Non-Gluten proteins identified as targets of immune response to wheat in celiac disease

Researchers at Columbia University Medical Center have found that, in addition to gluten, the immune systems of patients with celiac disease react to specific types of non-gluten protein in wheat. The results were reported online in the Journal of Proteome Research.

Celiac disease, an autoimmune disorder that affects about 1 percent of the U.S. population, is triggered by the ingestion of wheat and related cereals in genetically susceptible individuals. The immune response results in inflammation and tissue damage in the small intestine, which can lead to severe gastrointestinal symptoms, as well as a number of extra-intestinal manifestations. Gluten proteins, which represent about 75 percent of the total protein content of wheat grain, are known to be the primary triggers of the immune response in celiac disease. While the role of gluten in celiac disease has been extensively studied since the 1950s, the possible involvement of wheat non-gluten proteins has not been characterized and is poorly understood.

“This work is the first to attempt mapping of the B cell response to non-gluten proteins of wheat in celiac disease,” said the study’s principal investigator, Armin Alaedini, PhD, assistant professor of medicine (in the Institute of Human Nutrition and the Celiac Disease Center) at Columbia University.

Dr. Alaedini and postdoctoral fellows Sina Huebener and Melanie Uhde, in collaboration with a team of scientists at the U.S. Department of Agriculture, searched for the protein targets through two-dimensional separation techniques, immunoassays, and mass spectrometry. The new data identify a group of molecules known as serpins, in addition to four other types of wheat protein, as novel non-gluten immunogenic proteins in celiac disease.

Co-author Peter H. R. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine and director of the Celiac Disease Center at Columbia University Medical Center, said, “These results indicate that immunologic reactivity in celiac disease may not be limited to wheat gluten, but can involve certain non-gluten proteins, too. I think the findings have implications for understanding the mechanism of the disease and developing new therapeutics.”

What is gluten?
Gluten in the food industry often refers to storage proteins found in all grains. These storage proteins are beneficial in food production, adding flavor, texture or thickening.

Gluten-free refers only to specific storage proteins known to be harmful and potentially damaging for persons with glutenintolerances (celiac disease, dermatitis herpetiformis, and non-celiac gluten sensitivities). Gluten-free diets avoid the storage proteins found in wheat, rye, barley, and hybrids of these grains such as spelt and Kamut®.

Who should eat gluten-free food?
People who have been advised by their physician to be on a gluten-free diet should eat gluten-free foods. This would include persons with all forms of gluten intolerance.

What types of gluten intolerances are there?
Gluten intolerances are both autoimmune (genetic) and innate immune responses. Autoimmune gluten disorders include celiac disease and dermatitis herpetiformis. Persons with these conditions will suffer tissue damage in the intestine or skin when eating gluten. They may suffer a number of symptoms and related health issues as a result. Gluten sensitivity is an innate immune response, similar in reaction to lactose intolerance. Although this type of reaction does not cause damage to the intestine or skin, it may cause inflammation and other health-related problems. Avoiding gluten is the only way for persons with gluten-related disorders to maintain good health.

How do I know if I have celiac disease?
Blood tests are available to screen for celiac disease but a positive small bowel biopsy is required to confirm the diagnosis of celiac disease. Skin biopsies are used to diagnose dermatitis herpetiformis.

Non-Gluten proteins identified as targets of immune response to wheat in celiac disease The authors caution that it remains to be seen whether the identified proteins play a role in contributing to the intestinal damage in patients with celiac disease. Dr. Alaedini noted that, “Although we can’t draw direct conclusions about the pathogenic effects of the proteins yet, these findings should prompt a closer look into their potential involvement in the inflammatory processes at work in celiac disease.”

Immune Responses to Gluten = Gluten Allergy

Immune responses to gluten, the proteins found in cereal grains are a common cause of disease. The gastrointestinal tract is the primary target organ; however systemic disease is an important consequence of cereal grain ingestion in many patients. We think that the people diagnosed with celiac disease are a sub-population of a much larger group with gluten allergy.

The surface lining of the digestive tract is the largest and most critical interface between you and your environment. In the small intestine, the lining epithelial cells are involved in immune processes. They transfer immunoglobulins produced by lamina propria B-lymphocytes to the surface and interact with other cells of the immune system to induce an inflammatory response to stop microbial invasion. The surface epithelium processes food antigens, and presents antigens to lymphocytes. Both epithelial cells and intraepithelial lymphocytes participate in inflammatory reactions. Epithelial cells proliferate in celiac disease. Crypt hyperplasia is a common tissue response to mucosal damage in food allergy and infection. A cell-mediated type of allergy leads to many complicated consequences, especially increased permeability of the gastrointestinal tract (GIT) with more problems downstream.
Gliadin-specific T lymphocytes are found in the small intestinal mucosa and in the peripheral blood. The density of T cells is increased in the jejunal epithelium, an abnormality considered to be specific for celiac disease. Gluten specific T cell clones activated by gluten are key players in the pathogenesis of celiac disease. Antigen- induced production of cytokines was studied in lymphocytes that secreted interferon gamma, often at high concentrations (2000 U/ml); increased concentrations of other interleukins IL 4, IL 5, IL 6, IL 10, tumor necrosis factor (TNF), and transforming growth factor (TGF) beta are also found

A list of diseases that occur with increased frequency in celiac patients resembles the list of disorders reviewed under our descriptions of delayed pattern food allergy These diseases include diabetes, thyroid disease,  anemia, rheumatoid arthritis, sacroileitis, sarcoidosis, vasculitis, inflammatory lung disease, eye inflammation, cerebellar ataxia and schizophrenia. These and other immune-mediated disease can be linked to gluten ingestion. These associations suggest that people with a tendency to immune hypersensitivity diseases are vulnerable to food antigens that can cause systemic autoimmune disease. In their review of these associated disorders, Mulder and Tygart repeated the basic ideas that can explain the prolific ability of of gluten to cause disease downstream from a disordered gastrointestinal tract. They stated:

“Patients with (celiac disease and) selective IgA deficiency often have circulating antibodies to food proteins; they also have circulating immune complexes, suggesting that absence of an intestinal IgA barrier might allow the absorption of antigenic material from the gut. Antibodies to some of the antigens might cross react with the hosts self components and might indirectly produce autoimmune disease.”



This research was supported by the National Center for Advancing Translational Sciences, NIH (UL1 TR000040).

The authors report no financial or other conflicts of interest.

Celiac Disease Center at Columbia University provides comprehensive medical care for adults and pediatric patients with celiac disease, including nutrition and attention to the multiple associated conditions that occur in celiac disease. The center is involved in the care of thousands of patients with celiac disease and gluten sensitivity, providing better access to proper testing, diagnosis, treatment, and follow-up care.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast.


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Columbia University Medical Center

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