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  • Jefferson Adams
    Jefferson Adams

    What Can We Learn from T-cell Repertoires in Refractory Celiac Disease?

      Can T-cell Repertoires help us better understand refractory celiac disease?

    Caption: Photo: CC--Niaid.jpg

    Celiac.com 07/03/2017 - Refractory celiac disease (RCD) is a serious complication of celiac disease. There are two types, RCD I, and RCD II. Unlike RCD type I, RCD type II often leads to enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL.

    Using high-throughput sequencing (HTS), a team of researchers recently set out to establish the small-intestinal T-cell repertoire (TCR) in celiac disease and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis.

    The research team included J Ritter, K Zimmermann, K Jöhrens, S Mende, A Seegebarth, B Siegmund, S Hennig, K Todorova, A Rosenwald, S Daum, M Hummel, and M Schumann.

    They are variously affiliated with the Institute of Pathology, Charité-University Medicine, Berlin, Germany, the Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine, Berlin, Germany, HS Diagnomics GmbH, Berlin, Germany, the Center for Tumor Medicine, Charité-University Medicine, Berlin, Germany, the Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany, the Berlin Institute of Health, Berlin, Germany, the Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany.

    Their team examined DNA extracted from duodenal mucosa specimens of 9 control subjects, 10 active celiacs, 9 celiacs on a gluten-free diet, 8 RCD type I patients, 8 RCD type II patients, and 3 unclassified Marsh I cases collected from 2002 to 2013. To make their examination, they used TCRβ-complementarity-determining regions 3 (CDR3) multiplex PCR, followed by HTS of the amplicons.

    They generated an average of 106 sequence reads per sample, consisting of up to 900 individual TCRβ rearrangements.

    In RCD type II, the most frequent clonotypes (sequence reads with identical CDR3) represent about 43% of all TCRβ rearrangements. This was substantially higher than in control subjects (6.8%; p

    Repeat endoscopies in individual patients showed that the clonotypes remain stable for up to a few years without clinical symptoms of EATL. Individual patients with RCD type II showed unique dominant clonotypes that were un-related among patients. Celiac-associated, gliadin-dependent CDR3 motifs were only detectable at low frequencies.

    TCRβ-HTS analysis unravels the TCR in celiac disease, and allows for detailed analysis of individual TCRβ changes.

    Patients with RCD type II have unique, dominant TCRβ sequences that are critically different from known gliadin-specific TCR sequences, which indicates that these clonal T-cells expand on their own, with no influence from gluten stimulation.

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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
    Refractory Celiac Disease: Unlocking the Origin of Aberrant Lymphocytes
    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 08/17/2015 - In an interesting update, researcher Giuseppe Mazzarella, of the Immuno-Morphology Lab at the Institute of Food Sciences of the National Council Research in Avellino, Italy recently set out to examine the role of effector and suppressor T cells in celiac.
    Celiac disease is a T-cell-mediated immune disorder in which gliadin-derived peptides activate lamina propria effector CD4+ T cells.
    This activation triggers the release of cytokines, compatible with a Th1-like pattern, which play a crucial role in the development of celiac disease, and which control many aspects of the inflammatory immune response.
    Previous studies revealed that a novel subset of effector T cells, marked by expression of high levels of IL-17A, termed Th17 cells, plays a key role in celiac disease.
    Although these effector T cell subsets produce pro-inflammatory cytokines, which cause significant tissue damage in celiac sufferers, recent studies have suggested the existence of additional CD4(+) T cell subsets with suppressor functions.
    These subsets include type 1 regulatory T cells and CD25(+)CD4(+) regulatory T cells, expressing the master transcription factor Foxp3, which have important implications for the development and progression of celiac disease.
    Source:
    World J Gastroenterol. 2015 Jun 28;21(24):7349-56. doi: 10.3748/wjg.v21.i24.7349.

    Jefferson Adams
    Refractory Celiac Patient Successfully Treated With Mesenchymal Stem Cell Infusions
    Celiac.com 05/24/2016 - People with type II refractory celiac disease (RCD), suffer from severe malabsorption syndrome and face a poor prognosis, as there is currently no effective treatment.
    Prompted by the regenerative and immune-influencing properties of mesenchymal stem cells (MSCs), a research team recently set out to assess the viability, safety, and efficacy of a series of infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II RCD.
    The research team included R Ciccocioppo, A Gallia, MA Avanzini, E Betti, C Picone, A Vanoli, C Paganini, F Biagi, R Maccario, and GR Corazza. They are variously affiliated with the Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Cell Factory and Research Laboratory, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Clinic Cytometry Laboratory, Department of Hematology, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, all in Pavia, Italy.

    The team began by isolating, expanding, and characterizing mesenchymal stem cells using standard clinical protocols. For each patient, the team arranged to monitor malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes at the time of enrollment, at each infusion, and after 6 months.
    The also arranged to assess mucosal expression of interleukin (IL)-15 and its receptor. Once the team determined that the expansion of MSCs was feasible, they provided the patient with four systemic infusions of 2 × 106 MSCs per kg body weight 4 months apart, with no adverse effects.
    Over the course of the treatment, the patient experienced gradual and durable improvement of her condition, including normalized stool frequency, body mass index, laboratory test results, and mucosal architecture. Most impressively, the expression of IL-15 and its receptor almost completely vanished.
    Based on this clinical case, treatment of RCD with serial MSC infusions seems to offer a path to recovery from this life-threatening condition, while blocking the IL-15 pathogenic pathway.
    This is the first successful treatment of refractory celiac disease. Stay tuned for further developments regarding the use of stem cell infusions to treat refractory celiac disease.
    Source:
    Mayo Clin Proc. 2016 Apr 14. pii: S0025-6196(16)30004-0. doi: 10.1016/j.mayocp.2016.03.001.

    Jefferson Adams
    Suppressive Function of Regulatory T Cells Impaired in Celiac Patients
    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?
    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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