Many components of celiac disease are well understood, such as the accepted knowledge that wheat, barley and rye trigger an adaptive immune reaction in people with the condition, leaving people with an array of symptoms. The genes responsible for the genetic predisposition for celiac disease, HLA-DQ2 and HLA-DQ8, have also long since been identified. While research has provided a clear understanding of the role the adaptive immune system plays in celiac disease, the innate immune system’s function remains ambiguous. Notably, the innate immune system serves as the first line of defense against invading microbial and chemical stimuli and is essential for successful priming of adaptive immunity.

Within the past year, research has demonstrated that the innate immune system is also linked to a reaction to gluten containing foods, which is neither defined as celiac disease nor wheat allergy, as exemplified by the recognition of non-celiac gluten sensitivity (NCGS). Although NCGS remains not well understood, together celiac disease and NCGS (and to a smaller degree wheat allergy) make up part of the spectrum of gluten-related disorders. With an estimated 18 million Americans living with NCGS (that’s six times the number of people with celiac disease), it is imperative for researchers to better understand what causes this innate response in so many people. Further, having a deeper understanding about the innate immunity in celiac disease will also benefit science.

A recent study has leant insight by showing that the a-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, which are non-gluten pest resistant molecules found in the wheat plant, elicit an innate immune response in people with celiac disease. Moreover, they are possible triggers of inflammation in NCGS and other inflammatory intestinal and even non-intestinal disorders. Examples include inflammatory bowel disease and irritable bowel syndrome.

With first author Dr. Yvonne Junker and senior author Prof. Detlef Schuppan of Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, the study was conducted both in vitro (a “test tube” experiment) and in vivo (within a living organism in its natural state; in this case, the researchers conducted the study with mice (whose innate immune system is similar to that of man), in order to better understand the innate immunity in celiac disease.

The scientists discovered that the ingested, non-gluten ATIs work as activators of the innate immune response in the intestine and can also cause inflammation in other parts of the body. The researchers found that while ATIs are mainly present in the water-soluble albumin fraction of wheat, barley and rye, they are also a “contaminant” in purified gluten preparations. Their findings could explain why people with celiac disease whose symptoms have resided can experience inflammation and symptoms after only 1-4 hours upon ingesting gluten. This time period is too short for an adaptive immune response to begin and suggests that people with celiac disease, and potentially other intestinal immune disorders such as NCGS, have an increased sensitivity to the ATIs. Thus, the symptoms they experience may in fact be an innate immune response.

Another major finding in the study brings the TLR4 (toll like receptor 4) gene into play. When asked to discuss the role and importance of TLR4, Prof. Schuppan explained, “TLR4 is primarily the cellular receptor for a major product of certain bacteria (such as lipopolysaccharide, which causes the toxic shock syndrome) that are harmful to man and that serve as immediate danger signal for the innate immune system to react. Notably, the identified ATIs act as a nutritional lipopolysaccharide, though with lower potency, to activate TLR4 on intestinal innate immune cells.”

While this study has broad implications for celiac disease, the results can also be used for further studies in other disorders such as NCGS, irritable bowel syndrome, inflammatory bowel disease and even non-intestinal inflammatory disorders. Since ATIs are the molecules naturally found in all gluten containing plants (wheat, barley and rye) to defend themselves against pests and parasites, like the meal bug, it is possible (and already proven by the group’s unpublished data) that there is more of this molecule in today’s wheat, which has grown more pest resistant due to resistance breeding. Interestingly, ATIs have been known to trigger allergic reactions in people with “baker’s asthma” and other wheat allergies, which the researchers say makes it “tempting to speculate that their ability to stimulate TLR4 contributes to their allergenicity.” Ongoing studies are focused on determining the activity of ATIs in different gluten containing grains and cereals and gluten-free foods. In addition, the researchers are investigating the role of nutritional ATIs in celiac disease, and other inflammatory and allergic diseases.

Read the full study from PubMed.gov, a division of the US National Library of Medicine, National Institutes of Health.

This is not the first time that Prof. Schuppan, a biochemist and physician at both The Celiac Center at BIDMC and Mainz University in Germany, has made groundbreaking discoveries in the field of celiac disease. His group discovered tissue transglutaminase (TG2) as celiac disease autoantigen, on which modern laboratory tests for the condition are based. Currently, he and his collaborators in biotech are close to the first clinical studies using specific inhibitors for TG2 (a pill) as a novel non-dietary therapy for celiac disease.