Etiology

Celiac disease is a systemic autoimmune disorder triggered by gluten peptides from grains including wheat, rye, and barley. Almost all people with celiac disease carry one of 2 major histocompatibility complex class-II molecules (human leukocyte antigen [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 celiac disease. However, most DQ2- or DQ8-positive people never develop celiac 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 hypothesized 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. One large prospective birth cohort study of children with HLA-DQ2 and -DQ8 genotypes found that a higher gluten intake in the first five years of life was associated with an increased risk of celiac disease. The risk of celiac disease increased with every 1g/day increase in gluten from the reference amount.[11]

Reovirus infection has also been shown to promote inflammatory immunity and a decrease in oral tolerance to gluten.[12] In keeping with the hypothesis of viral infection as an environmental trigger of celiac disease, one case-control study reported an association between previous enterovirus infection during early childhood and later development of celiac disease.[13] 

Pathophysiology

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 celiac disease. These peptides are resistant to human proteases, allowing them to persist intact in the small intestinal lumen.[14] 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 intraepithelial lymphocytes, leading to epithelial damage.[15][16][17][18] In the submucosa, gluten peptides are deamidated by tissue transglutaminase (tTG), an enzyme normally involved in collagen cross-linking and tissue remodeling. Deamidation of the gliadin peptide allows for, first, high-affinity binding to the celiac-associated HLA peptides (DQ2 or DQ8) found on antigen-presenting cells, and second, activation of helper T (Th) cells.[19] For this reason people must carry either HLA-DQ2 (95% of patients with celiac disease) or HLA-DQ8 (5% of patients with celiac disease) to develop celiac disease. Stimulation of Th cells has 2 consequences. Cell death and tissue remodeling with villous atrophy and crypt hyperplasia are induced by Th1-derived cytotoxic T lymphocytes. Th2 triggers plasma cell maturation and subsequent antigliadin and anti-tTG antibody production.[20]

Classification

Subgroups of celiac disease

There is no formal classification of celiac disease. Common subgroups include:[1]

  1. Classic celiac disease: clinical symptoms and signs of malabsorption, including diarrhea, steatorrhea, weight loss or growth failure, abdominal pain and discomfort, and fatigue. Classic symptoms are found in <50% of patients.

  2. Atypical celiac disease: lacks the typical gastrointestinal symptoms of malabsorption; presents with other gastrointestinal symptoms, deficiency states (e.g., iron deficiency), or extraintestinal manifestations (e.g., fatigue, elevated liver enzymes, or infertility). Atypical disease likely accounts for the largest proportion of patients with a diagnosis of celiac disease.

  3. Asymptomatic celiac disease: serologic and histologic evidence of celiac disease, but without any evident symptoms, signs, or deficiency states. The proportion of celiac disease that is truly asymptomatic is not well known, but it is thought to account for at least 20% of patients.

  4. Nonresponsive celiac disease: clinical symptoms or laboratory abnormalities typical of celiac disease fail to improve within 12 months of gluten withdrawal, or typical symptoms or laboratory abnormalities recur while the patient is on a gluten-free diet.

  5. Refractory celiac disease: subtype of nonresponsive celiac disease. Persistence of clinical symptoms and signs with histologic abnormalities (villous atrophy) after at least 12 months on a strict gluten-free diet, and no evidence of another abnormality including overt lymphoma. The incidence of refractory celiac disease in patients with celiac disease is not well known, but may be approximately 1%.

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