The immune system is designed to protect the body against foreign invaders, neutralizing disease and infection. But organisms are all too happy to invite invasions several times a day through a seemingly innocuous act: eating. When food enters the digestive system, it has to be dealt with by the immune system just like everything else that finds its way into the body. Under normal circumstances, the immune defenses recognize that food is not a threat and lay down their arms. But in the case of food allergies or digestive disorders, certain types of food are treated as dangerous enemies, with unpleasant consequences for the person.
Celiac disease is one such disorder, where patients suffer painful symptoms after consuming gluten, a dietary protein found in wheat, barley, and rye. Rather than building up a tolerance to the protein that allows for untroubled digestion, the immune system treats gluten as a threat and activates its defensive weapons, including inflammatory factors that attack the lining of the small intestine. As a result, an innocent piece of bread for most people can be absolute misery for one of the 3 million Americans with celiac disease, causing abdominal pain, diarrhea, vomiting, and more serious chronic symptoms.
So far, the best treatment for celiac disease is plain old avoidance – a gluten-free diet to prevent digestive symptoms. Because the immune system is so complex, researchers have struggled to find the exact components responsible for the intolerance to gluten. But clues abound from patients treated at clinics such as the University of Chicago Celiac Disease Center, including unusually high levels of an immune factor called interleukin-15 in the patients’ intestines. That clue was the starting point for a new study published last week in Nature and led by Bana Jabri, associate professor of medicine at the Medical Center, that tracks down two triggers of celiac disease that may prove crucial to better treatments.
Interleukins are the messengers of the immune system, carrying signals that instruct the body’s defensive force to ramp up or stand down, depending on their context. In the gut, interleukin-15, or IL-15, was found by Jabri and colleagues to inhibit the activity of regulatory T cells, peacekeepers that block the immune response on targets that are considered non-threatening. After repeated exposure to gluten, most people build up a tolerance to the protein and are able to digest the nutrients in grains and breads without trouble. But for people with celiac disease, elevated IL-15 may interfere with this cease fire.
The researchers further tested their theory by engineering mice that over-expressed IL-15 in their digestive systems. When these mice were fed a protein found in eggs, another common food allergy trigger, the result was inflammation instead of tolerance – as is seen in celiac disease with gluten. Conversely, blocking IL-15 activity restored the normal response in the mice.
“We found that having elevated levels of IL-15 in the gut could initiate all the early stages of celiac disease in those who were genetically susceptible, and that blocking IL-15 could prevent the disease in our mouse model,” Jabri told John Easton.
With one foothold in the mechanism of celiac disease, the researchers were able to reveal several more components of the dysfunctional immune response, including other interleukins. But one surprising accomplice was found in retinoic acid, a component of vitamin A which was previously thought to be an anti-inflammatory agent. Adding retinoic acid to the mouse model for celiac disease enhanced the inappropriate immune response, rather than alleviating it. The result squares with reports of a link between a retionic acid-based acne treatment and the appearance of inflammatory bowel disease in some patients.
“It demonstrated that in the treatment of inflammatory intestinal diseases, vitamin A and its retinoic acid metabolites are likely to do more harm than good,” Jabri said.
To apply this new knowledge on the mechanisms of celiac disease, the next step will be to look at whether anti-IL-15 agents can help alleviate symptoms and improve tolerance to gluten, Jabri said. Anti-IL-15 medications are already being tested in rheumatoid arthritis, another disease caused by a trigger-happy immune system. Because the current study is the first to identify where the immune system goes awry in response to a dietary protein, similar approaches may also be relevant to other types of food allergies beyond celiac disease. Conversely, the ability of IL-15 and retinoic acid to mobilize an immune response could be turned around and used for good – in improving vaccines against truly dangerous invaders, such as bacteria which cause diarrheal disorders in developing countries where children are often deficient in vitamin A. After all, the trick is not to shut down the body’s defenses completely, but to simply direct them toward the true invaders: infectious bombs, not food.
Depaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, & Jabri B (2011). Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature PMID: 21307853
[Picture from the gluten-free recipe blog Straight Into Bed Cakefree and Dried]