Celiac disease occurs in a small percentage of genetically susceptible persons who have an HLA type that puts them at risk and who eat gluten as part of their diet. What triggers the disease is less clear. Observational studies suggest that the amount of gluten in the diet during the first years of life influences the risk of celiac disease. However, two studies investigated whether the intro duction of gluten in minute amounts during the first year of life in infants with a hereditary risk of celiac disease would affect the later occurrence of the disease, and both studies had a negative result. This negative outcome could be due to the small amounts of gluten that were chosen or the high risk of celiac disease in the selected patient groups. Disrupted microbiota of the gastrointestinal tract may be a risk factor, although breastfeeding is neither protective nor a risk fac tor. Frequent antibiotic use in early childhood may be associated with an increased risk of celiac disease. Mode and season of birth have been widely studied but are not clearly responsible. Several studies, although methodologically limited, suggest a role for viral triggers leading to loss of tolerance if it overlaps with the introduction of gluten.
Celiac disease is driven by gluten from wheat, rye, and barley and is caused by a reaction to glia dins and analogous proteins that have not de graded completely in the gastrointestinal tract (Fig. 1). Celiac disease has features of an autoimmune disease that is triggered by known exogenous antigens. When incompletely digested gliadin peptides pass through the gut wall, the ubiquitous enzyme tissue transglutaminase 2 (TG2) selectively deaminates specific glutamine residues. This interaction results in highly anti genic epitopes that are recognized by T cells and B cells. The B cells produce antibodies against both deamidated gliadin peptides and activated TG2 and also enables antigen uptake through the B-cell receptor and presentation to the gliadin reactive CD4 T cells central to the immune response. HLA-restricted presentation occurs specifically through HLA types HLA-DQ2.5 (encoded by DQA05* with DQB02*) or DQ8 (encoded by DQA03 DQB0302), which orchestrate a further cascade of events. CD8 T cells are recruited to drive cytotoxic effects directed against epithelial cells, and an innate immune response takes place at the epithelial cells with engagement of unconventional HLA antigens.
Fig1. Elements of the Pathogenesis of Celiac Disease in the Small Intestine. Gluten is incompletely digested into peptide fragments. These peptides transit the epithelium by several pathways and interact with tissue transglutaminase 2 (TG2). The peptides are deamidated and taken up by antigen-presenting cells (especially B cells) to engage with CD4 T cells driving the release of cytokines, including interleukin-2 and interferon-γ, and expansion of inflammatory cells. B cells develop into plasma cells that produce primarily IgA anti bodies. Intraepithelial lymphocytes (IELs) expressing the natural killer cell receptors NKG2D and NKG2C recognize HLA-E and class I major histocompatibility complex–related molecules and target enterocytes for cytolysis, which leads to mucosal destruction. DGP denotes deamidated gliadin peptide.
These inflammatory reactions lead to mucosal changes with an influx of lymphocytes into the surface epithelium, crypt hyperplasia due to expansion of the lamina propria with inflammatory cells, and villous atrophy, producing variable degrees of damage. TG2 is recognized as the primary autoantigen in celiac disease,25 triggering antibody formation mainly, but not solely, of the IgA isotype. It is notable that TG2 does not elicit a T-cell response without companion gliadin pep tides. Assays for tTG-IgA are widely available and are often used as the first step for the detection of celiac disease. Selective IgA deficiency occurs in 2 to 4% of patients with celiac disease and may lead to a false negative screening result for celiac dis ease with tTG-IgA. Measurement of serum IgA levels in the initial screening for celiac disease should avoid a false negative result.
