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Celiac disease.

Celiac disease (CD) is a common autoimmune disorder, induced by the intake of gluten proteins present in wheat, barley and rye. Contrary to common belief, this disorder is a protean systemic disease, rather than merely a pure digestive alteration. CD is closely associated with genes that code HLA-II antigens, mainly of DQ2 and DQ8 classes. Previously, it was considered to be a rare childhood disorder, but is actually considered a frequent condition, present at any age, which may have multiple complications. Tissue transglutaminase-2 (tTG), appears to be an important component of this disease, both, in its pathogenesis and diagnosis. Active CD is characterized by intestinal and/or extra-intestinal symptoms, villous atrophy and crypt hyperplasia, and strongly positive tTG auto-antibodies. The duodenal biopsy is considered to be the "gold standard" for diagnosis, but its practice has significant limitations in its interpretation, especially in adults. Occasionally, it results in a false-negative because of patchy mucosal changes and the presence of mucosal villous atrophy is often more severe in the proximal jejunum, usually not reached by endoscopic biopsies. CD is associated with increased rates of several diseases, such as iron deficiency anemia, osteoporosis, dermatitis herpetiformis, several neurologic and endocrine diseases, persistent chronic hypertransami-nasemia of unknown origin, various types of cancer and other autoimmune disorders. Treatment of CD dictates a strict, life-long gluten-free diet, which results in remission for most individuals, although its effect on some associated extraintestinal manifestations remains to be established.

Anemia, Iron-Deficiency↗

New developments in celiac disease.

Celiac disease remains a challenge to the clinician and scientist. It is clearly more prevalent than was previously suspected. Much interest is seen in identifying the genetic factors, which predispose to disease and the environmental agents that can trigger it. Genome-wide searches have identified a number of chromosomal susceptibility loci. Specific gliadin epitopes are being analyzed. New diagnostic options include the tissue transglutaminase enzyme-linked immunosorbent assay. Neurologic disease and bone disease are intriguing complications of celiac disease and are gradually being defined.

Journal Article↗

Serological diagnosis of celiac disease.

Celiac disease CD is an inflammatory disease of the small intestine brought about by exposure to gluten in genetically predisposed individuals. Celiac disease most often presents with non specific, or extra-intestinal, manifestations and, consequently, the disease remains under diagnosed. Untreated CD is associated with high morbidity and, therefore, early diagnosis is essential. The availability of non-invasive and relatively cheap serological tests has made it possible to screen large numbers of patients and resulted in increased, and earlier, diagnosis of patients with CD. However, these tests have varying degrees of sensitivities and specificities and the results generated can lead to a lot of confusion with regards to the diagnosis, or exclusion, of CD. In the present review, we discuss in detail these tests and suggest how they can be used in screening patients for CD with the hope that such information will help clinicians to select the right tests and interpret the generated results more effectively, and thus lead to improved identification and treatment of patients with CD.

Autoantibodies↗

IgA cross-reactivity between a nuclear autoantigen and wheat proteins suggests molecular mimicry as a possible pathomechanism in celiac disease.

Celiac disease patients display IgA antibody reactivity to wheat as well as to human proteins. We used serum IgA from celiac patients and, for control purposes, from patients with Crohn's disease, ulcerative colitis and from healthy individuals to identify celiac disease-specific IgA autoantigens in nitrocellulose-blotted extracts from various human cell types (epithelial, endothelial, intestinal cells, fibroblasts). The pattern, recognition intensity and time course of IgA autoreactivity was monitored using serial serum samples obtained from celiac children before and under gluten-free diet. By immunoblot inhibition and subcellular (cytosolic, nuclear) cell fractionation we identified a 55 kDa nuclear autoantigen expressed in intestinal, endothelial cells and in fibroblasts which was recognized by IgA antibodies of approximately half of the celiac disease patients and cross-reacted with wheat proteins. IgA reactivity to the 55 kDa autoantigen disappeared during gluten-free diet and was inhibited after pre-absorption of sera with wheat proteins but not with tissue transglutaminase, previously reported as the unique celiac disease-specific autoantigen. In conclusion, we defined a novel 55 kDa celiac disease-specific nuclear IgA autoantigen which shares epitopes with wheat proteins and which is different from tissue transglutaminase and calreticulin. Although the newly defined autoantigen was recognized much less frequently than tissue transglutaminase, our data suggest molecular mimicry between wheat and human proteins as a possible pathomechanism for the induction and/or maintenance of mucosal tissue damage in celiac disease.

Adolescent↗

Immunomodulatory strategies for celiac disease.

Celiac disease (CD) is the most common food-sensitive enteropathy in humans and is caused by the lack of immune tolerance (oral tolerance) to gluten. The identification of gluten-specific T cells in the lamina propria of celiacs and the strong association with HLA-DQ2 and -DQ8 genes support a central role of CD4(+) T cells in CD pathogenesis. Studies focused on the modulation of autoimmunity in different experimental models highlighted possible immune therapeutic protocols useful also for the management of CD. On the basis of these observations, a series of strategies have been designed: some of them are based on the identification of immunogenic epitopes and their suppression via enzymatic treatment or by using peptide analogues; others rely on the delivery of unmodified antigen through the nasal route or coadministered with downregulatory cytokines. studies are generally early stage but encouraging in paving a way for an alternative treatment for celiac disease.

Animals↗

Celiac disease and gluten-associated diseases.

Celiac disease develops from an autoimmune response to specific dietary grains that contain gluten. Diagnosis can be made based on the classical presentation of diarrhea, fatty stools, and abdominal bloating and cramping, as well as the presence of specific serum antibodies. In addition, gluten ingestion has increasingly been found to be associated with other conditions not usually correlated with gluten intolerance. The subsequent diversity of the clinical presentation in these cases can complicate decision-making and delay treatment initiation in conditions such as ataxia, headaches, arthritis, neuropathy, type 1 diabetes mellitus, and others. This review explores the etiology and pathology of celiac disease, presents support for the relationship between gluten and other diseases, and provides effective screening and treatment protocols.

Celiac Disease↗

[Type 1 diabetes and celiac disease].

Celiac disease is more prevalent in type 1 diabetic patients than in the general population. The exact reason for this association remains unknown. Two hypotheses are taken into consideration: either a common genetic background or an immune response against Langerhans islets triggered by celiac disease. This review presents recent data about this association and its consequences in clinical practice.

Celiac Disease↗

Celiac disease.

Celiac disease, or gluten-sensitive enteropathy, classically presents as diarrhea and weight loss in childhood, but it may also have protean manifestations and appear well into adult life. The increasing availability of noninvasive blood tests that are highly sensitive and specific for celiac disease enables primary care physicians to recognize the disorder in a wide variety of clinical situations. The authors believe that the disease is more common than supposed and thus offer this diagnostic review to increase awareness.

Adult↗

Pathomechanisms in celiac disease.

Celiac disease is an inflammatory disorder of the small intestine caused by an immune response to ingested wheat gluten and similar proteins of rye and barley. It affects at least 1 in 200 individuals, corresponding to roughly three million patients in Western Europe and Northern America alone. Data accumulated since the discovery of gluten specific T cells in the intestine of celiac disease patients the early 1990s have allowed the deciphering of the interplay between the triggering environmental factor, gluten, the main genetic risk factor, the HLA-DQ2/8 haplotypes and the autoantigen; the enzyme tissue transglutaminase (tTG). This established a key role of adaptive immunity orchestrated by lamina propria T cells responding to a set of gluten derived peptides. More recent work points to an important contribution of innate immunity triggered by a distinct gluten peptide and driven by the proinflammatory cytokine Interleukine-5 (IL-15). Together, these observations provide a unique explanation for the disease inducing capacity of gluten.

Celiac Disease↗

Pathomechanisms in celiac disease.

Celiac disease is a complex autoimmune disease which is characterized by a strong genetic association (HLA-DQ2 or -DQ8), gluten as nutritional etiological factor, and the enzyme tissue transglutaminase as endomysial autoantigen. Patients develop highly predictive IgA autoantibodies to tTG. Certain gluten peptides are presented by the disease-associated HLA-DQ2/DQ8 molecules leading to stimulation of gluten-specific T cells. This immune response which is driven in the lamina propria causes the mucosal transformation characteristic for celiac disease. Increased intestinal expression of tTG in patients with CD appears to play an important role in the pathogenesis of CD. Thus, modification of gluten peptides by tTG, especially deamidation of certain glutamine residues, can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. New therapeutic approaches aim at proteolytic destruction of immunodominant gliadin peptides that are resistant to intestinal enzymes by bacterial prolyl endopeptidases, the inhibition of tTG activity with highly specific enzyme inhibitors or at HLA-DQ2/DQ8 blocking peptide analogues.

Animals↗

The molecular basis of celiac disease.

Celiac disease is caused by inflammatory, gluten specific T cell responses in the small intestine. Invariably such responses are HLA-DQ2 or HLA-DQ8 restricted, providing an explanation for the strong association between celiac disease and these HLA-class II alleles. It is now clear that some native gluten sequences can bind to HLA-DQ2/8 and induce T cell responses. In addition, modification of gluten peptides by the enzyme tissue transglutaminase results in high affinity HLA-DQ2/8 binding peptides that can induce T cell responses. Thus, gluten molecules contain a large number of immunogenic peptides and this is likely to play an important role in the breaking of oral tolerance to gluten.

Animals↗

Reprogramming of CTLs into natural killer-like cells in celiac disease.

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.

Base Sequence↗

One-step cloning of anti tissue transglutaminase scFv from subjects with celiac disease.

Celiac disease is characterized by intestinal mucosal injury and malabsorption precipitated by dietary exposure to gluten of some cereals with a prominent role being played by gliadins, specific antigenic determinants found in wheat gluten. Patients suffering from celiac disease have serum antibodies recognizing gliadin, as well as the endomysial autoantigen tissue transglutaminase. Phage display antibody libraries have revealed ectopic production of anti-transglutaminase antibodies by intestinal lymphocytes with a biased use of the VH5 antibody gene family. Here we report a study on the pairing of VH and VL families in the antibodies to transglutaminase. Our results led to the construction of small phage display antibody libraries based on the amplification of the two genes in the VH5 family from intestinal lymphocytes. This method can be used for the rapid characterization of the anti-transglutaminase response in a potentially large number of subjects including asymptomatic patients whose serum antibodies may be undetectable.

Amino Acid Sequence↗

Endoscopic markers for celiac disease.

Celiac disease is common and can present with nonspecific upper gastrointestinal symptoms. Patients may therefore undergo esophagogastroduodenoscopy as their initial investigation. Markers of villous atrophy, which can be seen in the duodenum during endoscopy, are well described. They have limited sensitivity for patients with mild enteropathy and duodenal biopsies should be performed if there is strong suspicion of celiac disease irrespective of endoscopic appearance. Endoscopic markers do, however, allow the selection of patients with nonspecific symptoms for duodenal biopsy, and these markers should, therefore, be looked for routinely during esophagogastroduodenoscopy.

Atrophy↗

Reassessment of enteric endocrine cell hyperplasia in celiac disease.

Celiac disease is characterized by reversible, gluten-induced, architectural abnormalities of the intestinal mucosa. Villus atrophy is compensated for by an increase in the number of proliferating cells and an increase in crypt cell production rate, resulting in increased crypt length and girth. Several authors, employing various methods of quantitation, have reported enteric endocrine cell hyperplasia in celiac disease. The present study has re-evaluated enteric endocrine cell status in this disorder by employing methods of quantitation which more accurately take account of alterations of crypt morphology than those previously used. Numbers of endocrine cells expressed as cells per unit of crypt length are not increased in the celiac biopsies when contrasted with those from controls. Indeed, numbers of cells immunoreactive for gastrin, GIP, motilin and somatostatin were reduced in the celiac mucosa. Endocrine cell hyperplasia in the celiac small bowel is not as marked as was previously thought, and may lag behind that of the enterocyte population.

Adult↗

HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.

Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, alpha-gliadin AJ133612 and gamma-gliadin M36999. For alpha-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For gamma-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some gamma-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.

Amino Acid Sequence↗

Celiac disease.

Celiac disease is a genetically determined, permanent intolerance to gluten, a protein complex found in wheat, rye and barley. As many as 1:163 people are affected by it, but only a small percentage are aware of the condition, which begins either in infancy, with gastrointestinal symptoms, or in childhood and later years with non-Gl signs and symptoms, such as fatigue, depression, anxiety, anemia, stunted growth, and delayed puberty. A strong association with Type 1 diabetes and Down syndrome is also found, thus making screening mandatory for these subjects. Celiac disease is often entirely clinically silent, yet it must be detected in order to prevent long-term complications.

Adolescent↗