coeliac disease: primary or quaternary hyperparathyroidism?

Coeliac disease is a gluten-sensitive enteropathy of varying severity. Osteomalacia and hypocalcaemia can result from malabsorption of vitamin D and calcium, which, in turn, can lead to secondary hyperparathyroidism. If coeliac disease remains untreated for long, tertiary hyperparathyroidism can also develop through autonomy of the parathyroid glands via chronic stimulation. Primary hyperparathyroidism also has been reported in some cases of coeliac disease. We report the case of an adolescent with coeliac disease presenting with severe hypercalcaemia from a parathyroid adenoma. A 14 year-old girl was admitted to our department for delayed puberty and growth retardation. Laboratory examination revealed iron deficiency anaemia, low 25OH vitamin D level (7 ng/ml), high parathyroid hormone level (PTH) (955 pg/ml), and hypercalcaemia (13.4 mg/dl). Endoscopic biopsy was compatible with gluten enteropathy. Endomysium antibody was positive. A gluten-free diet was started. Her calcium returned to normal after excision of the parathyroid adenoma. After four months of the gluten-free diet, she began to mature, and puberty began with development of breasts and axillary-pubic hair growth. It has been suggested that autonomous four-gland hyperplasia or tertiary hyperparathyroidism may progress to adenoma formation, and that this should be termed "quaternary hyperparathyroidism". More studies are required to explain the relationship between coeliac disease and hyperparathyroidism.