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Failure of intradermal skin testing with gluten to produce delayed hypersensitivity reactions in patients with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is characterized by a rash and a gluten-sensitive enteropathy (GSE) indistinguishable from that of coeliac disease. T-cell-mediated mechanisms have been implicated in the pathogenesis of GSE. It seems feasible that intradermal injection of gluten, in patients known to have GSE, could lead to an influx of T cells sensitized to gluten, with subsequent development of a delayed hypersensitivity-type reaction. Six patients with DH and three normal subjects had intradermal injections of 'Frazer's fraction III' (FFIII; the partial peptic tryptic digest of gluten which is known to be antigenic) and phosphate-buffered saline (PBS) as a control. Skin biopsies were taken at PBS and FFIII injection sites at 48 h. In addition, two of the patients with DH had biopsies taken of FFIII injection sites at 6 h. Monoclonal antibodies and the avidin-biotin-peroxidase technique were used to stain for T cells in the skin biopsies. A monoclonal antibody to a neoepitope exposed in the terminal complement complex and an immunofluorescent method were used to detect the presence of terminal complement component in biopsies taken from two of the control subjects and two of the patients. Both patients and control subjects developed a weal and flare within a few minutes of injecting the FFIII, and this persisted for up to 6 h. No skin reaction was present in either the patients or the control subjects at 48 h. No skin reaction was visible at any time following injection of PBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗

The immune recognition of gluten in coeliac disease.

Coeliac disease, the most common intestinal disorder of western populations, is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten peptides that occurs in genetically susceptible individuals carrying the HLA-DQ2 or -DQ8 haplotype. Despite the recent progresses in understanding the molecular mechanisms of mucosal lesions, it remains unknown how increased amounts of gluten peptides can enter the intestinal mucosa to initiate the inflammatory cascade. Current knowledge indicates that different gluten peptides are involved in the disease process in a different manner, some fragments being 'toxic' and others 'immunogenic'. Those defined as 'toxic' are able to induce mucosal damage either when added in culture to duodenal endoscopic biopsy or when administered in vivo, while those defined as 'immunogenic' are able to specifically stimulate HLA-DQ2- or DQ8-restricted T cell clones isolated from jejunal mucosa or peripheral blood of coeliac patients. These peptides are able to trigger two immunological pathways: one is thought to be a rapid effect on the epithelium that involves the innate immune response and the other represents the adaptive immune response involving CD4+ T cells in the lamina propria that recognize gluten epitopes processed and presented by antigen presenting cells. These findings are the subject of the present review.

Celiac Disease↗

The impact of a gluten-free diet on adults with coeliac disease: results of a national survey.

UNLABELLED: OBJECTIVE We sought to evaluate the impact of the gluten-free diet on the 5,240 members of the Canadian Celiac Association (CCA). Data are presented on 2,681 adults (>or=16 years) with biopsy-proven celiac disease (CD). METHODS: A mail-out survey was used. Quality of life was evaluated using the 'SF12', and celiac-specific questions. RESULTS: Mean age was 56 years, mean age at diagnosis was 45 years, and 75% were female. The 'SF12' summary scores were similar to normative Canadian data, but were significantly lower for females and newly diagnosed patients. Respondents reported: following a gluten-free (GF) diet (90%), improvement on the diet (83%), and difficulties following the diet (44%), which included: determining if foods were GF (85%), finding GF foods in stores (83%), avoiding restaurants (79%), and avoiding travel (38%). Most common reactions to consumed gluten (among 73%) included pain, diarrhea, bloating, fatigue, nausea, and headache. Excellent information on CD and its treatment was provided by the CCA (64%), gastroenterologists (28%), dietitians (26%) and family doctor (12%). CONCLUSIONS: Quality of life in those with CD could be increased with early diagnosis, increased availability of gluten-free foods, improved food labelling, and better dietary instruction. Education of physicians and dietitians about CD and its treatment is essential.

Canada↗

Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease.

Lectins recognize carbohydrate moities of glycoproteins and glycolipids, and can elicit several biological effects, including cell agglutination, cell activation and mitogenesis. According to the gluten-lectin theory, celiac lesions represent a response to a toxic lectin, putatively wheat germ agglutinin (WGA). In this study we compared the serum antibody levels IgA, IgG and IgM to WGA and to gliadin in children under investigation for celiac disease (CD), as compared to reference children. We found that the levels of IgA and IgG to WGA as well as gliadin were significantly higher in celiac children on a gluten-containing diet, compared to children on gluten-free diet and reference children. These findings lend support to the concept that WGA is a biologically significant component of gluten. Since WGA can mimic the effects of epidermal growth factor (EGF) at the cellular level, we hypothesize that the crypt hyperplasia seen in celiac children could be due to a mitogenic response induced by WGA.

Adolescent↗

Gluten breakdown by lactobacilli and pediococci strains isolated from sourdough.

AIMS: To evaluate the growth and metabolic activity of lactobacilli and pediococci strains in a gluten base medium (GBM), formulated for a proper selection of proteolytic strains to be used in sourdough fermentation. METHODS AND RESULTS: Proteolytic activity by lactic acid bacteria (LAB) was evaluated by SDS-PAGE and by the amino acids released determined by reversed-phase high-performance liquid chromatography. Only 13 LAB (nine lactobacilli and four pediococci), among the 42 evaluated were able to utilize gluten as nitrogen source and to grow in GBM. Pediococcus pentosaceus CRL 797 showed a similar proteolytic activity to lactobacilli strains. In the majority of the cultures, basic amino acid group increased (c. 80% after 12 h incubation) mainly due to the release of ornithine, a flavour precursor of bread. Lysine, a limiting essential amino acid in wheat flour, increased by 150% in cultures of P. pentosaceus CRL 797. CONCLUSIONS: This study allows selecting P. pentosaceus CRL 797 and L. plantarum CRL 759 as potential starter culture for type III sourdough fermentation. It is shown for the first time that pediococci strains isolated from sourdough are proteolytically active on gluten. SIGNIFICANCE AND IMPACT OF THE STUDY: The physiological studies on gluten breakdown by LAB will contribute to the better selection of strains to produce breads with enhanced organoleptic characteristics.

Amino Acids↗

The natural history of gluten sensitivity: report of two new celiac disease patients resulting from a long-term follow-up of nonatrophic, first-degree relatives.

OBJECTIVE: Early studies revealed that up to 50% of non-atrophic, first-degree relatives of celiac disease patients exhibit features of gluten sensitivity. However, whether these features progress to a fully expressed celiac disease remain partially known. Our aim was to report two new patients resulting from a prospective, long-term surveillance of relatives who were nonatrophic at initial assessment. METHODS: After a median time of 86 months (range: 42-102 months) from the baseline assessment, we re-evaluated 44 first-degree relatives of propositi who had taken part in family studies and in whom baseline small intestinal biopsies were normal. At the baseline screening, 21 relatives had positive serum antigliadin antibodies and/or increased intraepithelial lymphocyte infiltration, and 23 did not. In addition, 11 of 18 had a celiac-like response to rectal gluten challenge and 16 of 34 possessed the characteristic HLA DQ2 haplotype (DQA1 0501 DQB1 0201). Re-evaluation was based on celiac-related serology antigliadin (AGA) and endomysial (EmA) antibodies. EmA-positive subjects underwent intestinal biopsy. RESULTS: At the end of the study, EmA was positive in only two subjects. Histological examination revealed flat small bowel mucosa in both. At baseline, both cases were EmA-negative and no minor histological changes were observed. One was a woman with positive baseline IgA and IgG AGA and a rectal gluten challenge with a celiac-like response; the other patient has presented only with a positive IgG AGA. In both cases, progression was detected in a clinically silent context. Both new patients had the characteristic HLA DQ2 haplotype. CONCLUSIONS: Our data suggest the need to re-evaluate relatives who have been negative on initial screening for celiac disease. Up to now, the progression to severe enteropathy was only observed in relatives who had presented some evidence of gluten sensitivity and the characteristic HLA DQ2 haplotype. Longer longitudinal studies are necessary to obtain definitive conclusions.

Adolescent↗

Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus.

OBJECTIVES: The association between celiac disease and insulin dependent diabetes mellitus (IDDM) is well established. Rectal gluten challenge has been used in patients with celiac disease and in first degree relatives as a tool to assess the mucosal immune response to gluten. The aim of this study was to assess the mucosal immune response to gluten in IDDM children by rectal gluten challenge. METHODS: Rectal biopsy specimens were obtained from 19 children with IDDM before and 6 h after rectal challenge with 2 g of a peptic tryptic digest of gliadin. A total of 16 treated celiac patients and 10 control subjects were also investigated. Epithelium and lamina propria CD3(+) and gamma delta(+) lymphocytes were counted with reference to a standard reference area of muscularis mucosae (10(4) microm(2)). RESULTS: After a local instillation of gliadin, a significant (>mean + 1 SD) percentage increment of lamina propria and epithelium CD3(+) and of lamina propria and epithelium gamma delta(+) lymphocytes was observed in five IDDM children, as compared to 11 and 13 celiac patients and one and two controls, respectively. A discriminant analysis allowed correct classification of 100% of patients with celiac disease and controls. The same analysis classified four of 19 IDDM children in the group of celiac patients. The positivity was associated with normal serology (antigliadin antibody, antiendomysial antibody, and antitissue transglutaminase antibodies) and a morphologically normal jejunal mucosa. All four patients had HLA-DQ alleles associated with celiac disease. CONCLUSIONS: Approximately 20% of IDDM children react to rectal instillation of gliadin. Long term follow-up is necessary to establish whether these subjects are at increased risk for developing celiac disease.

Adolescent↗

High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal.

OBJECTIVE: Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestation, and most celiac patients respond to a gluten-free diet (GFD). However, in some rare cases celiacs continue to experience GI symptoms after GFD, despite optimal adherence to diet. The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD. METHODS: We studied 15 celiac patients (five men, 10 women, mean age 36.5 yr, range 24-59 yr) who continued to experience GI symptoms after at least 6-8 months of GFD (even if of less severity). Antigliadin antibody (AGA) test, antiendomysial antibody (EMA) test, and sorbitol H2-breath test (H2-BT), as well as esophagogastroduodenoscopy (EGD) with histological evaluation, were performed before starting GFD. Bioptic samples were obtained from the second duodenal portion during EGD, and histopathology was expressed according to the Marsh classification. To investigate the causes of persistence of GI symptoms in these patients, we performed AGA and EMA tests, stool examination, EGD with histological examination of small bowel mucosa, and sorbitol-, lactose-, and lactulose H2-breath tests. RESULTS: Histology improved in all patients after 6-8 months of GFD; therefore, refractory celiac disease could be excluded. One patient with Marsh II lesions was fully compliant to his diet but had mistakenly taken an antibiotic containing gluten. Two patients showed lactose malabsorption, one patient showed Giardia lamblia and one patient Ascaris lumbricoides infestation, and 10 patients showed small intestinal bacterial overgrowth (SIBO) by lactulose H2-BT. We prescribed a diet without milk or fresh milk-derived foods to the patient with lactose malabsorption; we treated the patients with parasite infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet); at this visit all patients were symptom-free. CONCLUSIONS: This study showed that SIBO affects most celiacs with persistence of GI symptoms after gluten withdrawal.

Adult↗

Overweight in celiac disease: prevalence, clinical characteristics, and effect of a gluten-free diet.

BACKGROUND: It is well established that a minority of celiac patients present with "classic" symptoms due to malabsorption. However, few studies have focussed on the distribution of body mass index (BMI) in celiac populations and its relationship to clinical characteristics, or on its response to treatment. METHODS: We reviewed BMI measurements and other clinical and pathological characteristics from a database of 371 celiac patients diagnosed over a 10-yr period and seen by a single gastroenterologist. To assess response to gluten exclusion, we compared BMI at diagnosis and after 2 yr treatment in patients with serological support for dietary compliance. RESULTS: Mean BMI was 24.6 kg/m2 (range 16.3-43.5). Seventeen patients (5%) were underweight (BMI < 18.5), 211 (57%) were normal, and 143 (39%) were overweight (BMI > or = 25), including 48 (13% of all patients) in the obese range (BMI > or = 30.0). There was a significant association between low BMI and female gender, history of diarrhea, reduced hemoglobin concentration, reduced bone mineral density (BMD), osteoporosis, and higher grades (subtotal/total) of villous atrophy. Of patients compliant with a gluten-free diet, 81% had gained weight after 2 yr, including 82% of initially overweight patients. CONCLUSIONS: Few celiac patients are underweight at diagnosis and a large minority is overweight; these are less likely to present with classical features of diarrhea and reduced hemoglobin. Failed or delayed diagnosis of celiac disease may reflect lack of awareness of this large subgroup. The increase in weight of already overweight patients after dietary gluten exclusion is a potential cause of morbidity, and the gluten-free diet as conventionally prescribed needs to be modified accordingly.

Adult↗

IgA antibodies against gliadin and gluten in multiple sclerosis.

BACKGROUND: Multiple changes in antibodies against various antigens are found in multiple sclerosis (MS). OBJECTIVE: We wanted to measure immunoglobulin A (IgA) antibodies to some common food antigens in MS and also IgG against gliadin and gluten. METHODS: The IgA antibodies were measured in serum against gluten, gliadin, lactoglobulin, lactalbumin, casein and ovalbumin in patients with MS and controls using ELISA technique. IgG was likewise measured for gluten and gliadin. RESULTS: Highly significant increases compared with controls were found for IgA and IgG antibodies against gliadin and gluten. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative. CONCLUSIONS: The data presented indicate that there may be a possible moderately increased uptake of some specific proteins from the gut in MS compared with controls.

Adult↗

The gluten connection: the association between schizophrenia and celiac disease.

OBJECTIVE: Schizophrenia affects roughly 1% of the population and is considered one of the top 10 causes of disability worldwide. Given the immense cost to society, successful treatment options are imperative. Based on initial findings, gluten withdrawal may serve as a safe and economical alternative for the reduction of symptoms in a subset of patients. METHOD: A review of the literature relevant to the association between schizophrenia and celiac disease (gluten intolerance) was conducted. RESULTS: A drastic reduction, if not full remission, of schizophrenic symptoms after initiation of gluten withdrawal has been noted in a variety of studies. However, this occurs only in a subset of schizophrenic patients. CONCLUSION: Large-scale epidemiological studies and clinical trials are needed to confirm the association between gluten and schizophrenia, and address the underlying mechanisms by which this association occurs.

Autoimmune Diseases↗

A milligram of gluten a day keeps the mucosal recovery away: a case report.

In recent years it has been suggested that patients with celiac disease can be adequately followed up on the basis of merely clinical and serological response to a gluten-free diet. Thus, a duodenal biopsy some months after commencement of a gluten-free diet would no longer be necessary. We report here the case of a celiac patient in whom the ingestion of a milligram of gluten every day for 2 years prevented histological recovery in spite of satisfactory clinical and serological response. The literature regarding the minimal amount of gluten that could be harmless to celiac patients is reviewed.

Adult↗

Effect of gluten-free diet and adherence on growth and diabetic control in diabetics with coeliac disease.

AIMS: To study the effect of gluten-free diet on growth and diabetic control of children with type 1 diabetes mellitus and coeliac disease. METHODS: Twenty one children (mean age 7.5 years, range 1.6-12.9) with type 1 diabetes, primarily initially identified on the basis of symptoms and consecutively diagnosed with coeliac disease by biopsy over a 10 year period, were matched by sex, age at onset, and duration of diabetes with two diabetic controls without coeliac disease. Weight, height, haemoglobin A1c, and insulin requirements were measured before and for 12 months after the diagnosis and treatment of coeliac disease. Dietary awareness and adherence were assessed by structured questionnaire. RESULTS: A gluten-free diet resulted in a significant increase in weight-for-age z scores at 12 months after diagnosis (mean increase in z score 0.33) and in BMI (mean increase in z score 0.32). Increases in height did not achieve statistical significance. Controls showed no significant changes in weight, height, or BMI over the same period. Insulin dosage at diagnosis was less in coeliacs than in controls (mean difference 0.16 units/kg/day), but was similar to controls once a gluten-free diet had been established. Questionnaires were obtained in 20 patients. There appeared to be a relation between dietary awareness/adherence and growth parameters, but the small number of patients with "poor/fair" dietary adherence prevented meaningful analysis of this group. CONCLUSION: Identification and dietary treatment of coeliac disease in children with diabetes improved growth and influenced diabetic control. Evaluation of the outcome of treatment of coeliac disease in diabetics should include assessments of gluten intake.

Analysis of Variance↗

Genetic difference in HLA-DR phenotypes between coeliac disease and transitory gluten intolerance.

Genetic differences in HLA phenotypes were studied in coeliac disease to investigate why some patients do not react with mucosal damage after gluten challenge. Forty five children with coeliac disease and 16 with transitory gluten intolerance were typed; 76 subjects served as controls. HLA phenotypes in children with coeliac disease had significantly higher proportions of DR3/X and DR5/7 than controls (48.8% v 11.8% and 26.7% v 5.3%). Children with transitory gluten intolerance had lower DR3/X (43.8%) than children with coeliac disease and there were no DR5/7 phenotypes. Further analysis of similarly well defined cases might show whether genetic differences in the DR3/X and DR5/7 phenotypes can serve as a marker for the permanence of gluten intolerance.

Adolescent↗

Dermatitis herpetiformis: effect of gluten-free diet on skin IgA and jejunal structure and function.

To clarify the controversy about the effectiveness of a gluten-free diet in dermatitis herpetiformis, 10 highly motivated patients were investigated. The indices used to assess improvement included deposition of sub-epidermal IgA in unaffected skin, counts of intraepithelial lymphocytes, deposition of IgA in jejunal villi, and electrical tests of glucose absorption. In every patient subepidermal IgA concentrations fell after gluten withdrawal. In all but one patient the dose of dapsone necessary to control symptoms was reduced. Indeed, six patients stopped taking the drug completely within a year. In nine patients biopsy specimens were taken from the jejunum; seven showed abnormalities in jejunal morphology, eight had increased numbers of intraepithelial lymphocytes, and five had increased numbers of IgA-reactive cells in the lamina propria. Two of these three indices improved after gluten withdrawal, which confirmed that all nine patients were adhering to their diet. Routine screening for malabsorption proved to be unsatisfactory for showing the mild jejunal disease found in patients with dermatitis herpetiformis. The electrical test of glucose absorption showed subnormal results in all eight patients tested, however, and in six the results improved after gluten withdrawal.

Adult↗

Ultrastructural changes suggestive of immune reactions in the jejunal mucosa of coeliac children following gluten challenge.

The jejunal mucosa of eight coeliac children on a gluten-free diet and two non-coeliac children was studied by light and electron microscopy two to 98 hours after a single challenge dose of gluten. In all coeliac patients the early cytopathological reactions were principally confined to the structures within the subepithelial connective tissue. Changes were observed in the connective tissue fibrils, the basement membranes of epithelial and endothelial cells, the endothelium of small blood vessels, and the type and degree of inflammatory cell infiltration. The timing of these reactions was compatible with the concept that gluten acts as an antigen and combines with antibody in the form of immune complexes in the connective tissue close to the epithelium and to small blood vessels. These changes appeared to precede epithelial cell damage. No subepithelial tissue changes were seen in the non-coeliac patients after gluten challenge.

Antigen-Antibody Complex↗

Gluten-sensitive enteropathy: synthesis of antigliadin antibody in vitro.

The intestinal mucosa of patients with gluten-sensitive enteropathy responds to gluten challenge in vivo with a striking increase in IgA and IgM synthesis. Whether this increase in immunoglobulin synthesis is due in some part to the production of antigliadin antibodies is examined. Using an affinity chromatography technique it has been demonstrated that in six of seven patients with gluten-sensitive enteropathy approximately half of the net increase in IgA and IgM synthesis occurring after gluten challenge can be attributed to the synthesis of antigliadin antibody. These data strengthen the hypothesis that immunological phenomena are related to the pathogenesis of glutensensitive enteropathy.

Adolescent↗

The cellular infiltrate of the jejunum in adult coeliac disease and dermatitis herpetiformis following the reintroduction of dietary gluten.

The cellular infiltrate of the jejunal mucosa has been studied in patients with both treated and untreated adult coeliac disease and dermatitis herpetiformis and serially in treated patients before and after the reintroduction of gluten to the diet. In adult coeliac disease and dermatitis herpetiformis the jejunal mucosa showed similar abnormalities of the cellular infiltrate which was characterized by an increase in intraepithelial lymphocytes and lamina propria plasma cells and eosinophils, with the greatest numbers of cells occurring in untreated patients. At 24-48 hours following a single 25-g gluten challenge there was an increase in lamina propria plasma cells, lymphocytes and eosinophils and intraepithelial lymphocytes. This rise was sustained after seven days on a gluten-containing diet for all of these cell groups except lamina propria lymphocytes. These responses were essentially similar in both adult coeliac disease and in those dermatitis herpetiformis patients who had jejunal lesions before treatment. In dermatitis herpetiformis patients with normal jejunal morphology on a normal diet there was an upward trend in lamina propria plasma cells and intraepithelial lymphocytes within one to three weeks of taking extra dietary gluten. These results are compatible with the view that more than one immunological mechanism may be responsible for the pathogenesis of the jejunal lesion of coeliac disease and dermatitis herpetiformis.

Adult↗