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PubMed2000

Molecular basis of celiac disease.

Celiac disease (CD) is an intestinal disorder with multifactorial etiology. HLA and non-HLA genes together with gluten and possibly additional environmental factors are involved in disease development. Evidence suggests that CD4(+) T cells are central in controlling an immune response to gluten that causes the immunopathology, but the actual mechanisms responsible for the tissue damage are as yet only partly characterized. CD provides a good model for HLA-associated diseases, and insight into the mechanism of this disease may well shed light on oral tolerance in humans. The primary HLA association in the majority of CD patients is with DQ2 and in the minority of patients with DQ8. Gluten-reactive T cells can be isolated from small intestinal biopsies of celiac patients but not of non-celiac controls. DQ2 or DQ8, but not other HLA molecules carried by patients, are the predominant restriction elements for these T cells. Lesion-derived T cells predominantly recognize deamidated gluten peptides. A number of distinct T cell epitopes within gluten exist. DQ2 and DQ8 bind the epitopes so that the glutamic acid residues created by deamidation are accommodated in pockets that have a preference for negatively charged side chains. Evidence indicates that deamidation in vivo is mediated by the enzyme tissue transglutaminase (tTG). Notably, tTG can also cross-link glutamine residues of peptides to lysine residues in other proteins including tTG itself. This may result in the formation of complexes of gluten-tTG. These complexes may permit gluten-reactive T cells to provide help to tTG-specific B cells by a mechanism of intramolecular help, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD.

Animals↗

PubMed2006

Intestinal T cell responses to cereal proteins in celiac disease.

Celiac disease is caused by sensitivity to wheat gluten in genetically susceptible individuals. The etiological role of the other wheat-related cereals, barley, rye, and oats, is still debated. In order to investigate this issue further, in this study we examined the immune response of celiac mucosal T cell lines to fractions from all four cereals. Cell stimulation was assessed by measuring proliferation (employing (3)H-thymidine incorporation) or cytokine (IL-2, IFN-gamma) production. All five T cell lines demonstrated immunoreactivity to protein fractions from the four related cereals. In some cell lines, reactivity to wheat, barley, and rye was only evident when these cereal fractions had been pretreated with tissue transglutaminase. This study confirms the similar T cell antigenic reactivity of these four related cereals and has implications for their exclusion in the gluten-free diet. However, despite oats stimulation of T cell lines, this cereal does not activate a mucosal lesion in most celiac patients.

Adult↗

PubMed1992

Eicosanoids content in small intestinal mucosa of children with celiac disease.

Celiac disease (CD) is characterized by diarrhea, growth retardation, and weight loss in genetically susceptible subjects on a gluten-containing diet. The exact pathogenesis of CD is still obscure, but it is considered to be immunologically mediated. We have previously shown elevated prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) content in small intestinal mucosa obtained from active celiac children. In the present study, we found significantly elevated PGE2, leukotriene B4 (LTB4), and leukotrienes C4, D4, and E4 (LTC4D4E4) content in small bowel mucosa from children suffering from CD on a gluten-containing diet in comparison to control subjects. PGE2 was 25,278 +/- 7,761 vs. 4,478 +/- 426 pg/mg of protein (mean +/- SEM), respectively. LTB4 was 8,807 +/- 3,706 vs. 403 +/- 63 pg/mg of protein (mean +/- SEM), respectively. LTC4D4E4 was 15,369 +/- 4,085 vs. 2,998 +/- 279 pg/mg of protein (mean +/- SEM), respectively. We conclude that the elevated content of arachidonic acid metabolic products via cyclooxygenase and lipoxygenase pathways may contribute to the diarrhea and may be involved in the pathogenesis of mucosal injury.

Adolescent↗

PubMed2005

Neurologic presentation of celiac disease.

Celiac disease (CD) long has been associated with neurologic and psychiatric disorders including cerebellar ataxia, peripheral neuropathy, epilepsy, dementia, and depression. Earlier reports mainly have documented the involvement of the nervous system as a complication of prediagnosed CD. However, more recent studies have emphasized that a wider spectrum of neurologic syndromes may be the presenting extraintestinal manifestation of gluten sensitivity with or without intestinal pathology. These include migraine, encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barre-like syndrome, and neuropathy with positive antiganglioside antibodies. The association between most neurologic syndromes described and gluten sensitivity remains to be confirmed by larger epidemiologic studies. It further has been suggested that gluten sensitivity (as evidenced by high antigliadin antibodies) is a common cause of neurologic syndromes (notably cerebellar ataxia) of otherwise unknown cause. Additional studies showed high prevalence of gluten sensitivity in genetic neurodegenerative disorders such as hereditary spinocerebellar ataxia and Huntington's disease. It remains unclear whether gluten sensitivity contributes to the pathogenesis of these disorders or whether it represents an epiphenomenon. Studies of gluten-free diet in patients with gluten sensitivity and neurologic syndromes have shown variable results. Diet trials also have been inconclusive in autism and schizophrenia, 2 diseases in which sensitivity to dietary gluten has been implicated. Further studies clearly are needed to assess the efficacy of gluten-free diet and to address the underlying mechanisms of nervous system pathology in gluten sensitivity.

Autistic Disorder↗

PubMed2006

Gluten-free diet: the medical and nutrition management of celiac disease.

Celiac disease (CD) is a chronic disease causing inflammation of the proximal small intestine that occurs in genetically predisposed individuals when they eat gluten, which is the storage protein in wheat, barley, and rye. The disease injury usually resolves when gluten is excluded from the diet. Although the injury will heal, the reaction to gluten is permanent and will recur with the reintroduction of gluten. The condition is surprisingly common, affecting as many as 1% of white populations. The consequences of the disease are predominantly those of malnutrition due to maldigestion and malabsorption, such as diarrhea, weight loss, and anemia. Symptoms caused by inflammation of the small intestine are also common. CD, although it is common and its pathology is well understood, frequently goes undiagnosed, probably because of the nonspecific or vague nature of many of the symptoms that occur. The cornerstone of treatment for CD is elimination of gluten from the diet. In most patients diagnosed with CD, a strict gluten-free diet (GFD) alone should result in complete symptomatic and histologic resolution of the disease and reduce risk of complications. Noncompliance with diet is the leading cause of failure to respond in patients with CD. For these reasons, thorough assessment and counseling at the time of diagnosis and ongoing care are crucial. In this article, we address briefly what is known about the pathogenesis and diagnosis of CD and address its treatment in detail.

Celiac Disease↗

PubMed2006

Cutaneous manifestations in celiac disease.

Celiac disease (CD) is an autoimmune gluten-dependent enteropathy characterized by atrophy of intestinal villi that improves after gluten-free diet (GFD). CD is often associated with extra-intestinal manifestations; among them, several skin diseases are described in CD patients. The present review reports all CD-associated skin manifestations described in the literature and tries to analyze the possible mechanisms involved in this association. The opportunity to evaluate the possible presence of CD in patients affected by skin disorders is discussed.

Celiac Disease↗

PubMed2000

Serum antibodies in celiac disease.

Celiac disease is characterized by small intestinal damage which often leads to global malabsorption. For diagnosis an intestinal biopsy to demonstrate the mucosal changes is mandatory. However, serological tests are useful additional tools to confirm the diagnosis and to monitor therapy. These serological tests, which are based on the detection of antibodies against gliadin and autoantibodies against components of the extracellular matrix, are described in this article.

Autoantibodies↗

PubMed2002

New developments in childhood celiac disease.

Celiac disease (CD) is one of the most common lifelong disorders in Europe and the United States, in both children and adults. It is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. This review addresses new developments in CD with respect to pediatric patients and emphasizes the need for awareness among health-care professionals. The epidemiology, pathophysiology, diagnosis, and clinical spectrum of CD in children are highlighted.

Algorithms↗

PubMed2006

Sourdough lactobacilli and celiac disease.

Celiac disease (CD) is one of the most common food intolerance. The only effective treatment for CD is a strict adherence to a gluten-free diet throughout the patient's lifetime. Gluten-free products are not widely available and are usually more expensive than their gluten-containing counterparts. There is, therefore, an urgent need to develop safe and effective therapeutic alternatives, to develop high-quality gluten-free products and to investigate the potential of the bread making biotechnology following ancient protocols which include long-time fermentation by selected sourdough lactic acid bacteria. This review describes the most relevant results related to biotechnologies that use selected sourdough lactic acid bacteria and probiotics as starters for sourdough fermentation to investigate their potential to decrease the risk of gluten contamination in gluten-free products. As shown by studies in vitro on celiac intestinal tissue and in vivo on CD patients, the bacterial proteolytic activity is rather promising not only as currently demonstrated for eliminating traces of contaminant gluten but probably also in perspective for the manufacture of tolerated baked goods.

Bread↗

PubMed2005

Adaptive and innate immune responses in celiac disease.

Celiac disease (CD) is a complex small intestinal disorder due to a dysregulated immune response to wheat gliadin and related proteins which leads to a small intestinal enteropathy. It is generally accepted that CD is a T-cell mediated disease, in which, gliadin derived peptides, either in native form or deamidated by tissue transglutaminase, activate lamina propria infiltrating T lymphocytes which release proinflammatory cytokines. Recent studies indicate that gliadin contains also peptides able to activate an innate immune response. In particular, they induce a selective expansion of IEL, particularly TCRgamma/delta+ and CD8+TCR alpha/beta+ lymphocytes bearing the CD94 NK receptor, as well as a strong epithelial expression of MICA molecules which interact with NKG2D receptor expressed on TCRgamma/delta+ and NK cells. Most of the events of innate immune activation events are inhibited by antibodies neutralizing IL-15, thus confirming the key role of this cytokine as a mediator of intestinal mucosa damage induced by ingestion of gliadin. It remains to be established to what extent the ability of gliadin peptides to activate innate immunity relates to other biological properties exerted not only on celiac cells and tissues; the specificity of celiac patients is probably related to their genetic make up.

Animals↗

PubMed2003

Plasma motilin in untreated celiac disease.

Celiac disease (CD) is characterized by mucosal villous atrophy mostly confined to the proximal small intestine. Upper-gut motor abnormalities have been reported. Motilin, localized in cells in the proximal small intestine, is a trigger factor for the migrating motor complex. Plasma levels of motilin were studied in 16 untreated CD patients and in an age-matched control group of 18 healthy subjects by radioimmunoassay and by high-performance liquid chromatography (HPLC). The fasting levels of motilin and postprandial levels were significantly higher in CD patients compared to controls (P<0.01) and HPLC revealed a divergent individual pattern of the motilin fragments.

Adult↗

PubMed2006

Liver involvement in celiac disease.

Celiac disease may present as a cryptogenic liver disorder being found in 5-10 % of patients with a persistent and cryptogenetic elevation of serum aminotransferase activity. In fact, a wide spectrum of liver injuries in children and adults may be related to CD and in particular: (1) a mild parenchymal damage characterised by absence of any clinical sign or symptom suggesting a chronic liver disease and by non-specific histological changes reversible on a gluten-free diet; (2) a chronic inflammatory liver injury of autoimmune mechanism, including autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis, that may lead to fibrosis and cirrhosis, generally unaffected by gluten withdrawal and necessitating an immunosuppressive treatment; (3) a severe liver failure potentially treatable by a gluten-free diet. Such different types of liver injuries may represent a spectrum of a same disorder where individual factors, such as genetic predisposition, precocity and duration of exposure to gluten may influence the reversibility of liver damage. A rigorous cross-checking for a asymptomatic liver damage in CD individuals and conversely, for CD in any cryptogenic liver disorder including end-stage liver failure is recommended.

Celiac Disease↗

PubMed2005

[Cytokines in the pathogeny of celiac disease].

Celiac disease is manifested by an enteropathy caused by intolerance to gluten, a family of proteins found in wheat and other cereals. Following intestinal T-cell activation in predisposed individuals, different inflammatory mechanisms are triggered under the control of the cytokine balance including those with a pro-inflammatory Th1 pattern such as IFNgamma, TNFalpha, IL-15 and IL-18; and regulatory cytokines such as TGFbeta and IL-10. These cytokines, besides increasing the intensity of the activation and the number of immune cells within the intestinal mucosa, regulate the activity of epithelial growth factors and metalloproteinases, a group of molecules involved in the maintenance and turnover of the intestinal mucosa structure; in inflammatory conditions, they also induce the intestinal lesion responsible for malabsorption syndrome.

Celiac Disease↗

PubMed1994

T cell receptor gene expression and genotypes in celiac disease.

Celiac disease (CD) occurs as a result of an abnormal immune response, within the mucosa of the small bowel, to dietary gliadin peptides. To further characterize the intramucosal lymphocytes in patients with untreated CD, we compared T cell receptor (TCR) variable region gene expression in small bowel biopsies from patients with CD to that of normal small bowel. We also assessed TCR genotypes, using restriction fragment length polymorphisms (RFLPs) spanning the V beta gene locus, comparing 59 CD patients to 64 normals. The abnormal immune response in CD is polyclonal, without evidence of restriction or significantly increased expression of any TCR variable region gene families, compared to normal small bowel. No significant association was found between TCR genotypes, as defined by TCR V beta RFLPs, and CD.

Adult↗

PubMed2002

Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease.

Celiac disease (CD) is characterized by a striking expansion of gamma delta T cells in the intestine. These cells interact with MICA, a cell surface protein encoded by a major histocompatibility complex gene. We investigated whether MICA gene polymorphism could contribute to susceptibility to CD. DNA typing for HLA-DR, DQA1, DQB1, TNF-308, TNFa, TNFb and a triplet repeat polymorphism in the transmembrane region of the MICA gene were carried out. We performed case-control stratified association studies and transmission disequilibrium tests. Our results indicate that although there is no primary association between MICA polymorphism and CD, there is, in addition to HLA-DQ, a second susceptibility locus on the 8.1 ancestral haplotype in strong linkage disequilibrium with MICA A5.1 allele.

Alleles↗

PubMed2005

The IL-1 gene family and bone involvement in celiac disease.

Celiac disease (CD) is associated with decreased bone mineral mass. Its pathogenesis is multifactorial since both systemic and local mechanisms may play a role. Our objective was to determine whether single-nucleotide polymorphisms in genes encoding members of the interleukin-1 family are associated with bone damage measured by densitometry in a series of 71 adult CD patients assessed at diagnosis. When compared with non-carrier CD patients, carriers of allele T of the interleukin-1beta gene (IL1B-511T) had a significantly lower bone mass at the total skeleton level (p = 0.0484) and a greater prevalence of osteopenia/osteoporosis (p = 0.0102). To our knowledge, this is the first evidence on the association between a genetic predisposition and low bone mass in CD patients. This finding supports the postulated inflammation-associated bone loss pathogenesis as one of the causes of bone weakness in CD.

Adult↗

PubMed2006

Possible drug targets for celiac disease.

Celiac disease (CD) is an intestinal disorder caused by an altered immune response against wheat gluten, a common dietary antigen, and related cereal proteins. Both CD4+ and CD8+ T cells have a role in inducing the intestinal damage, although recent studies have also pinpointed the involvement of the innate immune response in CD pathogenesis. So far, the only available treatment for CD is the strict avoidance of gluten in the diet, but the poor compliance and the associated complications demand alternative therapies. During the last decade, the knowledge of genetic, molecular and cellular mechanisms leading to CD pathogenesis made great progress. The improved understanding of gluten peptides activating either adaptive or innate immune response, of HLA restriction molecules, as well as of cytokines that mediate most of the inflammatory reactions, opens several new promising perspectives for therapeutic intervention. This review discusses both molecular and cellular strategies to treat CD, including the use of proteolytic enzymes active on gluten peptides, antibodies neutralising IL-15 and IFN-gamma, drugs targeting HLA, regulatory cytokines and T cells.

Celiac Disease↗

PubMed1996

Gastric and esophageal intraepithelial lymphocytes in pediatric celiac disease.

Celiac disease (CD) is associated with marked mononuclear cell inflammation in the small intestinal mucosa. This study was performed to evaluate analogous changes in the gastric and esophageal mucosa of pediatric patients with CD, with emphasis on epithelial lymphocytosis. We evaluated intraepithelial lymphocytes (IELs) in 23 gastric (no.IELs/100 epithelial cells) and 14 esophageal mucosal biopsy specimens (IELs/hpf) from 23 pediatric cases of CD and 10 nonceliac matched controls. Four patients had postgluten withdrawal biopsy specimens reviewed, and one of these had further postgluten challenge biopsy specimens evaluated as well. Gastric specimens from the CD cases showed a significantly increased IEL count (20.5 +/- 14.4; range, 4-50) compared to controls (3.4 +/- 1.9; range, 1-8; p < 0.001), which also correlated directly with the histologic severity of the small intestinal disease as assessed by the degree of villous shortening. Sixteen (69.5%) of 23 gastric specimens showed > 8 IELs, which was the highest value obtained in control specimens. The four posttreatment specimens showed a significant reduction in the gastric IEL counts from a mean of 19.8 to 3.5 IELs/100 epithelial cells (p < 0.001). The single case that had a further postgluten challenge biopsy showed a return to the pregluten withdrawal IEL count. However, the degree of gastric intraepithelial lymphocytosis did not correlate with any of the clinical data, such as age, gender, presenting symptoms, or serum antibody levels (antigliadin, antireticulin, or antiendomysium). Furthermore, no differences were observed in the IEL count in CD esophageal specimens (5.3 +/- 2.6; range, 2-10) compared to controls (5.2 +/- 1.5; range, 3-8; p = 0.935). These findings suggest that an immune-mediated lymphocytic response linked to gluten occurs in the gastric epithelium, similar to that seen in the small intestine of pediatric patients with CD. Therefore, gastric intraepithelial lymphocytosis may represent a concurrent manifestation of CD rather than a separate entity in the pediatric population.

Biopsy↗