Coeliac disease is a systemic autoimmune disorder triggered by gluten peptides from grains including wheat, rye, and barley. Almost all people with coeliac disease carry one of two major histocompatibility complex class-II molecules (HLA-DQ2 or -DQ8) that are required to present gluten peptides in a manner that activates an antigen-specific T cell response. The requirement for DQ2 or DQ8 is a major factor in the genetic predisposition to coeliac disease. However, most DQ2- or DQ8-positive people never develop coeliac disease despite daily exposure to dietary gluten. The additional environmental or genetic factors that are required for loss of immune tolerance to dietary gluten are unknown. Factors that have been hypothesised to play a role include: the timing of initial gluten exposure; gastrointestinal infection leading to gluten antigen mimicry; or direct damage to the intestinal-epithelial barrier leading to abnormal exposure of the mucosa to gluten peptides. Reovirus infection has also been shown to promote inflammatory immunity and a decrease in oral tolerance to gluten.
Loss of immune tolerance to peptide antigens derived from prolamins in wheat (gliadin), rye (secalin), barley (hordein), and related grains is the central abnormality of coeliac disease. These peptides are resistant to human proteases, allowing them to persist intact in the small intestinal lumen. It is unknown how these peptides gain access to the lamina propria, but leading hypotheses include faulty tight junctions, endothelial cell transcytosis, sampling of the intestinal lumen by dendritic cells, and passage during resorption of apoptotic villous enterocytes.
In the intestinal submucosa these peptides trigger both innate and adaptive immune activation. The mechanism of innate immune activation is not fully known. Gluten peptides are clearly able to stimulate interleukin-15 production by dendritic cells, macrophages, and intestinal epithelial cells, which then stimulate intra-epithelial lymphocytes, leading to epithelial damage. In the submucosa, gluten peptides are de-amidated by tissue transglutaminase (tTG), an enzyme normally involved in collagen cross-linking and tissue remodelling. De-amidation of the gliadin peptide allows for, first, high-affinity binding to the coeliac-associated human leukocyte antigen (HLA) peptides (DQ2 or DQ8) found on antigen-presenting cells, and second, activation of helper T (Th) cells. For this reason people must carry either HLA-DQ2 (95% of patients with coeliac disease) or HLA-DQ8 (5% of patients with coeliac disease) to develop coeliac disease. Stimulation of Th cells has 2 consequences. Cell death and tissue remodelling with villous atrophy and crypt hyperplasia are induced by Th1-derived cytotoxic T lymphocytes. Th2 triggers plasma cell maturation and subsequent anti-gliadin and anti-tTG antibody production.
There is no formal classification of coeliac disease; however, it can be divided into common subgroups.
Classic coeliac disease: typical symptoms including diarrhoea, weight loss, abdominal pain and discomfort, and fatigue. Classic symptoms are found in <50% of patients.
Atypical coeliac disease: lacks the typical gastrointestinal symptoms of malabsorption; presents with deficiency states (e.g., iron deficiency) or extra-intestinal manifestations (e.g., fatigue, elevated liver enzymes, or infertility). However, atypical disease likely accounts for the largest proportion of patients with a diagnosis of coeliac disease.
Silent coeliac disease: serological and histological evidence of coeliac disease, but without any evident symptoms, signs, or deficiency states. The proportion of coeliac disease that is truly silent is not well known, but it is thought to account for at least 20% of patients.
Non-responsive coeliac disease: clinical symptoms or laboratory abnormalities typical of coeliac disease fail to improve within 6 months of gluten withdrawal, or typical symptoms or laboratory abnormalities recur while the patient is on a gluten-free diet.
Refractory coeliac disease: specific diagnosis within the category of non-responsive coeliac disease, defined as the persistence of clinical symptoms and histological abnormalities after at least 6 months on a strict gluten-free diet and in the absence of other evident causes or of overt lymphoma. The incidence of refractory coeliac disease in patients with coeliac disease is not well known but is felt to be approximately 1%.
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