Celiac Disease

Celiac disease (also known as gluten enteropathy or celiac sprue) is a disorder of malabsorption that occurs when there is an inappropriate immune response to gluten, a protein found in wheat. Celiac disease is not an atopic disorder because it does not involve the generation of IgE. Instead, the immune response in celiac disease is mediated by CD4+ helper T-cells.

Celiac disease was once thought to be a fairly rare disorder of children, but it is now recognized that celiac disease can develop in adulthood, that there can be a range of disease severity, and that the disorder may be fairly common (perhaps affecting as many as 1 in 100 people in certain parts of Europe and North America). There is a genetic component to celiac disease. All individuals who develop celiac disease express particular alleles of one type of MHC molecule. Other genetic and environmental factors probably play a role in the expression of the disease, since many more people carry these particular MHC alleles than have celiac disease, and many people don't develop celiac disease until late adulthood.

Pathogenesis

The figure shows a simplified illustration of our understanding of the pathogenesis of celiac disease. Peptides derived from gluten contain many proline and glutamine residues, making them resistant to digestion by pancreatic and brush border enzymes. These peptides gain access to the lamina propria (where MALT is located) either by transcytosis or by a paracellular route (moving between cells). Paracellular transport would involve a breakdown in the tight junctions between enterocytes to cause an increase in intestinal permeability.  There is some evidence that this occurs more frequently in individuals with celiac disease.

Once in the lamina propria, an enzyme modifies these peptides, making them even more antigenic. They are engulfed and displayed on the surface of antigen presenting cells (APC's) by MHC II molecules. They stimulate CD4+ helper T-cells, which secrete cytokines that orchestrate the inflammatory response that leads to tissue damage.  One cytokine in particular (IL-15) stimulates intraepithelial lymphocytes, promoting their recruitment, survival, and cell-killing properties.

celiac
        pathogenesis


The consequence of the tissue damage is a change in the mucosa in the small intestine. This can be observed in a duodenal biopsy, which is a key test in the diagnosis of celiac disease. Instead of the normal architecture of tall villi and deep crypts, what is observed in celiac disease is a flattened mucosa. (Look at Figure 2 in this article to see an image of duodenal biopsy specimens.)  This can greatly decrease the surface area of the small intestine, causing malabsorption of nutrients, which can cause diarrhea and malnutrition. Duodenal tissue also shows increased numbers of lymphocytes.
(Off-campus access: open LINK TO PROXY SERVER. Next, paste the URL [http://content.nejm.org/cgi/content/full/346/3/180/F2] in the "URL to proxy" box and click login.)

There is a broad range in the severity of symptoms. When the disease is detected in early childhood, it usually causes severe malabsorption, diarrhea, and a failure to thrive. Adults with celiac disease may have diarrhea and experience weight loss, but often the initial clinical presentation is iron-deficiency anemia. This occurs because the mucosal changes are concentrated in the duodenum, where iron absorption takes place. Some individuals with an immune response to gluten do not have gastrointestinal symptoms at all, but instead get a skin rash, which is termed dermatitis herpetiformis. It is not completely understood why a skin rash develops in some people, but the link to gluten is clear because the rash goes away when gluten is removed from the diet.

Treatment

At present , the only treatment for celiac disease is the elimination of gluten from the diet. This is not as easy as it sounds, since gluten is a frequent additive to many prepared foods, or may be a contaminant of foods such as oats.

One treatment that is being developed would seek to reduce the effects of residual gluten in the diet, requiring less vigilance from the patient. There are bacterial and plant enzymes capable of digesting the immunostimulatory peptides that resist digestion by human digestive enzymes. These enzymes would need to be produced commercially and then used as dietary supplements.

Another approach seeks to block the breakdown in the epithelial barrier of the intestine. Increased intestinal permeability has been observed in celiac disease (and also some other autoimmune disorders). Peptides derived from gluten stimulate the release of zonulin, a regulatory molecule that causes tight junctions to open up, increasing intestinal permeability. A drug that is in development blocks zonulin receptors, and so may help prevent gluten peptides from reaching the lamina propria to stimulate the immune response.

Optional

Reference for linked article above:  Farrell, R.J. and Kelly, C.P. (2002) Celiac Sprue.  New England Journal of Medicine 346:  180-188 (link)
[URL: http://www.nejm.org/doi/full/10.1056/NEJMra010852]

For a more recent review, see:  Green, Peter H.R. and Cellier, Christophe (2007) Celiac Disease.  New England Journal of Medicine  357:  1731-43 (link)
[URL: http://www.nejm.org/doi/full/10.1056/NEJMra071600]

In 2011, a team of UW undergraduates won a prize for engineering an enzyme that could digest gliadin at the pH of the stomach.  (Gliadin is the proline and glutamine-rich polypeptide in gluten that resists digestion and causes the immune response). This link describes their work.  This work has also been published in:  Gordon, S.R. et al. (2012) Computational Design of an Alpha-Gliadin Peptidase. J. Am. Chem. Soc. 134(50):  20513-20520 (link)
[URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526107/]

Off-campus access: open LINK TO PROXY SERVER. Next, type in the URLs given above.


Quick Quiz


Fill-in Answer Correct False Correct Answer
1. What structure, found between adjacent epithelial cells, might be compromised in people who have celiac disease?
2. Antigen presenting cells display gluten peptides bound to MHC II molecules on their surface, leading to an immune response. Where does this occur? [apical surface of epithelium; lamina propria; submucosa]
3. What type of white blood cell orchestrates the immune response in celiac disease? (Be specific).
4. A duodenal biopsy is a key test for diagnosis of celiac disease. What structures are missing from the duodenal mucosa in celiac disease?
5. Name the skin rash that occurs in some individuals with celiac disease.


(Spelling must be correct)




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