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  • Jefferson Adams
    Jefferson Adams

    Chronic Celiac Inflammation Permanently Changes Tissue-Resident Immunity

      Chronic inflammation causes permanent changes to tissue-resident immunity in celiac disease patients.

    Caption: Image: CC--vicariousdancin

    Celiac.com 03/04/2019 - Tissue-resident lymphocytes play a key role in immune surveillance, but there’s not much data on how these cells respond to chronic inflammation. A team of researchers recently set out to assess how well tissue-resident lymphocytes respond to chronic inflammation. The research team included Toufic Mayassi; Kristin Ladell; Herman Gudjonson; Jamie Rossjohn; David A. Price; and Bana Jabri.

    In celiac disease, the team found that gluten-induced inflammation substantially reduced levels of naturally occurring Vγ4 +/Vδ1 + intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. 

    Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4 +/Vδ1 + IELs occurred together with the expansion of gluten-sensitive, interferon-γ-producing Vδ1 + IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. 

    Eliminating dietary gluten normalized BTNL8 expression, but was not enough to restore the physiological Vγ4 +/Vδ1 + subset among TCRγδ + IELs. Together, the data show that long-term inflammation permanently changes the tissue-resident TCRγδ + IEL compartment in celiac disease. What exactly does that mean? Some of the takeaways include:

    • Innate-like Vδ1 + IELs are superseded by interferon-γ-producing Vδ1 + IELs in celiac disease
    • The Vδ1 + IEL TCR repertoire is permanently reshaped in celiac disease
    • A molecular signature defines Vδ1 + IEL expansions in active celiac disease
    • Loss of BTNL8 expression coincides with permanent loss of BTNL3/8-reactive γδ + IELs in celiac disease

    Even on a gluten-free diet, chronic inflammation causes permanent changes to the tissue-resident TCRγδ + IEL compartment in celiac patients. Further study is needed to determine the full significance of these findings.

    Read more in: CELL



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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Jefferson Adams
    Celiac.com 05/19/2010 - Enteropathy-associated T cell lymphoma is a serious complication of celiac disease, and a major cause of mortality in untreated celiac disease.
    One possible trigger for Enteropathy-associated T cell lymphoma development is chronic exposure of intraepithelial lymphocytes (IELs) to strong anti-apoptotic signals, that is, signals that interfere in the normal mortality of the IEL cells. These signals are triggered by IL-15, a cytokine that is over-expressed in the enterocytes of people with celiac disease.
    However, researchers have not yet fully mapped the signaling pathway by which IL-15 transmits these anti-apoptotic signals. Researchers consider type II refractory celiac disease (RCDII) to be a middle step between celiac disease and enteropathy-associated T cell lymphoma.
    Eliminating abnormal IELs at the RCDII stage would likely block EATL development. So far, though, scientists have not found successful immunosuppressive and/or chemotherapeutic approaches able to accomplish this, and RCDII outcomes remain very poor.
    A team of researchers recently set out to map the IL-15–driven survival pathway in human IELs, and to determine whether IL-15 triggered pathway in human intraepithelial lymphocytes represents a possible new target in type II refractory celiac disease and enteropathy-associated T cell lymphoma.
    The research team was made up of Georgia Malamut, Raja El Machhour, Nicolas Montcuquet, Séverine Martin-Lannerée, Isabelle Dusanter-Fourt, Virginie Verkarre, Jean-Jacques Mention, Gabriel Rahmi, Hiroshi Kiyono, Eric A. Butz, Nicole Brousse, Christophe Cellier, Nadine Cerf-Bensussan, and Bertrand Meresse.
    The are variously affiliated with INSERM U989, the Université Paris Descartes, Faculté de Médecine René Descartes, the Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, the Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM U1016, the Department of Pathology, AP-HP, of the Hôpital Necker-Enfants Malades in Paris, with the Division of Mucosal Immunology, Department of Microbiology and Immunology at the Institute of Medical Science at the University of Tokyo in Japan, and the Inflammation Department of AMGEN Inc., in Seattle, Washington, USA.
    Their current findings reveal that the survival signals IL-15 directs to freshly isolated human IELs, and to human IEL cell lines derived from celiac disease patients with type II refractory celiac disease, depend on anti-apoptotic factors Bcl-2 and/or Bcl-xL.
    The signals require IL-15Rβ, Jak3, and STAT5 for proper function, but functioned independently of PI3K, ERK, and STAT3. In support of these findings, the team recorded elevated levels of Bcl-xL, phospho-Jak3, and phospho-STAT5 in IELs from patients with active celiac disease and RCDII.
    Moreover, by incubating patient duodenal biopsies with a fully humanized human IL-15–specific Ab, the team effectively blocked Jak3 and STAT5 phosphorylation.
    Also, treatment with IL-15–specific Ab caused IEL cell mortality, and wiped out the massive IEL build-up in mice over-expressing human IL-15 in their gut epithelium.
    The study marks the first successful mapping of the IL-15–driven survival pathway in human IELs, and demonstrates that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.
    These findings will likely help to pave the way for the development of successful immunosuppressive and/or chemotherapeutic treatments that destroy abnormal IELs at the RCDII stage and help to block EATL development, improving outcomes for RCDII patients.
    Source:

    Journal of Clinical Investigation doi:10.1172/JCI41344

    Jefferson Adams
    Celiac.com 10/25/2012 - Abnormal intraepithelial lymphocytes (IELs) are the main feature of refractory celiac disease type II (RCDII). However, researchers still don't know exactly how these abnormal IELs originate.
    A pair of researchers recently commented on efforts to learn how these abnormal IELs might come about.
    The pair were Victor F. Zevallos, and Detlef Schuppan, of the center for Molecular and Translational Medicine, Department of Medicine I at the University Medical Center of Johannes Gutenberg University Mainz, in Mainz, Germany.
    Their commentary focuses on efforts by a separate research team, Schmitz, et al., which had already used a broad spectrum of cell specific markers, RNA array and immunological techniques, to explore abnormal IEL cell lines from four RCDII patients, and compare them with IELs from the fetal intestine, the intestine of children and adults and the thymus.
    IELs are highly varied lymphocytes cells with innate and adaptive features that live in the small and large intestine. IELs play an important role in maintaining gut tolerance to common food antigens versus defense against pathogens.
    A number of nutritional factors influence the development and spread of IELs, especially vitamins and their active metabolites, such as retinoic acid, and phytochemicals such as ligands of the aryl hydrocarbon receptor from cruciferous vegetables.
    However, when IELs activate and expand uncontrollably in response to chronic inflammatory conditions in the gut, they trigger mucosal damage, which can lead to celiac disease, and in some cases, to malignant cancers.
    Up to 5% of people with celiac disease, especially those who are over fifty years old when diagnosed, continue to suffer from clinical symptoms and villous atrophy even when following a gluten-free diet.
    After excluding ongoing gluten consumption and other potential underlying diseases, all four patients studied by Schmitz could be diagnosed with RCD, which is classically classified as type I or type II, based on the histological co-expression of CD3 and CD8 in RCDI, or absence of such co-expression in RCDII.
    Read the entire report in Gut.
    Source:
    Gut doi:10.1136/gutjnl-2012-303030

    Jefferson Adams
    Celiac.com 12/22/2016 - The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. A team of researchers recently set out to better understand the mechanisms by which innate intraepithelial lymphocytes develop in the intestine and become cancerous in celiac disease patients.
    The research team included J Ettersperger, N Montcuquet, G Malamut, N Guegan, S Lopez-Lastra, S Gayraud, C Reimann, E Vidal, N Cagnard, P Villarese, I Andre-Schmutz, R Gomes Domingues, C Godinho-Silva, H Veiga-Fernandes, L Lhermitte, V Asnafi, E Macintyre, C Cellier, K Beldjord, JP Di Santo, N Cerf-Bensussan, and B Meresse.
    They are variously affiliated with the INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine; Laboratory of Human Lymphohematopoiesis; Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades; the Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine in Paris, France; AP-HP, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 75015 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; INSERM U 668, Paris, France; Paris-Descartes Bioinformatic Platform, 75015 Paris, France; and with the Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa in Lisbon, Portugal.
    The team was able to show, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals.
    In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes necessary for T cell differentiation were silenced, and precursors were reprogrammed into innate cells with T cell marks, including intracellular CD3 and T cell rearrangements.
    In the intraepithelial lymphoma complicating celiac disease, iCD3(+) innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15.
    The research team observed and described gut T cell-like innate IELs, decoded their pathway of change, and showed their malignant transformation in celiac disease.
    This study offers an exciting glimpse into the hard work being done in the far corners of celiac disease and cancer research.
    Source:
    Immunity. 2016 Sep 20;45(3):610-25. doi: 10.1016/j.immuni.2016.07.018. Epub 2016 Sep 6.

    Jefferson Adams
    Celiac.com 05/31/2018 - Explaining the genetics of many diseases is challenging because most genetic associations occur in regulatory regions that just aren’t very well understood and documented. In an effort to provide better genetic information about certain regulatory regions, a team of researchers recently used new computational methods to demonstrate that transcription factors (TFs) occupy multiple loci associated with individual complex genetic disorders. Their work has important implications for celiac disease, and numerous other medical disorders.
    The research team included John B. Harley, Xiaoting Chen, Mario Pujato, Daniel Miller, Avery Maddox, Carmy Forney, Albert F. Magnusen, Arthur Lynch, Kashish Chetal, Masashi Yukawa, Artem Barski,  Nathan Salomonis, Kenneth M. Kaufman, Leah C. Kottyan and Matthew T. Weirauch.
    They are variously affiliated with the Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; the Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; the Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; US the Department of Veterans Affairs Medical Center, Cincinnati, OH, USA; the Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; the Division of Allergy & Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; and the Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
    The group conducted an assessment of 213 phenotypes and 1,544 TF binding datasets that identified 2,264 relationships between hundreds of TFs and 94 phenotypes, including androgen receptor in prostate cancer and GATA3 in breast cancer.  In one interesting finding, the team noted that the gene loci for systemic lupus erythematosus risk are occupied by the Epstein–Barr virus EBNA2 protein, along with many co-clustering human TFs, which suggests gene–environment interaction.
    Similar EBNA2-anchored connections are seen in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.  Allele-dependent DNA binding and downstream effects on gene expression support genetic mechanisms dependent on EBNA2. These results indicate that such mechanisms are operating across risk loci within disease phenotypes, which offers a new hypothesis for the origins of numerous diseases, including celiac disease.
    Such complex gene–environment interactions may help explain the origins of numerous autoimmune diseases. Specifically, Epstein–Barr virus (EBV) infection is associated with the autoimmune mechanisms and epidemiology of systemic lupus erythematosus (SLE), increasing SLE risk by as much as 50-fold in children. 
    Despite strong associations between EBV and multiple autoimmune diseases, the underlying molecular mechanics are not understood. That said, genome-wide association studies (GWAS) have identified more than 50 possible European-ancestry SLE susceptibility loci, offering strong support for germline DNA polymorphisms altering SLE risk. 
    The team’s analyses found strong connections with an EBV gene product (EBNA2), offering a potential origin of gene–environment interaction, along with a set of human transcription factors and cofactors (TFs), in SLE and six other auto-immune diseases. 
    The team presents allele- and EBV-dependent TF binding interactions and gene expressions that nominate cell types, molecular agents and environmental factors to disease mechanisms for more than 85 diseases and physiological phenotypes. The team’s analysis suggest that numerous causal autoimmune combinations may act through allele-dependent binding of these proteins, altering downstream gene expression. 
    These results offer promise for the development of future therapies for manipulating the action of these proteins in individuals harboring risk alleles at EBNA2-bound loci.
    The team’s current current data point to particular TFs and cell types for 94 phenotypes, offering ways to verify, via experiment and exploration, the potential molecular and cellular origins of disease risk, potentially including celiac disease. 
    As new genetic association and TF binding data are collected, approaches such as this will undoubtedly identify additional disease mechanisms. As researchers gain an understanding of the genetics behind the origins of numerous diseases, look for them to make progress on new methods of testing, diagnosis and treatment of many of these conditions.  
    Source:
    NATURE GENETICS | VOL 50 | MAY 2018 | 699–707 

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    Doritos does make a few gluten-free versions.     
    Just wanted to chime in. During my 2 plus years of healing I had joint pain and muscle pain with some of the nightshade mainly peppers and tomato. I stopped them. I can now eat them again. My theory is when my gut gets cc my holey gut dumps some of my food in my blood stream and my already ticked off immune system let's me know what is allowed. Apparently for a time nightshades  of potato, tomatos, and peppers were an issue. I was able to gradually introduce potatoes first and then tomatos, then
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