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Stephen Gislason MD Mechanisms Despite many years of study , the mechanism of Celiac Disease has not been finally determined. While there is no reason to think that a single mechanism is responsible, we prefer the immune-mediated explanations of the disease. A T cell-mediated or type IV reaction to gluten is likely the major cause of the gut lesions and increased permeability to gluten and other food antigens leads to whole-body consequences. There are four possible mechanisms involved at the bowel level:
A cell-mediated type of allergy is likely involved with a host of complicated consequences, especially increased permeability of the gastrointestinal tract (GIT) with more problems downstream. The surface lining of the digestive tract is the largest and most critical interface between the organism and its environment. The lining epithelial cells are involved in immune processes. They transfer immunoglobulins produced by lamina propria B lymphocytes to the surface and interact with other cells of the immune system to induce an inflammatory response to microbial invasion: enzymatic processing of dietary antigens, expression of class I and II MHC antigens, presentation of antigens to lymphocytes, expression of adhesive molecules mediating interaction with intraepithelial lymphocytes and components of extracellular matrix, production of cytokines and probable participation in T cell development of intraepithelial lymphocytes. Both epithelial cells and intraepithelial lymphocytes participate in inflammatory reactions. Epithelial cells proliferate in celiac disease. Crypt hyperplasia is a common tissue response to mucosal damage in food allergy and infection. Gliadin-specific T lymphocytes are found in the small intestinal mucosa and in the peripheral blood. The density of T cells is increased in the jejunal epithelium, an abnormality considered to be specific for celiac disease. Gluten specific T cell clones activated in situ by gluten play a central part in the pathogenesis of celiac disease. Antigen induced production of cytokines was studied in lymphocytes which secreted interferon (IFN) gamma, often at high concentrations ( 2000 U/ml); some secreted in addition interleukin (IL) 4, IL 5, IL 6, IL 10, tumour necrosis factor (TNF), and transforming growth factor (TGF) beta. High IFN gamma concentrations in combination with TNF alpha, might be involved in several pathological features of the celiac lesion. Tighe and Ciclitira reported: "There is a strong genetic influence on the susceptibility to celiac disease. The immunogenetics of the disease implicate certain HLA DQ alleles. These HLA molecules have been shown to be necessary in the binding and presentation of gliadin peptides to antigen-specific T cells. The isolation of antigen-specific T cells has led to the confirmation of a toxic T-cell epitope of the gliadin protein (residues 31-49) and it would appear likely that additional toxic epitopes may be similarly characterized in the near future. Additional toxic T-cell epitopes may also be present within gliadins, but this identification of a toxic gliadin sequence for the first time raises the possibility of future manipulation of the wheat genome (and other toxic cereals) that could lead to the development of new graminae cereals with the properties of wheat, but which do not induce toxicity in patients with coeliac disease." The HLA-DQ(alpha1*0501, beta1*0201) heterodimer encoded by the alleles HLA-DQA1*0501 and HLA-DQB1*0201 confer the primary disease susceptibility. Celiac Disease - A Prototype of Delayed Pattern Food AllergyOften, an assortment of related whole-body problems accompanies celiac disease. We think the related problems are typical of delayed pattern food allergy and use celiac disease research information to create a model of food allergy. Celiac patients have increased gastrointestinal permeability and demonstrate the whole-body effects of food allergy, including brain dysfunction, arthritis, and inflammatory lung disease. The celiac patient should seriously consider complete diet revision, not just gluten exclusion in an effort to avoid problems downstream from their GIT. A list of related disorders resembles the list of disorders reviewed in the working hypothesis - delayed pattern food allergy! Diabetes, thyroid disease, purpura, anemia, rheumatoid arthritis, sacroileitis, sarcoidosis, vasculitis, lung disease, myositis, eye inflammation, encephalopathy and cerebellar atrophy and schizophrenia are all linked to gluten intolerance. These associations suggest a tendency to immune hypersensitivity diseases and a possible role for food antigens in causing systemic autoimmune disease.The prevalence of celiac disease among children with diabetes (IDDM) is 50 times more likely than chance. IgA deficiency is 10 times more common in celiac patients than in the general population. In their review of these associated disorders, Mulder and Tygart repeated the basic idea of pathogenesis of systemic disease downstream from a disordered gastrointestinal tract. They stated: "Patients with (celiac disease and) selective IgA deficiency often have circulating antibodies to food proteins; they also have circulating immune complexes, suggesting that absence of an intestinal IgA barrier might allow the absorption of antigenic material from the gut. Antibodies to some of the antigens might cross react with the host's self components and might indirectly produce autoimmune disease." Structural similarities between external antigen and self components are one of the possible causes of autoimmunity. One study described the presence of similar structures shared by gliadin and enterocyte surface molecules recognized by antigliadin mAbs. Another study showed that reactions of the patient's serum with parathyroid tissue were due to endomysial antibodies, common in CD and were not parathyroid specific. Beyond Gluten While proteins are clearly involved in celiac disease, other components of cereal grains may also be involved. Lectins are potentially active substances in many plant foods. Falth-Magnusson suggested that: "Lectins are 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). Levels of IgA and IgG to WGA and gliadin were higher in celiac children on a gluten-containing diet, compared to children on gluten-free diet and reference children. 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". Lymphocyte Proliferation and Lymphoma A striking association is that celiac disease predisposes patients to the eventual development of lymphoma. If this relationship is re-stated as "cereal grains cause cancer" the implication is more easily understood. There is evidence that strict adherence to a gluten-free diet long term will reduce the incidence of lymphoma. Anti-gliadin antibodies are most commonly found in the immune complexes, associated with major systemic disease. Increased Gut Permeability as a Mechanism of Systemic Disease
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