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    Suppressive Function of Regulatory T Cells Impaired in Celiac Patients


    Jefferson Adams


    • Does Treg cell dysfunction play a major role in celiac disease pathogenesis?


    Image Caption: Is Treg cell dysfunction a key factor in celiac disease development? Photo: Zappys Technology Solutions

    Celiac.com 06/21/2017 - Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease. What does that mean?


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    Although researchers understand the effector T-cell response in patients with celiac disease pretty well, they really don't know very much about the role played by regulatory T cells (Treg cells) in the loss of tolerance to gluten. To get a better picture, a team of researchers recently set out to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells.

    The research team included L Cook, CML Munier, N3 Seddiki, D van Bockel, N Ontiveros, MY Hardy, JK Gillies, MK Levings, HH Reid, J Petersen, J Rossjohn, RP Anderson, JJ Zaunders, JA Tye-Din, AD Kelleher.

    For the study, gluten-free patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. The research team collected peripheral blood before and after challenge. To effectively measure the gluten-specific CD4+ T-cell response, they combined traditional IFN-γ ELISpot with a test for antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation, but relies instead on antigen-induced co-expression of CD25 and OX40 (CD134).

    During the gluten challenge, levels of circulating gluten-specific Treg cells and effector T cells both rose sharply, peaking on the sixth day.

    The team recounts surprise on discovering that about 80% of the ex vivo circulating gluten-specific CD4+ T cells were FOXP3+CD39+Treg cells, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Treg cells. Even though they saw normal suppressive function in peripheral polyclonal Treg cells from celiac patients, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells showed sharply reduced suppressive function compared with polyclonal Treg cells.

    The team's study offers the first estimates of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of celiac patients.

    FOXP3+CD39+ Treg cells made up the majority of all circulating gluten-specific CD4+ T cells, but they showed reduced suppressive function, indicating that Treg cell dysfunction might be a key factor in celiac disease development.

    This type of research is crucial to help document the genetic physiology of celiac disease, which will help researchers to better understand and treat the disease itself.

    Source:

    • J Allergy Clin Immunol. 2017 Mar 8. pii: S0091-6749(17)30343-3. doi: 10.1016/j.jaci.2017.02.015.

       

      The researchers are variously affiliated with the Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia; the Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia; the Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia, Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; the Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom; the Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; ImmusanT, Cambridge, Massachusetts; and the Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Australia.

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  • About Me

    Jefferson Adams is a freelance writer living in San Francisco. He has covered Health News for Examiner.com, and provided health and medical content for Sharecare.com. His work has appeared in Antioch Review, Blue Mesa Review, CALIBAN, Hayden's Ferry Review, Huffington Post, the Mississippi Review, and Slate, among others.

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  • Related Articles

    Jefferson Adams
    Celiac.com 04/28/2016 - The development of celiac disease has been tied to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but existing data are unclear and contradictory.
    A research team recently set out to examine the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with celiac disease risk using meta-analysis.
    The research team included Cong-Cong Guo, Man Wang, Feng-Di Cao, Wei-Huang Huang, Di Xiao, Xing-Guang Ye, Mei-Ling Ou, Na Zhang, Bao-Huan Zhang, Yang Liu, Guang Yang, and Chun-Xia Jing.

    They are variously affiliate with the Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, the Department of Stomatology of the First Affiliated Hospital of Jinan University, Guangzhou, the Department of Parasitology, School of Medicine, Jinan University, Guangzhou, and the Key Laboratory of Environmental Exposure and Health in Guangzhou, Jinan University, Guangzhou, China.
    The team began by searching PubMed and Web of Science for RGS1 rs2816316 and IL12A rs17810546 with celiac disease risk. They then estimated the odds ratio (OR) and 95% confidence interval (CI) of each SNP. They retrieved a total of seven studies, and used Stata 12.0 to perform statistical analyses.
    The available data indicated the minor allele C of rs2816316 was negatively associated with celiac disease (C vs. A: OR = 0.77, 95% CI = 0.74–0.80), while they did find a positive association for the minor allele G of rs17810546 (G vs. A: OR = 1.37, 95% CI = 1.31–1.43).
    They found that the co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and celiac disease. They found no evidence of any publication bias.
    The team's meta-analysis indicates a connection between RGS1 and IL12A and celiac disease, and provides a strong support for deeper study into the roles of RGS1 and IL12A in the development of celiac disease.
    Source:
    Int. J. Mol. Sci. 2016, 17(4), 457; doi:10.3390/ijms17040457

    Jefferson Adams
    Celiac.com 05/30/2016 - People with HLA genes have the highest risk factor for developing autoimmune disorders. The vast majority of people with celiac disease carry the HLA DQA1*05 and DQB1*02 alleles, both of which encode the DQ2.5 molecule.
    A research team recently set out to examine the implications for anti-gluten T cell response of the preferential expression of HLA-DQ2.5 genes associated with celiac disease with respect to non-predisposing HLA genes. The research team included L Pisapia, A Camarca, S Picascia, V Bassi, P Barba, G Del Pozzo, and C Gianfrani. They are variously affiliated with the Institute of Protein Biochemistry-CNR, the Institute of Genetics and Biophysics-CNR in Naples, Italy, and the Institute of Food Sciences-CNR in Avellino, Italy.
    In order to activate pathogenic CD4+ T lymphocytes, that is, to trigger active celiac disease, it is necessary for the body to form complexes between DQ2.5 and gluten peptides on antigen-presenting cells (APCs). It is widely accepted by clinicians that the DQ2.5 genes establish the different intensities of anti-gluten immunity, depending on whether they are in a heterozygous or a homozygous configuration, that is, whether both genes are activated, or only one gene is activated.
    The research team's recent study shows that, in celiac patients, HLA DQA1*05 and DQB1*02 gene expression is much higher than expression of non-celiac-associated genes. This, in turn, impacts protein levels and causes a comparable cell surface exposure of DQ2.5 heterodimers between DQ2.5 homozygous and heterozygous celiac patients. As a consequence, the magnitude of the anti-gluten CD4+ T cell response is strictly dependent on the antigen dose, and not on the DQ2.5 gene configuration of APCs.
    These findings are important, because they support the idea that the expression of DQ2.5 genes is an important risk factor in celiac disease.
    The preferential expression of DQ2.5 alleles observed in this study offers a new explanation of why these genes are so frequently associated with celiac disease and with other autoimmune disorders.
    Source:
    J Autoimmun. 2016 Apr 12. pii: S0896-8411(16)30029-4. doi: 10.1016/j.jaut.2016.03.016.

    Jefferson Adams
    Celiac.com 08/09/2016 - Some researchers have suggested that gluten may not be the actual trigger of symptoms in non-celiac gluten sensitivity. Others feel that gluten is definitely the trigger, especially in certain cases.
    A team of researchers recently set out to evaluate patients with clinical non-celiac gluten sensitivity (NCGS), who presented with lymphocytic enteritis, positive celiac genetics and negative celiac blood tests. The team felt that the results would confirm that gluten is, in fact, the trigger of symptoms in this subgroup of patients.
    The research team included M Rosinach, F Fernández-Bañares, A Carrasco, M Ibarra, R Temiño, A Salas, and M Esteve. They are variously affiliated with the Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain, the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain, and with the Department of Pathology, Hospital Universitari Mutua Terrassa, Terrassa in Barcelona, Spain.
    The team conducted a double-blind randomized clinical trial of gluten vs placebo re-challenge on 18 patients over 18 years of age, HLA-DQ2/8+, negative celiac serology and gluten-dependent lymphocytic enteritis, and GI symptoms, with clinical and histological remission at inclusion.
    Eleven of the patients received 20 grams per day of gluten, while the seven others received a non-gluten placebo. The team measured clinical symptoms, quality of life (GIQLI), and presence of gamma/delta+ cells and transglutaminase deposits.
    The results showed that 91% of patients had clinical relapse during gluten challenge compared with just 28.5% after placebo (p = 0.01). Clinical scores and GIQLI worsened after gluten, but not after placebo (p<0.01).
    This study shows that gluten is definitely the trigger for symptoms in a subgroup of patients with clinical NCGS. After a gluten-free diet patients experienced positive celiac genetics, lymphocytic enteritis, and clinical and histological remission.
    Source:
    PLoS One. 2016 Jul 8;11(7):e0157879. doi: 10.1371/journal.pone.0157879. eCollection 2016.

    Jefferson Adams
    Celiac.com 05/18/2017 - Researchers understand pretty well that celiac disease is driven in part by an accumulation of immune cells in the duodenal mucosa as a consequence of both adaptive and innate immune responses to undigested gliadin peptides.
    Mast cells are innate immune cells that produce a majority of co-stimulatory signals and inflammatory mediators in the intestinal mucosa. A team of researchers recently set out to evaluate the role of mast cells in the development of celiac disease.
    The research team included Barbara Frossi, PhD, Claudio Tripodo, MD, Carla Guarnotta, PhD, Antonio Carroccio, MD, Marco De Carli, MD, Stefano De Carli, MD, Marco Marino, MD, Antonino Calabrò, MD, and Carlo E. Pucillo, MD.
    They are variously affiliated with the Department of Gastroenterology and Digestive Endoscopy at the University Hospital of Udine in Udine, Italy; the Department of Medical and Biological Sciences, University of Udine, Udine, Italy; the Second Unit of Internal Medicine, University of Udine, Udine, Italy; the Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University Hospital of Florence, Florence, Italy; the Tuscany Referral Center for Adult Coeliac Disease, AOU Careggi, Florence, Italy; the Department of Health Science, University Hospital of Palermo in Palermo, Italy; and the Department of Internal Medicine and Specialist at the University Hospital of Palermo in Palermo, Italy.
    For their study, the research team scored intestinal biopsy results from celiac patients according to Marsh classification, and characterized those results for leukocyte infiltration and MC distribution. They also characterized mast cell reactivity to gliadin and its peptides via in vitro assays.
    The team found that infiltrating mast cells reflected the severity of mucosal damage, and their numbers were increased in patients with higher Marsh scores. They noted that mast cells responded directly to non-immunodominant gliadin fragments by releasing pro-inflammatory mediators.
    Their immunohistochemical analysis of infiltrating mast cells, along with the effects of gliadin peptides on intestinal mast cells, indicates that patients in with advanced celiac disease face an increase in pro-inflammatory mast cell function. This result was also tied to increased neutrophil accumulation, the prevalence of M1 macrophages, and the severity of tissue damage.
    This study clearly describes the progressive stages of celiac disease, and shows that mast cells are a prominent feature of the inflammatory process.
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     Source:
    Journal of Allergy, & Clinical Immunology. DOI: http://dx.doi.org/10.1016/j.jaci.2016.08.011

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    Celiac.com 06/21/2018 - Would you buy a house advertised as ‘gluten-free’? Yes, there really is such a house for sale. 
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    Bakery On Main started in the small bakery of a natural foods market on Main Street in Glastonbury, Connecticut. Founder Michael Smulders listened when his customers with Celiac Disease would mention the lack of good tasting, gluten-free options available to them. Upon learning this, he believed that nobody should have to suffer due to any kind of food allergy or dietary need. From then on, his mission became creating delicious and fearlessly unique gluten-free products that were clean and great tasting, while still being safe for his Celiac customers!
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    Celiac.com 06/20/2018 - Currently, the only way to manage celiac disease is to eliminate gluten from the diet. That could be set to change as clinical trials begin in Australia for a new vaccine that aims to switch off the immune response to gluten. 
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    Jefferson Adams
    Celiac.com 06/19/2018 - Could baking soda help reduce the inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease? Scientists at the Medical College of Georgia at Augusta University say that a daily dose of baking soda may in fact help reduce inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease.
    Those scientists recently gathered some of the first evidence to show that cheap, over-the-counter antacids can prompt the spleen to promote an anti-inflammatory environment that could be helpful in combating inflammatory disease.
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    The research was funded by the National Institutes of Health.
    Read more at: Sciencedaily.com

    Jefferson Adams
    Celiac.com 06/18/2018 - Celiac disease has been mainly associated with Caucasian populations in Northern Europe, and their descendants in other countries, but new scientific evidence is beginning to challenge that view. Still, the exact global prevalence of celiac disease remains unknown.  To get better data on that issue, a team of researchers recently conducted a comprehensive review and meta-analysis to get a reasonably accurate estimate the global prevalence of celiac disease. 
    The research team included P Singh, A Arora, TA Strand, DA Leffler, C Catassi, PH Green, CP Kelly, V Ahuja, and GK Makharia. They are variously affiliated with the Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Lady Hardinge Medical College, New Delhi, India; Innlandet Hospital Trust, Lillehammer, Norway; Centre for International Health, University of Bergen, Bergen, Norway; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Gastroenterology Research and Development, Takeda Pharmaceuticals Inc, Cambridge, MA; Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy; Department of Medicine, Columbia University Medical Center, New York, New York; USA Celiac Disease Center, Columbia University Medical Center, New York, New York; and the Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India.
    For their review, the team searched Medline, PubMed, and EMBASE for the keywords ‘celiac disease,’ ‘celiac,’ ‘tissue transglutaminase antibody,’ ‘anti-endomysium antibody,’ ‘endomysial antibody,’ and ‘prevalence’ for studies published from January 1991 through March 2016. 
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    This systematic review and meta-analysis showed celiac disease to be reported worldwide. Blood test data shows celiac disease rate of 1.4%, while biopsy data shows 0.7%. The prevalence of celiac disease varies with sex, age, and location. 
    This review demonstrates a need for more comprehensive population-based studies of celiac disease in numerous countries.  The 1.4% rate indicates that there are 91.2 million people worldwide with celiac disease, and 3.9 million are in the U.S.A.
    Source:
    Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037.