Adaptive and innate immune responses in celiac disease

University of Naples Federico II, Napoli, Campania, Italy
Immunology Letters (Impact Factor: 2.51). 08/2005; 99(2):141-5. DOI: 10.1016/j.imlet.2005.02.017
Source: PubMed


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.

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    • "The main genetic influence on CD is the HLA locus [5], specifically MHC class II genes that encode HLA-DQ2 (HLA-DQ2.5 and HLA-DQ2.2) and HLA-DQ8 heterodimers. The prevalence of disease is usually reported to be about 1% in the general US population [6] but there "
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    ABSTRACT: Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.
    Journal of Immunology Research 06/2015; 2015:1-10. DOI:10.1155/2015/123653 · 2.93 Impact Factor
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    • "The only approach able to minimize the CD symptoms and currently used as prophylaxis is the strict compliance to a gluten-free diet (GFD), which consists on the removal of all gluten containing products, such as starchy and pasta from the diet, or the exchange of these products for products with a reduced gluten content [2]. Similar to many other autoimmune diseases, CD involves innate and adaptive immune responses [3,4]. The innate response causes a primary impairment of villi in the small intestine, increasing epithelial permeability allowing the entry of proteins from the lumen to the lamina propria [1]. "
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    ABSTRACT: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD. A thorough analysis of the developed model provided the following results:1.TG-2 inhibitor treatment leads to insignificant decrease in antibody levels, and hence remains higher than in healthy individuals.2.TG-2 inhibitor treatment does not lead to any significant increase in villous area.3.The model predicts that the most effective treatment of CD would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APC. The model predicts that the treatment of CD by such gluten peptide analogs can lead to a decrease in antibody levels to those of normal healthy people, and to a significant increase in villous area. The developed mathematical model of immune response in CD allows prediction of the efficacy of TG-2 inhibitors and other possible drugs for the treatment of CD: their influence on the intestinal villous area and on the antibody levels. The model also allows to understand what processes in the immune response have the strongest influence on the efficacy of different drugs. This model could be applied in the pharmaceutical R&D arena for the design of drugs against autoimmune small intestine disorders and on the design of their corresponding clinical trials.
    BMC Systems Biology 07/2013; 7(1):56. DOI:10.1186/1752-0509-7-56 · 2.44 Impact Factor
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    • "e l s e v i e r . c o m/ l o c a t e / j c s the adaptive system (Gianfrani et al., 2005). These peptides are generated in the gastrointestinal tract when gluten is partially proteolyzed by digestive enzymes. "
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    ABSTRACT: Gluten proteins are the basis of the rheological properties of wheat derived products, such as bread and pasta. Their particular amino acidic composition (high proline and glutamine content) is responsible for the poor gluten digestibility. Some of the high molecular weight peptides that are generated in the gastrointestinal tract are involved in an autoimmune entheropathy called celiac disease. In this work we compared the amount of peptides containing sequences involved in adaptive and immune responses, which were produced after simulated gastrointestinal digestion of prolamins extracted from different durum wheat varieties and in-bred lines. Peptides containing sequences involved in celiac disease were quantified using an isotopically labeled peptide as internal standard. The results demonstrated a very high variability in the amount of pathogenic peptides produced by different lines, showing a strong contribution of the genetic component. At the same time, the variability in total protein and gluten content was lower; the weak correlation between pathogenic peptides and the amount of gluten proteins gives rise to the possibility of a varietal selection aimed to maintain good rheological properties, but simultaneously reducing the exposure to peptides eliciting an immunological response in celiac predisposed subjects. These varieties might be useful for celiac disease prevention.
    Journal of Cereal Science 01/2013; 59(1). DOI:10.1016/j.jcs.2013.10.006 · 2.09 Impact Factor
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