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Chemokine Protein CXCR3 Receptor Found in Celiac Disease
| Author: Lorraine Savage |
| Article Date: 9/1/2008 |
Scientists at the Mucosal Biology Research Center at the University of Maryland School of Medicine (UMMC) in Baltimore have recently identified the intestinal chemokine protein CXCR3 as the key receptor in celiac disease.
Affecting 1 in 133 Americans and 1 in 300 Europeans, celiac, or coeliac, is a genetic auto-immune disease triggered by the protein gliadin, a component of the protein gluten found in wheat, rye, and barley. Gliadin induces the release of the human protein zonulin, which is responsible for the permeability of the small intestine. In celiac patients, gluten enters the intestines and triggers an immune response. The mystery had been in learning how gluten was able to gain access in the intestine.
In 2000, researchers at UMMC found that increased levels of zonulin contribute to autoimmune disorders such as celiac, diabetes, multiple sclerosis, and rheumatoid arthritis. Zonulin, induced by gliadin, modulates the immune system. Acting like a gatekeeper, zonulin encourages the permeability of the small intestines, allowing allergens, such as gluten, to enter the immune system, triggering antibodies in response. [These findings were published in the April 29, 2000 issue of the journal Lancet.]
After long-term activity, these antibodies cause damage to the intestines, destroying villi, interfering with the absorption of nutrients, causing diarrhea and pain, and stunting the growth of children. Other problems include osteoporosis, nerve damage, and seizures. The best treatment for celiac disease is restricting all gluten foods from the diet and assuring the patient receives enough nutrition from safe foods.
In the 2008 study, researchers at UMMC wanted to identify the molecular basis of gliadin interaction with intestinal mucosa which lead to the permeability of the intestines. Scientists examined human and mouse intestinal epithelium cell linings and lamina propria mucous membranes. They found that gliadin binds with the intestinal chemokine receptor CXCR3. Also part of this binding are at least 2 alpha-gliadin 20mer synthetic peptides. [These findings appear in the July 2008 issue of Gastroenterology.]
Celiac patients exhibit elevated levels of mucosal CXCR3. When gliadin binds to CXCR3, MyD88-dependent zonulin release is increased, leading to intestinal permeability and the ability of gluten to enter the intestines and trigger the immune response. When gluten is removed from the diet, CXCR3 expression levels return to baseline.
The research in finding CXCR3 was significant in that scientists have now identified how foreign antigens enter the body and cause a faulty immune response. Further study is required to find a way to block or reduce zonulin activity and prevent the activation of the immune response. Research into finding a drug that can block zonulin in celiac patients is underway. Perhaps there will be a drug that allows celiac patients to digest gluten, similar to pills available to lactose-intolerant people. Such a celiac drug could be worth $1 billion a year.