Aetiology and pathogenesis

The healthy small intestinal epithelium is maintained by constant cell turnover, and the balance between normal shedding of old epithelial cells at the tips of villi and the formation of new cells from stem cells in the crypts maintains a 2:1 ratio between villus height and crypt depth. The lamina propria contains a small number of lymphocytes, macrophages, fibroblasts, capillary endothelial cells and other cells. The epithelium itself contains a population of resident intraepithelial lymphocytes that maintain surveillance against potential pathogens.

In genetically susceptible individuals, immunological reaction to gluten-derived gliadin peptides develops upon dietary exposure. The exact genes causing coeliac disease have not been identified but certain major histocompatibility complex (MHC) class II gene alleles are strongly associated with the condition. Early dietary exposure to gluten, particularly after weaning from milk, may increase the risk of developing the disease.

The ubiquitous cellular enzyme tissue transglutaminase (tTG), which normally cross-links glutamine residues with lysine in connective tissue proteins, plays an essential role in the pathogenesis, by converting glutamine residues in native gliadin peptides to glutamate, creating more immunogenic peptides. However no disease-associated polymorphisms in the tTG gene have been identified.

Lymphocytes react with the modified gliadin peptides on the surface of antigen-presenting cells and proliferate, increasing the number of intraepithelial and lamina propria lymphocytes. Activated lymphocytes secrete inflammatory mediators, including the cytokines, g-interferon and tumour necrosis factor a (TNFa), recruiting and activating more inflammatory cells, altering the proliferative rate of intestinal epithelial stem cells, and increasing the rate of programmed cell death (apoptosis) in mature enterocytes. This creates an oedematous, swollen intestinal mucosa, with short, thick, blunt villi and deeper than normal crypts (subtotal villus atrophy), and the reduced epithelial surface area and compromised epithelial digestive and absorptive capacity leads to malabsorption.

The concentration of dietary gluten is highest proximally in the intestine and therefore coeliac disease affects the duodenum and proximal jejunum most severely.

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