Scientists have identified a protein fragment in many cereal grains that may cause the autoimmune disorder, Celiac Sprue, and an enzyme that may help treat the disorder. Celiac Sprue requires strict adherence to a gluten-free diet, and affects approximately one in 200 individuals, according to U.S. and Norwegian researchers. The team reports its findings in the journal Science, published by the American Association for the Advancement of Science.
Although Celiac Sprue is relatively common, scientists generally know little about its specific cause or how to treat it, according to study author Chaitan Khosla of Stanford University.
"When I do presentations about the disease, typically the response I get is, 'Who is Celiac Sprue?'" Khosla said. "This disease has been overlooked in a very serious way by the basic science, clinical, and pharmaceutical communities."
The disorder is a major burden for people who have it, according to Khosla. Gluten proteins, which occur naturally in wheat, rye, and barley, are used in many other foods, as certain forms of food starch, flavorings, or processing agents. For "celiacs," even small amounts of gluten can cause a variety of symptoms, many digestion-related. Over the long term, eating gluten can cause serious damage to their small intestines.
"If you are diagnosed with Celiac Sprue, typically the physician gives you a referral to a dietician, who gives you a book about the size of a New York City phone book, that lists all the things you can't eat. The bottom line is, if you go into a typical grocery store with that phone book, it will tell you that you can't buy 90 percent of the things in the store," Khosla said.
The main toxic components of gluten are a family of proteins called gliadins, which, like all dietary proteins, can be broken down into subunits called peptides. Khosla and his colleagues have identified a large gliadin peptide that does not break down during digestion, and likely triggers celiacs' immune systems upon reaching the small intestine, the authors suggest.
"The peptide is essentially like sand. If most people ate it, not much would happen to it. It would just go through the gut. But in the small intestines of celiacs, this peptide is highly inflammatory," Khosla said.
The researchers also identified a bacterial enzyme that breaks down this and related peptides, suggesting that adding it or a similar enzyme to celiacs' diets might allow them to eat some gluten. Products like Lactaid, for lactose intolerant individuals, contain an analogous enzyme that breaks down lactose, Khosla explained.
Exactly how the peptide causes intestinal damage isn't completely clear yet. Thus far, scientists have figured that the autoimmune reaction to gluten is related to a gene shared by 90 percent of celiacs, called HLA-DQ2. The gene plays a role in one of the immune system's strategies for recognizing and destroying foreign peptides, or "antigens."
Specifically, the gene encodes a key receptor on the surface of certain immune cells. The receptor binds to antigens, "displaying" them to activate certain T cells to launch a specialized attack.
It's generally agreed that the HLA-DQ2 receptor seems to be prone to binding with gluten peptides, which are first modified by an enzyme in the small intestine called "tissue transglutaminase" to make them a particularly "sticky" match. The T cells then mistake the modified peptides for a foreign antigen and attack the body's own tissue.
Khosla and colleagues identified their candidate peptide by exposing gliadin proteins to various enzymes that simulated the digestion process. A relatively large fragment, made up of 33 amino acids, stayed intact throughout these experiments, and also proved resistant to digestion in live rats.
The peptide was also readily modified by tissue transglutaminase, the authors found, and the resulting product was a potent stimulant of inflammatory T cells isolated from small intestines of celiacs.
Although other peptides capable of triggering celiac-specific T cells have been identified from gluten, they are structurally related to the peptide identified in this study. Thus, Khosla and his colleagues believe that the same bacterial enzyme could also destroy those peptides, although this yet to be shown. Another outstanding question is why some people with the HLA-DQ2 gene do not have the disorder at all.
"That's a major unanswered mystery about the disease that hopefully will be answered in the next few years," Khosla said.
The other authors of the study are Lu Shan, Isabelle Parrot, Felix Hausch, Ferda Filiz, and Gary M Gray, of Stanford University, in Stanford, CA; and Øybind Molberg and Ludvig M. Sollid, of the University of Oslo, in Oslo, Norway. The study was supported by the National Science Foundation, the Research Council of Norway, the European Commission, Stanford University, and Fondation pour la Recherche Medicale.
Journal
Science