Celiac disease is one of the most prevalent autoimmune gastrointestinal disorders, but as the case of Ms J illustrates, diagnosis is often delayed or missed. Based on serologic studies, the prevalence of celiac disease in many populations is estimated to be approximately 1% and has been increasing steadily over the last 50 years. Evaluation for celiac disease is generally straightforward and uses commonly available serologic tests; however, the signs and symptoms of celiac disease are nonspecific and highly heterogeneous, making diagnosis difficult. Although celiac disease is often considered a mild disorder treatable with simple dietary changes, in reality celiac disease imparts considerable risks, including reduced bone mineral density, impaired quality of life, and increased overall mortality. In addition, a gluten-free diet is highly burdensome and can profoundly affect patients and their families. For these reasons, care of individuals with celiac disease requires prompt diagnosis and ongoing multidisciplinary management.
A, Duodenal biopsy specimen from Ms J's upper endoscopy showing villous shortening and an increased number of intraepithelial lymphocytes, consistent with celiac disease. B, Biopsy specimen of normal duodenum for comparison. Magnification ×200; hematoxylin-eosin stain.
In the subepithelium of the small intestine, native (partially digested) gluten peptides are deamidated by the enzyme tTG. While tTG is ubiquitous, it is predominantly stored intracellularly in an inactive state and released in the presence of inflammation and activated by higher levels of extracellular calcium ions. Deamidation leads to change in shape and charge of the gluten peptides, permitting high-affinity binding to HLA-DQ2 and -DQ8 on APCs such as dendritic cells and macrophages. Only HLA-DQ2 and -DQ8 are able to bind gluten peptides strongly enough to trigger an inflammatory reaction, so the presence of at least 1 of these molecules is a prerequisite for development of celiac disease. Naive T cells that have been activated by deamidated gluten presented by APCs are then able to stimulate both a TH1 cytotoxic and TH2 humoral antibody response. The TH2 response leads to production of antibodies against native gluten peptide, deamidated gluten peptide, and tTG. Antibodies to the self-protein tTG are produced because tTG is often still complexed with deamidated gluten peptides during presentation by APCs. This directed anti-self immune response is the major autoimmune component of celiac disease. TCR indicates T-cell receptor; IFN, interferon.
Gluten peptides are poorly digested by mammalian digestive enzymes and reach the small intestinal mucosa as large polypeptides. Gluten peptides are able to cross the mucosa into the subepithelium by transcellular and/or paracellular pathways. In the subepithelium, gluten peptides are deamidated by tissue transglutaminase (Figure 2) and trigger cytotoxicity leading to mucosal damage and humoral immunity leading to antibody production. Detailed understanding of the pathophysiology of celiac disease has allowed for creation of highly targeted potential nondietary therapies (blue boxes). These include (A) alteration of gluten-containing foods through the use of alternative or genetically modified wheat varieties or through specialized food processing techniques; (B) degradation of gluten proteins in the stomach and small intestinal lumen by selected proteases; (C) preventing gluten passage into the subepithelium of the small intestine through the use of tight junction agonists; and (D) reinduction of tolerance to gluten though immune desensitization.
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