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Review
. 2015 Feb;3(1):3-11.
doi: 10.1093/gastro/gou065. Epub 2014 Oct 17.

The Present and the Future in the Diagnosis and Management of Celiac Disease

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Free PMC article
Review

The Present and the Future in the Diagnosis and Management of Celiac Disease

Natalia E Castillo et al. Gastroenterol Rep (Oxf). .
Free PMC article

Abstract

Celiac disease is an autoimmune enteropathy caused by gluten in genetically predisposed individuals. In celiac disease, adaptive and innate immune activation results in intestinal damage and a wide range of clinical manifestations. In the past, celiac disease was thought to result in signs and symptoms solely related to the gastrointestinal tract. Now, more than half of the adult population presents with extra-intestinal manifestations that can also be expected to improve on a gluten-free diet. For this reason, it is recommended that physicians have a low threshold of suspicion for celiac disease. Current knowledge of the immune pathogenesis of this autoimmune disease has served as a catalyst for the development of novel diagnostic tools and therapeutics. Over the years, highly sensitive and specific serological assays, in addition to genetic markers, have been found to target specific steps in the cascade pathway of celiac disease. Also the advent of the gluten challenge has enabled experts to design diagnostic algorithms and monitor clinical responses in clinical trials. The gluten challenge has provided substantial benefit in the advance of novel therapeutics as an adjuvant treatment to the gluten free diet. Generally, a strict gluten-free diet is highly burdensome to patients and can be limited in its efficacy. Alternative therapies-including gluten modification, modulation of intestinal permeability and immune response-could be central to the future treatment of celiac disease.

Keywords: autoimmune diseases; celiac disease; gluten-free diet.

Figures

Figure 1.
Figure 1.
Celiac disease pathogenesis and potential novel therapeutics. Gluten peptides found in wheat, barley and rye will generate an inflammatory reaction in the small intestines of susceptible individuals. (a) Gliadin peptides will reach the lamina propria either by transcellular or paracellular transport mediated by zonulin. (b) De-amination by tissue transglutaminase (tTG) Type 2 increases binding affinity to human leukocyte antigen (HLA) Class II DQ2 (less common DQ8). (c) Peptide HLA-DQ complexes can induce an adaptive TH1 response that will increase cytokine production predominantly IFN-γ and matrix metalloproteinases (MMPs). The inflammatory cascade is responsible for the intestinal changes (crypt hyperplasia and atrophy of the intestinal villi) commonly seen in individuals with celiac disease. The innate immune system also contributes to the pathogenesis of celiac disease. (d) Up-regulation of interleukin-15 (IL-15) by epithelial and dendritic cells in the lamina propria seems to be involved in epithelial changes that are associated with refractory celiac disease Type 2 and T- cell lymphoma. Possible novel, targeted therapies are indicated in numbers. In the intestinal lumen, gluten immunogenicity can be reduced either by (i) genetically engineered grains, (ii) active proteases including ALV003, AN-PEP and STAN1 that will specifically degrade gluten into small non-immunogenic fragments and (iii) gluten binders; (iv) in the intestinal epithelium, Larazotide acetate (formerly AT-001) enhances tight junction (TJ) assembly and reduces paracellular transport of gluten to the lamina propria; (v) adaptive immune response may be reduced by blocking antigen presentation with transglutaminase 2 (TG2) inhibitors and HLA blocking peptides; (vi) lymphocyte blocking and anti-cytokine therapy (anti-IL-15) are other potential treatment approaches that targets TH1 activation and innate immune response.
Figure 2.
Figure 2.
Proposed algorithm for celiac disease diagnosis. GFD = gluten free diet; HLA = human leukocyte antigen; CD = celiac disease; DGP = de-amidated gliadin peptide; tTG = tissue transglutaminase.

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