Celiac Abstracts 5

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The management of complicated celiac disease

         (Al-toma, Verbeek et al. 2007) Download

Refractory celiac disease (RCD) is being defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of CD must be looked for, including the presence of antibodies in the untreated state and the presence of celiac-related HLA-DQ markers. In contrast to patients with a high percentage of aberrant T-cells, patients with RCD I seem to profit from an immunosuppressive treatment. RCD II is usually resistant to medical therapies. Response to corticosteroid treatment does not exclude underlying enteropathy-associated T-cell lymphoma. Cladribine seems to have a role, although it is less than optimal in the treatment of these patients. It may be considered, however, as the only treatment thus far studied that showed significant reduction of aberrant T cells, seems to be well tolerated, and may have beneficial long-term effects in a subgroup of patients showing significant reduction of the aberrant T-cell population. Autologous stem cell transplantation (ASCT) seems promising in those patients with persisting high percentages of aberrant T cells. The first group of patients treated with ASCT showed improvement in the small intestinal histology, together with an impressive clinical improvement. However, it remains to be proven if this therapy delays or prevents lymphoma development.

Celiac disease: from gluten to autoimmunity

            (Briani, Samaroo et al. 2008) Download

Celiac disease, also known as gluten-sensitive enteropathy and nontropical sprue, is a prevalent autoimmune disorder that is triggered by the ingestion of wheat gluten and related proteins of rye and barley in genetically susceptible individuals. The immune response in celiac disease involves the adaptive, as well as the innate, and is characterized by the presence of anti-gluten and anti-transglutaminase 2 antibodies, lymphocytic infiltration in the epithelial membrane and the lamina propria, and expression of multiple cytokines and other signaling proteins. The disease leads to inflammation, villous atrophy, and crypt hyperplasia in the small intestine. In addition to the intestinal symptoms, celiac disease is associated with various extra-intestinal complications, including bone and skin disease, anemia, endocrine disorders, and neurologic deficits. Gluten-free diet is currently the only effective mode of treatment for celiac disease, but better understanding of the mechanism of the disease is likely to add other choices for therapy in the future.

Clinical response to gluten withdrawal is not an indicator of coeliac disease

            (Campanella, Biagi et al. 2008) Download

OBJECTIVE: Although the diagnosis of coeliac disease requires specific histological and serological findings, patients considered to be affected by coeliac disease only on the basis of clinical improvement after gluten withdrawal are commonly referred to our outpatient clinic. The objective of this study was to investigate whether the clinical response of gastrointestinal symptoms to gluten withdrawal and subsequent dietary re-introduction could be an indicator of the presence of coeliac disease. MATERIAL AND METHODS: From December 1998 to January 2007, 180 patients on a gluten-free diet because of a diagnosis of coeliac disease not based on proper diagnostic criteria came to our out-patient clinic. In 112 of these patients, gluten was re-introduced into their diet. Subsequent duodenal biopsies and endomysial antibodies confirmed the diagnosis of coeliac disease in 51 of them. The relationship between improvement/worsening of symptoms and withdrawal/re-introduction of dietary gluten was analysed. RESULTS: Gastrointestinal symptoms improved in 64.7% of coeliac patients and 75.0% of non-coeliac patients after gluten withdrawal (chi(2) test, p=NS). Gluten re-introduction was followed by clinical exacerbation in 71.4% of coeliac patients and 54.2% of non-coeliac patients (chi(2) test, p=NS). The positive predictive value for clinical improvement after gluten withdrawal was 36%; the positive predictive value for clinical exacerbation after gluten re-introduction was 28%. CONCLUSIONS: Clinical response to either withdrawal or re-introduction of dietary gluten has no role in the diagnosis of coeliac disease.

Tissue transglutaminase in celiac disease: role of autoantibodies

            (Caputo, Barone et al. 2009) Download

In celiac disease (CD), gluten, the disease-inducing toxic component in wheat, induces the secretion of IgA-class autoantibodies which target tissue transglutaminase (tTG). These autoantibodies are produced in the small-intestinal mucosa, and, during gluten consumption, they can also be detected in patients' serum but disappear slowly from the circulation on a gluten-free diet. Interestingly, after adoption of a gluten-free diet the serum autoantibodies disappear from the circulation more rapidly than the small-intestinal mucosal autoantibody deposits. The finding of IgA deposits on extracellular tTG in the liver, kidney, lymph nodes and muscles of patients with CD indicates that tTG is accessible to the gut-derived autoantibodies. Although the specific autoantibody response directed against tTG is very characteristic in celiac patients, their role in the immunopathology of the celiac mucosal lesion is a matter of debate. Here we report a brief summary of anti-tTG antibody effects demonstrating that these antibodies are functional and not mere bystanders in the disease pathogenesis. In fact, they inhibit intestinal epithelial cell differentiation, induce intestinal epithelial cell proliferation, increase epithelial permeability and activate monocytes and disturb angiogenesis.

A deregulated immune response to gliadin causes a decreased villus height in DQ8 transgenic mice

            (D'Arienzo, Stefanile et al. 2009) Download

Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+ T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-gamma secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling.

Galectin-10, eosinophils, and celiac disease

         (De Re, Simula et al. 2009) Download

Celiac disease (CD) is a chronic intestinal disease caused by intolerance to dietary wheat gluten in genetically susceptible individuals. There are a number of important open questions that impede the full explanation of the pathogenesis of this disease. We analyzed protein expression pattern in gut biopsies of CD subjects. Patients were selected and grouped according to histological inflammatory degree. Groups consisted of nine individuals with CD: three patients had a Marsh 0, three a Marsh I-II, and three a Marsh III. All CD patients showed a human leukocyte antigen DQ2/8 variant. Controls were three individuals with an excluded CD diagnosis. For the first time, galectin-10 expression was found related to the histological grade (P = 0.0092) and with the number of eosinophils in the lesion (P = 0.0040). Results suggest galectin-10 is a novel marker for evaluating CD tissue damage and eosinophils as a possible target for therapeutic approaches. Moreover, our data provide insights into alterations associated with CD tissue damage and pathogenesis.

Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease

            (Di Sabatino, Pickard et al. 2007) Download

BACKGROUND & AIMS: Dendritic cells (DCs) play a crucial role in immune responses by controlling the extent and type of T-cell response to antigen. Celiac disease is a condition in which T-cell immunity to gluten plays an important pathogenic role, yet information on DCs is scant. We examined mucosal DCs in celiac disease in terms of phenotype, activation/maturation state, cytokine production, and function. METHODS: Mucosal DCs from 48 celiacs and 30 controls were investigated by flow cytometry. In situ distribution of DCs was analyzed by confocal microscopy. Interferon (IFN)-alfa, interleukin (IL)-4, IL-5, IL-12p35, IL-12p40, IL-18, IL-23p19, IL-27, and transforming growth factor-beta transcripts were measured by real-time reverse-transcription polymerase chain reaction in sorted DCs. DC expression of IL-6, IL-12p40, and IL-10 was assessed by intracellular cytokine staining. The effect of IFN-alfa and IL-18 blockade on the gluten-induced IFN-gamma response in celiac biopsy specimens grown ex vivo also was investigated. RESULTS: Mucosal DCs were increased in untreated, but not treated, celiacs. The majority of them were plasmacytoid with higher levels of maturation (CD83) and activation (CD80/CD86) markers. Higher transcripts of Th1 relevant cytokines, such as IFN-alfa, IL-18, and IL-23p19, were produced by celiac DCs, but because IL-12p40 was undetectable, a role for IL-23 is unlikely. Intracellular cytokine staining of celiac DCs showed higher IL-6, but lower IL-10 expression, and confirmed the lack of IL-12p40. Blocking IFN-alfa inhibited IFN-gamma transcripts in ex vivo organ culture of celiac biopsy specimens challenged with gluten. CONCLUSIONS: These data suggest that IFN-alfa-producing DCs contribute to the Th1 response in celiac disease.

Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia

            (Dickerson, Stallings et al. 2010) Download

BACKGROUND: Increased immune sensitivity to gluten has been reported in schizophrenia. However, studies are inconsistent about this association. METHODS: The sample of 471 individuals included 129 with recent-onset psychosis, 191 with multi-episode schizophrenia, and 151 controls. Immunoglobulin (Ig)G and IgA antibodies to gliadin and to tissue transglutaminase, and IgG antibodies to deamidated gliadin were measured. Quantitative levels of antibodies in the psychiatric groups were compared with controls. All participants were categorized as to whether their levels of antibodies met standardized cutoffs for celiac disease. HLA DQ2 and HLA DQ8 alleles were detected by real-time polymerase chain reaction. RESULTS: Individuals with recent-onset psychosis had increased levels of IgG (odds ratio [OR] 5.50; 95% confidence interval [CI] 2.65-11.42) and IgA (OR 2.75; 95% CI 1.31-5.75) antibodies to gliadin compared with control subjects. Individuals with multi-episode schizophrenia also had significantly increased levels of IgG antibodies to gliadin (OR 6.19; 95% CI 2.70-14.16). IgG antibodies to deamidated gliadin and IgA antibodies to tissue transglutaminase were not elevated in either psychiatric group, and fewer than 1% of individuals in each of the groups had levels of these antibodies predictive of celiac disease. There were no significant differences in the distribution of the HLA DQ2/8 alleles among the groups. CONCLUSIONS: Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Systemic autoimmune disorders in celiac disease

            (Fasano 2006) Download

PURPOSE OF REVIEW: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established. RECENT FINDINGS: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease. SUMMARY: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

Celiac disease pathogenesis: the proinflammatory cytokine network

            (Garrote, Gomez-Gonzalez et al. 2008) Download

In susceptible individuals, the adaptive response, mediated by the activation of antigen-specific T lymphocytes, drives a proinflammatory response, which ends in an immune-mediated enteropathy characterized by villous atrophy, crypt hyperplasia, and recruitment of intraepithelial lymphocytes. In addition, some gluten peptides are able to induce an innate immune response in intestinal mucosa. The molecular mechanisms and the cells involved in the initial stages of the gluten-intestinal mucosa interaction are poorly understood to date. There is evidence of a direct toxic effect of gluten peptides in several biological models. However, the failure to control the inflammatory response may be one of the factors underlying gluten intolerance in these individuals. The cytokine network involved in celiac disease is characterized by abundant interferon-gamma in the intestinal mucosa. In addition, the production of interleukin (IL)-15, IL-18, and IL-21 is linked to gluten intake, which can drive the inflammatory response probably sustained by IL-18, IL-21, and perhaps IL-27 through STAT1 and STAT5 pathways, whereas neither IL-12 nor IL-23 plays a significant role in pathogenic mechanisms. Herein we describe the involvement of these activation pathways in the context of the pathogenesis of celiac disease.

Pathways of gliadin transport in celiac disease

         (Heyman and Menard 2009) Download

Celiac disease (CD) is an inflammatory enteropathy induced by gluten/gliadins in genetically susceptible individuals. In patients with active CD, an abnormal retro-transport of IgA/gliadin immune complexes is observed. This retro-transport is mediated by the expression of CD71 on the apical pole of enterocytes and promotes the entry of harmful gliadin peptides in the intestinal mucosa and the triggering of abnormal immune responses to gliadin peptides. Our results indicate a CD71-mediated transcytosis of gliadin peptides that may participate in the pathogenesis of CD in genetically predisposed individuals.

Coeliac disease and Type 1 diabetes mellitus - the case for screening

         (Holmes 2001) Download

AIM: To review the relationship between coeliac disease and Type 1 diabetes mellitus with emphasis on prevalence of coeliac disease, presentation and implications for screening. METHODS: Papers collected over many years by the author have been included in the review and a literature search employing Medline was undertaken to August 2000. Search words used were coeliac disease and diabetes mellitus. RESULTS: Twenty papers exploring the prevalence of coeliac disease by serological screening of Type 1 diabetes in children, eight in adults and two including both groups were found. An additional 48 papers are included and relate to serological screening tests for coeliac disease, expressions and complications of coeliac disease, the value of GFD and the genetics of the two conditions. Unless formal screening studies are undertaken coeliac disease will not be diagnosed because patients are asymptomatic, have atypical symptoms or even in those with symptoms the diagnosis is overlooked. Based on small bowel biopsy, diagnosis the prevalence of coeliac disease in Type 1 diabetes in children is 1:6 to 1:103 and in adults 1:16 to 1:76. Patients may improve following the start of a gluten-free diet (GFD) in terms of symptoms, growth in children, serum antibody levels, haematological and biochemical indices, morphology of the small intestinal mucosa and control of diabetes. CONCLUSION: Coeliac disease commonly occurs in Type 1 diabetes. It is recommended that screening for coeliac disease should be part of the routine investigation and offered to all patients because of the high prevalence and the potential benefits of treatment with a GFD. This includes control of symptoms, stabilization of diabetes and prevention of complications associated with coeliac disease. The cost per patient diagnosed with coeliac disease from the existing population with Type 1 diabetes would be pound860 and for those newly arising pound950.

What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis

            (Hopper, Hadjivassiliou et al. 2008) Download

BACKGROUND & AIMS: The optimal serologic tests for the detection of celiac disease and follow-up assessment remains controversial. Our aim was to evaluate all current immunologic assays for diagnosing celiac disease using the gold standard of duodenal biopsy. We also assessed whether tissue transglutaminase (tTG) antibody is a quantitative marker for histologic severity. METHODS: Consecutive adult patients referred for gastroscopy without a previous known diagnosis of celiac disease were recruited (group 1). Concurrently, patients with a known diagnosis of celiac disease on a gluten-free diet for more than 1 year undergoing repeat duodenal biopsy were identified (group 2). All patients had duodenal biopsies and serologic analysis performed for immunoglobulin(Ig) A and antibodies to human immunoglobulin (Ig)A-tTG, IgA-gliadin, IgG-gliadin, and IgA-endomysial antibody. RESULTS: Two thousand patients were recruited in the first group. Seventy-seven (3.9%) patients were diagnosed with new celiac disease. The sensitivity, specificity, positive predictive value, and negative predictive value for IgA tTG were 90.9%, 90.9%, 28.6%, and 99.6%. When adopting a 2-step approach using tTG first and then EMA the sensitivity, specificity, positive predictive value, and negative predictive value was 85.7%, 98.6%, 71.7%, and 99.7%, respectively. The use of nondeamidated IgA/IgG gliadin antibodies conferred no additional diagnostic benefit when considering the detection of adult celiac disease. In the second group 48 patients with celiac disease on a gluten-free diet were identified. Sixteen of 48 of these patients had persisting villous atrophy, but 7 of 16 (44%) had a normal tTG level. CONCLUSIONS: IgA tTG alone is a sensitive marker for celiac disease. A normal tTG level does not predict recovery of villous atrophy in patients with celiac disease on a gluten-free diet.

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

            (Lindfors, Kaukinen et al. 2009) Download

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.

Palmoplantar pustulosis and gluten sensitivity: a study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet

            (Michaelsson, Kristjansson et al. 2007) Download

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic inflammatory disease affecting mainly smoking women. Some patients also have psoriasis. A subgroup of patients with psoriasis has been shown to have silent gluten sensitivity with relevance for their psoriasis. Nothing is known about gluten sensitivity in PPP. OBJECTIVES: To find out whether any patients with PPP are gluten-sensitive and whether this might be relevant for the PPP activity. PATIENTS AND METHODS: One hundred and twenty-three patients (113 women) with PPP participated. Screening for IgA antibodies against gliadin and tissue transglutaminase (tTG) was performed, the duodenal mucosa in patients with and without these antibodies was studied and the effect of a gluten-free diet (GFD) was followed up. RESULTS: Twenty-two patients (18%) had IgA antibodies against gliadin and nine of 94 (10%) against tTG. Twelve patients with antibodies and 11 without underwent gastro-duodenoscopy. Four displayed villous atrophy, whereas all other specimens were judged as essentially normal at routine staining. However, with immunohistochemistry, the numbers of CD3+ and CD8+ lymphocytes in the epithelium were found to be increased in patients with any type of antibody, although they were most numerous in those with both types of antibodies. Seven of 123 patients (6%) had coeliac disease (three previously diagnosed). Patients with antibodies who adhered to the GFD displayed total or nearly total clearance of the skin lesions and normalization of the antibody levels. CONCLUSIONS: Patients with PPP should be screened for antibodies against gliadin and tTG. Those with antibodies can be much improved on a GFD regardless of the degree of mucosal abnormalities.

The absence of a mucosal lesion on standard histological examination does not exclude diagnosis of celiac disease

            (Mohamed, Feighery et al. 2008) Download

Some patients with undiagnosed celiac disease have minor mucosal lesions that may not be apparent during routine histological analysis. Twenty-five such patients of our institution were discharged to their primary-care physicians despite having positive endomysial antibody serology. To re-evaluate diagnosis for these patients, immunohistological staining with antibodies to CD2, CD3, CD7, CD8, CD69, and Ki67 was conducted on original biopsies from twenty patients. Clinical, serological, and histological investigations were offered to all fourteen patients who attended for review. We observed a significantly greater (P < 0.0001) numbers of intraepithelial lymphocytes and Ki67-positive enterocytes in sections from these twenty patients than for normal controls. Of the fourteen patients who attended for further review, firm diagnosis of celiac disease was made for seven patients and diagnosis was likely for another two. Our study clearly revealed that over-reliance on standard histological findings results in failure to diagnose celiac disease.

Meta-analysis: coeliac disease and hypertransaminasaemia

            (Sainsbury, Sanders et al. 2011) Download

Background There may be a positive association between coeliac disease and serum hypertransaminasaemia but evidence is conflicting. Aims To conduct a systematic review and meta-analysis to determine the prevalence of coeliac disease in adults presenting with cryptogenic serum hypertransaminasaemia and the prevalence of hypertransaminasaemia in patients with newly diagnosed coeliac disease. Methods MEDLINE and EMBASE were searched up to August 2010. Case series and case-control studies recruiting adults with either cryptogenic hypertransaminasaemia that applied serological tests for coeliac disease and/or distal duodenal biopsy to participants or newly diagnosed biopsy-proven coeliac disease that assessed serum transaminases were eligible. The pooled prevalence of coeliac disease in individuals presenting with abnormal serum transaminases and the pooled prevalence of hypertransaminasaemia in newly diagnosed coeliac disease were calculated with 95% confidence intervals (CI). Results Eleven eligible studies were identified. Pooled prevalences of positive coeliac serology and biopsy-proven coeliac disease in cryptogenic hypertransaminasaemia were 6% (95% CI 3% to 10%) and 4% (95% CI 1% to 7%) respectively. Pooled prevalence of abnormal serum transaminases in newly diagnosed coeliac disease was 27% (95% CI 13% to 44%). Exclusion of gluten led to normalisation of serum transaminase levels in 63% to 90% of patients within 1 year. Conclusions Undetected coeliac disease is a potential cause for cryptogenic hypertransaminasaemia in 3% to 4% of cases. More than 20% of individuals with newly diagnosed coeliac disease may have abnormal serum transaminases and these normalise on a gluten-free diet in the majority of cases.

Celiac disease: from pathogenesis to novel therapies

            (Schuppan, Junker et al. 2009) Download

Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4(+) T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically.

Celiac disease: risk assessment, diagnosis, and monitoring

            (Setty, Hormaza et al. 2008) Download

Celiac disease is an autoimmune disorder occurring in genetically susceptible individuals, triggered by gluten and related prolamins. Well identified haplotypes in the human leukocyte antigen (HLA) class II region (either DQ2 [DQA*0501-DQB*0201] or DQ8 [DQA*0301-DQB1*0302]) confer a large part of the genetic susceptibility to celiac disease.Celiac disease originates as a result of a combined action involving both adaptive and innate immunity. The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrating HLA-DQ2 or -DQ8 restrictive binding motifs across various gluten proteins. As for innate immunity, through specific natural killer receptors expressed on their surface, intra-epithelial lymphocytes recognize nonclassical major histocompatibility complex (MHC)-I molecules such as MICA, which are induced on the surface of enterocytes by stress and inflammation, and this interaction leads to their activation to become lymphokine-activated killing cells. Four possible presentations of celiac disease are recognized: (i) typical, characterized mostly by gastrointestinal signs and symptoms; (ii) atypical or extraintestinal, where gastrointestinal signs/symptoms are minimal or absent and a number of other manifestations are present; (iii) silent, where the small intestinal mucosa is damaged and celiac disease autoimmunity can be detected by serology, but there are no symptoms; and, finally, (iv) latent, where individuals possess genetic compatibility with celiac disease and may also show positive autoimmune serology, that have a normal mucosa morphology and may or may not be symptomatic.The diagnosis of celiac disease still rests on the demonstration of changes in the histology of the small intestinal mucosa. The classic celiac lesion occurs in the proximal small intestine with histologic changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Currently, serological screening tests are utilized primarily to identify those individuals in need of a diagnostic endoscopic biopsy. The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%). Anti-endomysium antibodies-IgA (EMA), on the other hand, have close to 100% specificity and a sensitivity of greater than 90%. The interplay between gliadin peptides and TG2 is responsible for the generation of novel antigenic epitopes, the TG2-generated deamidated gliadin peptides. Such peptides represent much more celiac disease-specific epitopes than native peptides, and deamidated gliadin antibodies (DGP) have shown promising results as serological markers for celiac disease. Serology has also been employed in monitoring the response to a gluten-free diet.Despite the gluten-free diet being so effective, there is a growing demand for alternative treatment options. In the future, new forms of treatment may include the use of gluten-degrading enzymes to be ingested with meals, the development of alternative, gluten-free grains by genetic modification, the use of substrates regulating intestinal permeability to prevent gluten entry across the epithelium, and, finally, the availability of different forms of immunotherapy.

Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome

            (Wahnschaffe, Schulzke et al. 2007) Download

BACKGROUND & AIMS: Gluten sensitivity might cause abdominal symptoms in the absence of villous atrophy. We examined the prevalence of celiac disease-associated serum antibodies in diarrhea-dominant irritable bowel syndrome (d-IBS) patients and their efficacy in combination with HLA-DQ2 expression to predict the response to gluten-free diet. METHODS: HLA-DQA1*0501/DQB1*0201 expression and celiac disease-associated IgA and IgG serum antibodies against gliadin and tissue-transglutaminase were measured in 145 patients with d-IBS, 74 patients with untreated and treated celiac disease, and 57 patients with active IBD. Follow-up antibody levels, stool frequency, and gastrointestinal symptom scores were determined in 41 d-IBS patients (26 women, 15 men; median age, 46 years, range, 30-67 years) who participated in a nonrandomized evaluation of 6 months of gluten-free diet. RESULTS: Increased celiac disease-associated serum IgG, but not IgA, was found in the majority of patients with treated (55%) as in most patients with untreated celiac disease (97%). In d-IBS patients, celiac disease-associated serum IgG antibodies (37%) and HLA-DQ2 expression (39%) were more frequent than in IBD patients (18% and 23%, respectively). After 6 months of gluten-free diet, stool frequency and gastrointestinal symptom score returned to normal values in 60% of d-IBS patients who were positive and in 12% who were negative for HLA-DQ2 and celiac disease-associated serum IgG; both parameters combined yielded positive and negative predictive values of 56% (95% confidence interval, 30%-80%) and 88% (69%-97%), respectively. CONCLUSIONS: Celiac disease-associated serum IgG and HLA-DQ2 expression can identify likely responders to gluten-free diet in d-IBS patients.


Al-toma, A., W. H. Verbeek, et al. (2007). "The management of complicated celiac disease." Dig Dis 25(3): 230-6.

Briani, C., D. Samaroo, et al. (2008). "Celiac disease: from gluten to autoimmunity." Autoimmun Rev 7(8): 644-50.

Campanella, J., F. Biagi, et al. (2008). "Clinical response to gluten withdrawal is not an indicator of coeliac disease." Scand J Gastroenterol 43(11): 1311-4.

Caputo, I., M. V. Barone, et al. (2009). "Tissue transglutaminase in celiac disease: role of autoantibodies." Amino Acids 36(4): 693-9.

D'Arienzo, R., R. Stefanile, et al. (2009). "A deregulated immune response to gliadin causes a decreased villus height in DQ8 transgenic mice." Eur J Immunol 39(12): 3552-61.

De Re, V., M. P. Simula, et al. (2009). "Galectin-10, eosinophils, and celiac disease." Ann N Y Acad Sci 1173: 357-64.

Di Sabatino, A., K. M. Pickard, et al. (2007). "Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease." Gastroenterology 133(4): 1175-87.

Dickerson, F., C. Stallings, et al. (2010). "Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia." Biol Psychiatry 68(1): 100-4.

Fasano, A. (2006). "Systemic autoimmune disorders in celiac disease." Curr Opin Gastroenterol 22(6): 674-9.

Garrote, J. A., E. Gomez-Gonzalez, et al. (2008). "Celiac disease pathogenesis: the proinflammatory cytokine network." J Pediatr Gastroenterol Nutr 47 Suppl 1: S27-32.

Heyman, M. and S. Menard (2009). "Pathways of gliadin transport in celiac disease." Ann N Y Acad Sci 1165: 274-8.

Holmes, G. K. (2001). "Coeliac disease and Type 1 diabetes mellitus - the case for screening." Diabet Med 18(3): 169-77.

Hopper, A. D., M. Hadjivassiliou, et al. (2008). "What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis." Clin Gastroenterol Hepatol 6(3): 314-20.

Lindfors, K., K. Kaukinen, et al. (2009). "A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease?" Amino Acids 36(4): 685-91.

Michaelsson, G., G. Kristjansson, et al. (2007). "Palmoplantar pustulosis and gluten sensitivity: a study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet." Br J Dermatol 156(4): 659-66.

Mohamed, B. M., C. Feighery, et al. (2008). "The absence of a mucosal lesion on standard histological examination does not exclude diagnosis of celiac disease." Dig Dis Sci 53(1): 52-61.

Sainsbury, A., D. S. Sanders, et al. (2011). "Meta-analysis: coeliac disease and hypertransaminasaemia." Aliment Pharmacol Ther.

Schuppan, D., Y. Junker, et al. (2009). "Celiac disease: from pathogenesis to novel therapies." Gastroenterology 137(6): 1912-33.

Setty, M., L. Hormaza, et al. (2008). "Celiac disease: risk assessment, diagnosis, and monitoring." Mol Diagn Ther 12(5): 289-98.

Wahnschaffe, U., J. D. Schulzke, et al. (2007). "Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome." Clin Gastroenterol Hepatol 5(7): 844-50; quiz 769.