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    Structure-Based Selection of Small Molecules to Alter Allele-Specific MHC Class II Antigen Presentation


    Jefferson Adams

    Celiac.com 12/05/2011 - Class II major histocompatibility molecules are one of the main points of susceptibility for a number of autoimmune disorders, including type 1 diabetes.


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    A team of researchers recently set out to investigate structure-based selection of small molecules to alter allele-specific MHC Class II antigen presentation

    Photo: CC-sanofi_pasteurThe research team included Aaron W. Michels, David A. Ostrov, Li Zhang, Maki Nakayama, Masanori Fuse, Kristen McDaniel, Bart O. Roep, Peter A. Gottlieb, Mark A. Atkinson, and George S. Eisenbarth.

    They are variously affiliated with the Barbara Davis Center for Childhood Diabetes at the University of Colorado Denver, the Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, in Gainesville, FL, and with the Department of Immunohaematology and Blood Transfusion at Leiden University Medical Center in Leiden, The Netherlands.

    In the NOD mouse model of spontaneous autoimmune diabetes, Human DQ8 and I-Ag7 imparts diabetes risk by modulating presentation of specific islet peptides in the thymus and surrounding area.

    To define small molecules that could live in specific structural pockets along the I-Ag7 binding groove, the research team made use of an in-silico molecular docking program to review a vast “drug-like” chemical library.

    They were hoping to either promote or inhibit presentation to T cells of the autoantigen insulin B chain peptide, which consists of amino acids 9–23.

    By making use of both murine and human cells, the team's results show that small molecules can in fact influence specific TCR signals in the presence of cognate target peptides, based upon the targeted structural pocket.

    The effect of a compound on TCR response varied among targeted pockets, with pocket 1 and 6 compounds inhibiting TCR response, and molecules targeted at pocket 9 promoting peptide responses.

    It takes just nanomolar levels of the inhibitory molecules to block the insulin B chain peptide, which consists of amino acids 9–23, endogenous insulin, and islet-stimulated T cell responses.

    At concentrations as low as 10 nM, Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells, upregulates IL-10 secretion, and prevents diabetes in NOD mice.

    These studies offer a new way to identify small molecules that can both stimulate and inhibit T cell responses, thus offering a potential for future therapeutic treatment options.

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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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    Jefferson Adams
    Celiac.com 04/23/2007 - A study published in a recent issue of the journal Gut suggests that wheat gliadin might trigger pathological development in mucosal cells that are already abnormal, but otherwise tolerated, within the intestinal tracts of individuals with celiac disease.
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    Diana Gitig Ph.D.
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    Source:

    Am. J Gastroenterol advance online publication 11 January 2011; doi:10.1038/ajg.2010.487

    Jefferson Adams
    Celiac.com 03/28/2012 - A clinical research team wanted to determine if adding ascorbate (vitamin C) to gliadin-stimulated biopsy culture could reduce the mucosal immune response to gliadin in people with celiac disease.
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    Allergol Immunopathol (Madr). 2012 Jan-Feb;40(1):3-8.

    Jefferson Adams
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    Journal of Pediatric Gastroenterology & Nutrition: March 2015 - Volume 60 - Issue 3 - p 357–359. doi: 10.1097/MPG.0000000000000602

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    Jefferson Adams
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    Roxanne Bracknell
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    Jefferson Adams
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    Premium ingredients, bakeshop delicious recipes, and happy customers were our inspiration from the beginning— and are still the cornerstones of Bakery On Main today. We are a fiercely ethical company that believes in integrity and feels that happiness and wholesome, great tasting food should be harmonious. We strive for that in everything we bake in our dedicated gluten-free facility that is GFCO Certified and SQF Level 3 Certified. We use only natural, NON-GMO Project Verified ingredients and all of our products are certified Kosher Parve, dairy and casein free, and we have recently introduced certified Organic items as well! 
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    Source:
    FoodProcessing.com.au