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Celiac.com 10/21/2024 - Wheat has been a staple in human diets for centuries, but for individuals with celiac disease and gluten sensitivities, consuming wheat can lead to serious health complications. The culprit? Gluten, particularly the gliadin fractions found in wheat, which trigger immune responses in those affected by celiac disease. A new study presents groundbreaking advancements in the field of gluten-free wheat production. Researchers have successfully used CRISPR/Cas9 technology to target and reduce gluten content by editing the genes responsible for the immunogenic gliadin proteins. Targeting Gliadin Genes with CRISPR/Cas9 The researchers in this study focused on two major groups of gliadin proteins: gamma (γ) and omega (ω) gliadins. These proteins are known to contain key epitopes that trigger adverse immune reactions in people with celiac disease. By designing eight specific single guide RNAs (sgRNAs), they were able to target and introduce mutations into these gliadin genes. Through the use of CRISPR/Cas9 multiplexing, a total of 59 wheat lines were produced, with 20 showing successful mutations in the target genes. This step marked a significant advance in reducing the gluten content of wheat. Massive Reduction in Gluten Content One of the most striking findings of the study was the 97.7% reduction in gluten content in the edited wheat lines. This was confirmed through various methods, including Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) and monoclonal antibodies. The reduction was most noticeable in γ-gliadins and ω1,2-gliadins, while α-gliadins saw smaller decreases. These reductions make the modified wheat an incredibly promising candidate for gluten-free food products, although some limitations remain when it comes to fully eliminating all immunogenic components. Combining Multiple Mutations In addition to targeting γ- and ω-gliadins, the researchers took an extra step by crossing these modified lines with CRISPR/Cas9 lines that had already been edited for α-gliadins. This approach resulted in wheat lines with multiple mutations across different gliadin families, further enhancing the reduction of gluten content. By combining multiple edits, the research has moved closer to producing wheat that is significantly safer for people with celiac disease or gluten sensitivities. Quantifying the Success: R5 and G12 Monoclonal Antibody Tests To measure the gluten content in the edited wheat lines, the study used two monoclonal antibody tests, R5 and G12, which are standard in the food industry for detecting gluten in products. The R5 antibody is specifically raised against rye ω-secalins, which are similar to wheat ω-gliadins, while the G12 antibody targets α-gliadins. Both tests showed significant reductions in gluten, with some lines showing up to 97.7% less gluten. However, there were discrepancies between the two tests, with the G12 test showing slightly higher gluten content. This suggests that while the wheat lines are substantially gluten-reduced, there is still room for further refinement in achieving a completely gluten-free product. Future Implications: The Path to Non-Transgenic, Immune-Safe Wheat While previous efforts had been made to develop low-gluten wheat, this study is notable for demonstrating the feasibility of using CRISPR/Cas9 to edit multiple genes simultaneously in polyploid bread wheat. The result is a collection of wheat lines with drastically reduced levels of immunogenic proteins, moving closer to the goal of producing wheat that is safe for individuals with celiac disease. Importantly, these modified wheat lines are non-transgenic, meaning they do not contain foreign DNA, which may make them more acceptable to consumers and regulators. The next steps involve further testing, including stimulation assays using peripheral blood mononuclear cells (PBMCs) from individuals with celiac disease. These tests will help researchers identify which wheat lines cause the least immune response, with the ultimate goal of producing wheat that can be safely used in gluten-free products. A Step Toward Gluten-Free Wheat for Celiac Disease Patients For individuals with celiac disease, the promise of gluten-free wheat represents a potential game-changer. This study has made significant strides toward that goal by reducing the immunogenic gliadin proteins that cause adverse reactions. While further testing and development are necessary, the application of CRISPR/Cas9 technology in wheat breeding holds great promise for the future of gluten-free diets. The study does not specifically address the baking properties of the new wheat varieties with reduced gluten content. However, this is an essential consideration when developing gluten-free or gluten-reduced wheat. Gluten plays a critical role in baking, as it provides dough with its elasticity, structure, and ability to trap air during fermentation, leading to the light and airy texture of bread and other baked goods. When gluten is removed or reduced, it can significantly alter these properties, resulting in denser, less cohesive baked products. Therefore, it's crucial that any new gluten-free wheat varieties maintain similar baking characteristics, or alternative methods, such as adding binders like xanthan gum or psyllium husk, may be needed to replicate the qualities gluten imparts in baking. Balancing the reduction of immunogenic proteins with maintaining functional qualities is key to making the wheat practical for food production. This research is especially meaningful for those with celiac disease because it offers hope for a future where they can enjoy wheat-based foods without fear of triggering harmful immune responses. By creating wheat with drastically reduced gluten content, researchers are opening doors to new gluten-free food options that could improve the quality of life for millions of people worldwide. Read more at: academic.oup.com

Celiac.com 06/06/2020 - Patients with depression are told they have a chemical imbalance. If someone else in their family is also depressed, the “gene card” is played. “Your depression is genetic”, they are told. I have been in practice for over 20 years and I find the above data to be false. Consistently we find patients who are suffering from depression and anxiety to be gluten sensitive. How could a food cause depression? Let’s take a look: After the digestive tract, the system most commonly affected by gluten is the nervous system. It is thought that depression can be caused by gluten in one of two ways, inflammation and protein absorption. The first is through the inflammatory changes caused by gluten. A gluten sensitive individual’s immune system responds to the protein gliadin. Unfortunately, that protein is structurally similar to body proteins, including those of the brain and nerve cells. A cross reaction can occur when the immune system “confuses” body proteins with gliadin proteins. This is called cellular mimicry and the result is inflammation where the body is attacking its own tissues. When inflammation happens in the brain and nervous system, a variety of symptoms can occur, including depression. Research shows that patients with symptoms involving the nervous system suffer from digestive problems only 13% of the time. This is significant because mainstream medicine equates gluten sensitivity almost exclusively with digestive complaints. In a study examining blood flow in the brain, 15 patients with untreated celiac disease were compared to 15 patients treated with a gluten-free diet for one year. The findings were amazing. In the untreated group, 73% had abnormalities in brain circulation by testing while only 7% in the treated group showed any abnormalities. The patients with the brain circulation problems were frequently suffering from anxiety and depression as well. In addition to circulation problems, other research looks at the association between gluten sensitivity and its interference with protein absorption. Specifically the amino acid tryptophan can be deficient. Tryptophan is a protein in the brain responsible for a feeling of well-being and relaxation. A deficiency can be correlated to feelings of depression and anxiety. Our society is too willing to accept “chemical imbalance” as an explanation for their symptoms. Instead of getting to the root cause of the condition, we simply swallow a pill—a pill that in the case of anti-depressants has very dangerous and sometimes lethal side effects. The frequency with which we are able to successfully taper patients off their anti-depressants is considered “unbelievable” by many mainstream doctors, yet we do it regularly. How is that possible? We actually diagnose the root cause of the depression. Frequently the culprit is gluten.

Celiac.com 10/25/2021 - Celiac disease is an autoimmune disorder marked by a strong immune response to dietary gluten proteins, which causes gastrointestinal symptoms, and damages the small intestine. Despite being fairly common, the only current treatment for celiac disease is a strict gluten-free diet. A number of clinical trials have looked to impede or reduce the immune response, many by targeting gluten proteins via immunosuppression, enhanced protein degradation or protein sequestration. Some data indicates that polyphenols may provide protection from celiac disease damage by disrupting the enzymatic hydrolysis of gluten proteins, sequestering gluten proteins from recognition by critical receptors in pathogenesis, and driving a reduction in inflammation. Researchers Charlene B. Van Buiten, and Ryan J. Elias recently set out to review mechanisms by which polyphenols can protect against celiac disease, critically assess recent works, and sketch out future applications for using polyphenols to protect against celiac disease. Van Buiten and Elias are affiliated with the Department of Food Science and Human Nutrition, College of Health and Human Sciences, Colorado State University, Fort Collins, Colorado, and the Department of Food Science, College of Agricultural Sciences, Pennsylvania State University, University Park, Pennsylvania. Their review highlights ways in which polyphenols can protect against celiac disease, offers a critical assessment of recent studies, and sketches potential applications for treating celiac disease in this manner. Their review appears in the International Journal of Molecular Science. Read more in Int. J. Mol. Sci. 2021, 22(2), 595

Celiac.com 03/28/2020 - In theory, celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. A team of researchers recently set out to investigate the safety and efficacy of negatively charged, 500 nm, poly (lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. The research team included Tobias L. Freitag, Joseph R. Podojil, Ryan M. Pearson, Frank J. Fokta, Cecilia Sahl, Marcel Messing, Leif C. Andersson, Katarzyna Leskinen, Päivi Saavalainen, Lisa I. Hoover, Kelly Huang, Deborah Phippard, Sanaz Maleki, Nicholas J.C. King, Lonnie D. Shea, Stephen D. Miller, Seppo K. Meri, and Daniel R. Getts. Negatively charged, 500 nm, poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. TIMP-GLIA did not elevate maturation markers on cultured human dendritic cells, or activate T cells from patients with active or treated celiac disease. The team assessed the model 1 delayed-type hypersensitivity, the model 2 HLA-DQ8 transgenic, and the model 3 gliadin memory T cell enteropathy models of celiac disease. Injections of TIMP-GLIA substantially reduced gliadin-specific T cell generation in models 1 and 2. Further, injections reduced inflammatory cytokine secretion in all three models, circulating gliadin-specific IgG/IgG2c in models 1 and 2, ear swelling in model 1, gluten-dependent enteropathy in model 3, and body weight loss in model 3. In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, showed increased levels of FOXP3, and gene expression markers associated with improved tolerance. Injecting gluten-sensitive mice with TIMP-GLIA nanoparticles nearly eliminated the immune response to gliadin, and reduced markers of inflammation and enteropathy. This approach might be refined and used to develop new treatments for celiac disease in humans. Read more in Gastroenterology The researchers are variously affiliated with the Department of Bacteriology and Immunology; the Translational Immunology Research Program; the Department of Microbiology and Immunology at Cour Pharmaceutical Development Company, Northbrook, IL, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Helsinki, Finland; Precision for Medicine, Frederick, MD, USA; the Discipline of Pathology, School of Medical Sciences, Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, Australia; the Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Celiac.com 11/28/2020 - Non-celiacs show Interleukin 15 production when challenged with gliadin peptides. A recent study by a team of Spanish researchers puts the world on notice that gluten may trigger adverse reactions in both celiacs and non-celiacs alike. The research team was made up of Doctors E. Arranz, D. Bernardo, L. Fernandez-Salazar, J. A. Garrote and their colleague S. Riestra, all based in Spain. According to the current medical wisdom, innate immunity to gluten plays a critical role in the development of celiac disease. This innate immune response is caused by a reaction to the ‘toxic’ gluten peptides that are mediated by a chemical in the white blood cells called interleukin 15, which stimulates these cells to react against foreign proteins like the 19-mer. The reaction is independent of genetic HLA markers associated with celiac disease. This causes epithelial stress and triggers the intraepithelial lymphocytes to turn into natural killer (NK)-like cells, which then causes enterocyte cells to die resulting in a compromised permeability of the cells lining of the gut…and, violà, celiac disease! It is by breaching this intestinal lining that peptides such as the 33-mer, come into contact with the lamina propria, which triggers general immune reactions. The specific response in celiac disease has been pretty well documented, but until recently, no one had described any differential factors between people with celiac disease and those without. Since the toxic 19-mer triggers its damaging effects independent of the celiac associated HLA markers, researchers wondered whether the innate immune response was common in people with and those without celiac disease. They wondered whether the adaptive response is found only in those susceptible to celiac disease. The gliadin-challenged patients with celiac disease who were on a GFD, showed increased nitrite levels, which those without celiac disease did not show. Only patients with celiac disease showed modifications to what are called adaptive mediators (STAT1, STAT3, IFNc). The samples of those celiac patients on a gluten-free diet showed interferon levels that were 80 times higher than those without celiac disease, along with a slightly higher production of nitrites. This appears to be the first time that researchers have described an interleukin 15-mediated innate response to gliadin and gliadin peptides in people without celiac disease, as well as the first time they have described an IL15-mediated innate response to the ‘non-toxic’ deaminated immuno-dominant 33-mer peptide. What this all means is that, for the first time, scientists have documented harmful effects of gluten on people without celiac disease. This hypothesis seems to be born out by the fact that all individuals who took part in the study, both those with and those without celiac disease, showed an innate immune response to gluten, though only those with celiac disease showed an adaptive immune response to gluten. Clearly, before doctors can draw any hard and fast conclusions, they will need to do more studies on larger groups. The research team also suggests that people with celiac disease have a lower threshold for triggering an adaptive TH1 response than do non-celiacs. The reason for the differences in threshold levels between celiacs and non-celiacs might be the result of higher levels of immune reactions in celiac patients compared to those without celiac disease. That’s one possibility. The difference in threshold levels might also have to do with some kind of defect in permeability of the gut membrane in those with celiac disease, or a greater immune sensitivity to equivalent quantities of toxic gliadin fractions which might come from a higher density of interleukin 15 receptors in patients with celiac disease. Source: Gut 2007;56:889–890

Celiac.com 07/23/2020 - Celiac disease is a common inflammatory autoimmune condition that is influenced by both genetic factors and environmental triggers. Researchers still don't know very much about the early genesis of celiac disease. A team of researchers recently set out to describe the interplay between type 2 transglutaminase (TG2), gliadin peptide 31-43 and anti-TG2 antibodies in celiac disease. The team included Stefania Martucciello, Silvia Sposito, Carla Esposito, Gaetana Paolella, and Ivana Caputo. They are variously affiliated with the Department of Chemistry and Biology; and the European Laboratory for the Investigation of Food-Induced Diseases (ELFID) at the University of Salerno in Fisciano (SA), Italy Gluten is a protein found in wheat, rye and barley, and is the main factor implied in the onset of celiac disease, which involves both innate and adaptive immune responses to gluten. The immune-triggering potential of some gluten sequences are increased by the deamidation of specific glutamine residues by type 2 transglutaminase (TG2), an enzyme whose expression is up-regulated in the intestine of celiacs. The α-gliadin peptide 31-43 is a short gluten chain that resists intestinal proteases, and which seems to modulate TG2 function in the gut. Interestingly, TG2 can also influence the biological activity of this α-gliadin peptide 31-43. A strong auto-immune response to TG2 is a classic sign of celiac disease. Auto-antibodies exert biological effects on multiple cells. These effects partly overlap with those caused by α-gliadin peptide 31-43. In their recent review, the team poses a scenario in which TG2, anti-TG2 antibodies and peptide 31-43 come together to synergistically trigger and promote celiac disease. If their hypothesis is correct, further study could help researchers better understand celiac development and potentially point the way to new measures of prevention and/or treatment for celiac disease. Stay tuned for more articles on the role of TG2, anti-TG2 antibodies and peptide 31-43 in the development of celiac disease. Read more at Int J Mol Sci. 2020 May; 21(10): 3673

Celiac.com 04/01/2020 - Some people with celiac disease have symptoms even when they follow a gluten-free diet. Even though the most likely culprit in these cases is cross-contamination, or some other type of food sensitivity, some people have suggested that the problem may have to do with certain foods that trigger a celiac-like gut reaction. But, is that really true? A few years back, a team of researchers set out to figure out if such symptoms might come from either cross-contamination with gluten-containing foods, or cross-reactivity between α-gliadin and non-gluten foods eaten as part of an otherwise gluten-free diet. Researcher Aristo Vojdani, and colleagues with the Immunosciences Lab used ELISA and dot-blot to gauge the reactivity of affinity-purified polyclonal and monoclonal α-gliadin 33-mer peptide antibodies against gliadin and other food antigens often eaten by celiacs who are following a gluten-free diet. The team also assessed the immune reactivity of these antibodies with various tissue antigens. According to their results, these antibodies to cow’s milk, milk chocolate, milk butyrophilin, whey protein, casein, yeast, oats, corn, millet, instant coffee and rice, triggered significant immune reactivity. These results seemed to confirm that certain foods might be "cross-reacting," and triggering celiac-like symptoms in celiac patients on a gluten-free diet. Questions About Vojdani Methodology Taken at face value, the 2013 Vojdani study would seem to support the idea of otherwise gluten-free foods being cross-reactive, and causing celiac-like symptoms in people with celiac disease. However, a 2019 review of that study by Christina L. Graves Ph. D, with the University of North Carolina at Chapel Hill Department of Biology, casts serious doubt on the methodology and findings of the Vojdani study. Ms. Graves' review, 19 Gluten Cross-Reactive Foods Busted Myth, appears at Paleofoundation.com, and she really highlights the flaws in the Vojdani study, and they are many. Also, for something as simple as corn zein, "...celiac disease-specific antibodies don’t appear to cross-react to corn zein. The rice/gluten cross-reactive study cited by Vojdani & Tarash 2013 is specific for IgE mediated responses, whose dominant epitopes are different than the epitopes recognized by anti-α-gliadin antibodies presented in this study. Graves takes care not to step on too many toes by noting that she is only seeking "to highlight the importance of being rigorous with our own research and reporting within the ancestral health community and to highlight that the rationale for the avoidance of some foods may have arrived through the inflated interpretation of inconclusive results." With respect to the types of tests used to show cross-rectivity, Graves adds "The Celiac Disease Center does not currently recognize Enterolabs or Cyrex stool tests for cross-reactivity (or for celiac disease for that matter). [20] Simply, they are “not sensitive or specific enough” and just haven’t held water (yet) in the scientific arena." Graves may tread lightly in her comments, but her methodical take down of the Vojdani study casts serious doubt on the study's methods, and conclusions, about cross-reactivity. Moreover, there has been no substantial confirmation of the Vojdani findings since the original publication, and there has, so far, been no credible rebuttal to Graves' finding regarding the study. Thus, it is sensible to conclude that Graves is correct, the Vojdani study methods and conclusions are seriously flawed, and that there is no good data to support to claims that cross-reactivity in certain non-gluten foods can trigger celiac-like symptoms in people with the disease. Put simply, until we get more convincing study, with solid evidence to the contrary, there is no good evidence to support the idea of non-gluten cross-reactivity in people with celiac disease. Read 19 Gluten Cross-Reactive Foods Busted Myth by Christina L. Graves Ph. D at Paleofoundation.com. Read the original Vojdani Study in Food and Nutrition Sciences 04(01):20-32 · January 2013.

Celiac.com 02/01/2020 - Traditionally, gluten is defined as a cohesive, elastic protein that remains when starch is rinsed from wheat flour dough. Gluten is the stuff that makes bread soft and pliable. It's the stuff that makes wheat paste sticky. It's also what causes so much trouble for people with celiac disease. Here are some quick facts about gluten and gliadin. Gluten is actually made up of many different proteins. During digestion, the gut breaks down both gliadin and glutenin proteins into smaller units, called peptides, polypeptides or peptide chains. These peptide chains are made up of strings of amino acids--very much like beads on a string. Gluten Triggers Immune Reaction in Celiac Disease Only wheat contains true gluten. However, rye and barley contain proteins that are similar enough to gluten to cause an immune reaction in people with celiac disease. Oat proteins have similar, but slightly different polypeptide chains and may or may not be harmful to celiac patients. There is scientific evidence supporting both possibilities. There are two main types of proteins in gluten: gliadin and glutenin. While there are differences between the two, the main thing they have in common is that they trigger an autoimmune reaction in people with celiac disease. One peptide in particular triggers an adverse reaction in celiac patients when introduced directly into the small intestine. This peptide includes 19 amino acids strung together in a specific sequence. Although the likelihood that this particular peptide is harmful is strong, other peptides may also be harmful, including some derived from glutenin. What Does it Mean to Be Gluten-Free? When celiac patients talk about eating "gluten-free" or a following a "gluten-free diet," they are really just talking about avoiding the harmful peptides from wheat, rye, barley, and possibly oats. This means eliminating all foods and ingredients made from these wheat, rye, barley, such as food starch prepared from wheat, and malt made from barley, even if these foods don't contain gluten in the strict sense. So, going "gluten-free" has become shorthand for avoiding unsafe foods and ingredients that can harm people with celiac disease or gluten-intolerance, and eating foods and ingredients that are safe. Corn and Rice Do Not Contain Gluten In recent years, especially among non-celiacs, the term gluten has been stretched to include corn proteins (corn gluten), and there is a glutinous rice, although in the latter case, glutinous refers to the stickiness of the rice rather than to its containing gluten. Both corn and glutinous rice are safe for people with celiac disease.

Celiac.com 01/30/2020 - There is a strong association between human leukocyte antigen (HLA) locus and T cell-mediated autoimmune disorders. Researchers understand that HLA-DQ2.5-mediated celiac disease is triggered by the ingestion of gluten, but they don't know much about genetic and environmental risk factors that might contribute to disease. In an effort to find out more, including whether T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease suggests role of microbial exposure, a team of researchers recently set out to spot microbe-derived copycats of gliadin epitopes, along with "a parental bacterial protein that is processed by antigen-presenting cells, and activated gliadin reactive HLA-DQ2.5-restricted T cells, taken from celiac disease patients." The research team included Jan Petersen, Laura Ciacchi, Mai T. Tran, Khai Lee Loh, Yvonne Kooy-Winkelaar, Nathan P. Croft, Melinda Y. Hardy, Zhenjun Chen, James McCluskey, Robert P. Anderson, Anthony W. Purcell, Jason A. Tye-Din, Frits Koning, Hugh H. Reid & Jamie Rossjohn Among the findings "[c]rystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides show that molecular mimicry underlies cross-reactivity toward the gliadin epitopes." Accordingly, the fact that gliadin reactive T cells involved in celiac disease development cross-react with bacterial peptides suggests that microbial exposure could be an environmental factor in celiac disease. Read more in: Nature Structural & Molecular Biology volume 27, pages 49–61(2020). The researchers are variously affiliated with the Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia; the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia; the Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; the Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; the he Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia; the Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; and with ImmusanT of Cambridge, MA, USA.

Celiac.com 08/15/2019 - Does the cystic fibrosis transmembrane conductance regulator play a pathogenic role in celiac disease? Usually, when people consume dietary proteins, their guts prevent local inflammatory and immune responses, and encourage oral tolerance to the proteins. However, for about one out of a hundred people worldwide, gluten and related cereals trigger an HLA DQ2/8-restricted TH immune and antibody response, which develops into celiac disease, if untreated. Prior epithelial stress and innate immune activation are required to break oral tolerance to gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Does the cystic fibrosis transmembrane conductance regulator play a pathogenic role in celiac disease? A team of researchers recently set out to shed some light on the way gliadin subverts host intestinal mucosal defenses. The research team included Valeria R Villella, Andrea Venerando, Giorgio Cozza, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Mara C Spinella, Vasilis Oikonomou, Giorgia Renga, Antonella Tosco, Federica Rossin, Stefano Guido, Marco Silano, Enrico Garaci, Yu-Kai Chao , Christian Grimm, Alessandro Luciani, Luigina Romani, Mauro Piacentini, Valeria Raia, Guido Kroemer & Luigi Maiuri. Their team demonstrated that the a-gliadin-derived LGQQQPFPPQQPY peptide (P3–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell-autonomous or environmental stress. P3–43 binds to, and reduces ATPase activity of, the nucleotide-binding domain- (NBD) of CFTR, thus impairing CFTR function. This creates epithelial stress, tissue transglutaminase and inflammasome activation, NF-jB nuclear translocation and IL-5 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX-770 reduces gliadin-induced inflammation and promotes tolerance in gluten-sensitive mice and cells from patients with celiac disease. The team's results show that CFTR plays an early and crucial role in guiding gliadin activities, and reveals a new therapeutic possibility for treating celiac disease. Stay tuned for more developments on this and related stories. Read more at the EMBO Journal (209) 38: e000 The researchers are variously affiliated with the European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy; the Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy; the Department of Molecular Medicine, University of Padova, Padova, Italy; the Department of Health Sciences, University of Eastern Piedmont, Novara, Italy; the Department of Experimental Medicine, University of Perugia, Perugia, Italy; the Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy; the Department of Biology, University of Rome “Tor Vergata”, Rome, Italy; Department of Chemical, Materials and Production Engineering, Federico II University Naples, Naples, Italy; the Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Roma, Italy; University San Raffaele and 21 IRCCS San Raffaele, Rome, Italy; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Munich (LMU), Munich, Germany; the Institute of Physiology CH, University of Zurich, Zurich, Switzerland; the National Institute for Infectious Diseases IRCCS “L. Spallanzani”, Rome, Italy; the Centre de Recherche des Cordeliers, Equipe11 labellisée Ligue Nationale Contrele Cancer, Paris, France; the Centre de Recherche des Cordeliers, INSERM U1138, Paris, France; the Université Paris Descartes, Paris, France; the Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; the Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; and the Department of Women’s and Children’s Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Celiac.com 08/05/2019 - The relationship between mental health, gluten sensitivity, and celiac disease has not been well researched. Some studies have shown that people with schizophrenia and bipolar disorder have elevated levels of antibodies to gliadin. A team of researchers recently set out to examine longitudinally the levels of antibody reactivity to gliadin in acute mania. The sample included 60 individuals assessed during a hospital stay for acute mania, 39 at a 6-month follow-up, and a sample of 143 non-psychiatric control subjects. The research team included Faith Dickerson, Cassie Stallings, Andrea Origoni, Crystal Vaughan, Sunil Khushalani, and Robert Yolken. They are variously affiliated with the Stanley Research Program at Sheppard Pratt, Baltimore, MD, USA, and the Stanley Neurovirology Laboratory, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA. The team used enzyme immunoassay to measure antibodies to gliadin. They used regression models to analyze the relationship between the antibodies and the clinical progress of patients with mania. Using multivariate analyses, the team found that patients with mania had significantly higher levels of IgG antibodies to gliadin at baseline, but not other markers of celiac disease, compared with control subjects. At the six month follow-up, however, these levels did not differ substantially from those of control subjects. In patients with mania, elevated levels after six months were strongly associated with re-hospitalization in the 6-month follow-up period. Based on these results, the team concludes that the monitoring and control of gluten sensitivity could be helpful in managing individuals hospitalized with acute mania. Stay tuned for more on this and related stories. Source: Psychiatry Research. Volume 196, Issue 1, 30 March 2012, Pages 68-71.

Celiac.com 03/14/2019 - Researchers still don’t know much about the mechanisms driving inflammatory responses against certain antigens in food. To get more information, a team of researchers recently set out to see if p31-43 peptide (p31-43) from α-gliadin can trigger an innate immune response in the gut, and whether this might trigger pathological adaptive immunity. The research team included María Florencia Gómez Castro, Emanuel Miculán, María Georgina Herrera, Carolina Ruera, Federico Perez, Eduardo Daniel Prieto, Exequiel Barrera, Sergio Pantano, Paula Carasi, and Fernando Gabriel Chirdo. They are variously affiliated with the Instituto de Estudios Inmunológicos y Fisiopatológicos (CONICET), Universidad Nacional de La Plata, La Plata, Argentina, the Instituto de Fisicoquímica y Químicas Biológicas, Dr. Alejandro Paladini (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina, the Laboratorio de Nanoscopía y Fisicoquímica de Superficies (CONICET), Universidad Nacional de La Plata, La Plata, Argentina, and the Biomolecular Simulations Group, Institut Pasteur de Montevideo, Montevideo, Uruguay. Researchers do not currently understand the receptors and mechanisms responsible for the induction of innate immunity by p31-43. In their recent paper on the subject, the research team offers evidence that conformational changes in the peptide may allow it to activate the NLRP3 inflammasome. When researchers treated normal mice with p31-43, but not with scrambled or inverted peptides, the mice developed enteropathy in the proximal small intestine, which is associated with higher levels of type I interferon and mature IL-1β. P31-43 demonstrated a sequence-specific spontaneous ability to form structured oligomers and aggregates in vitro and to activate the ASC speck complex. The enteropathy caused by p31-43 in live mice occurred only in the presence of NLRP3 or caspase 1, and was restricted by treatment with caspase 1 inhibitor Ac-YVAD-cmk. Together, the data show that p31-43 gliadin naturally forms oligomers, which trigger the NLRP3 inflammasome. Moreover, this pathway is necessary for intestinal inflammation and pathology when p31-43 is given orally to mice. This innate activation of the NLRP3 inflammasome could play a key role in the early stages of celiac disease development. Read more at Front Immunol. 2019

Celiac.com 01/02/2019 - Way back in 2011, a team genetic engineering researchers at the University of Washington began to develop a new treatment for celiac disease. The team’s early research suggested that an oral enzyme that could break down the gluten proteins would be an ideal therapy for celiac disease. Taken before meals by a person with celiac disease, such an enzyme would ideally neutralize all trace of gluten before they could trigger an immune response. Their search to develop such a treatment would take them nearly a decade of effort. To fuel their goals, the team made use of pioneering computer software, called the Rosetta Molecular Modeling Suite, that helps design new proteins, including enzymes. They began by selecting a protein-digesting enzyme that was already known to work well in acidic conditions. However, the selected enzyme lacked the gluten-killing ability the team sought. Using a video game-like interface to Rosetta called Fold-it, the team created versions of the enzyme that would target gluten proteins. The team then chose about 100 of their most promising enzyme designs. They then physically created each of those designer enzymes in the lab and tested their ability to break down gluten. By combining the best performing enzymes, the team was able to create a prototype gluten-degrading enzyme, which they named KumaMax, as it is derived from the starter enzyme, kumamolisin. After years of additional tweaking of the prototype enzyme at the University of Washington’s Institute for Protein Design, the team was able to begin Phase I clinical trials on KumaMax. If clinical trials go well, the team is looking to follow with testing on human celiac patients. The results could give rise to a new commercially available enzymatic treatment for celiac disease. Read more at: ASCH.ORG