|
1
|
Esteve M, Arau B, Martín-Cardona A. Coeliac Disease, Microscopic Colitis, and Exclusion Diets-A Commemorative Issue in Honor of Dr. Fernando Fernández-Bañares. Nutrients 2025; 17:1537. [PMID: 40362843 PMCID: PMC12073211 DOI: 10.3390/nu17091537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
On the occasion of the passing of Dr [...].
Collapse
Affiliation(s)
- Maria Esteve
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Beatriz Arau
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Albert Martín-Cardona
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| |
Collapse
|
|
2
|
Galipeau HJ, Verdu EF. Is the microbiome important in celiac disease? J Can Assoc Gastroenterol 2025; 8:S51-S55. [PMID: 39990507 PMCID: PMC11842898 DOI: 10.1093/jcag/gwae047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2025] Open
Abstract
Celiac disease (CeD) is an autoimmune condition driven by gluten in genetically predisposed individuals. CeD is characterized by small intestinal villous atrophy but presents with a spectrum of gastrointestinal and systemic manifestations. Its only treatment is a strict, life-long adherence to a gluten-free diet, which is difficult to manage and does not always lead to symptomatic or mucosal recovery. About 40% of the population express the CeD-associated risk genes, but only 1%-2% of the worldwide population has CeD. This, along with the rising prevalence of CeD suggests other cofactors in disease pathogenesis. The gut microbiome has been implicated in CeD based on epidemiology studies and clinical associations. Mechanistic studies using relevant in vitro and in vivo preclinical models have begun to elucidate mechanisms through which microbes can influence CeD. Ultimately, a better understanding of these cofactors and their mechanisms will provide rationale intervention strategies and novel therapeutic targets to prevent or treat CeD.
Collapse
Affiliation(s)
- Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton L8K4K1, Canada
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton L8K4K1, Canada
| |
Collapse
|
|
3
|
Martín-Cardona A, Carrasco A, Arau B, Vidal J, Tristán E, Ferrer C, Gonzalez-Puglia G, Pallarès N, Tebé C, Farrais S, Núñez C, Fernández-Bañares F, Esteve M. γδ+ T-Cells Is a Useful Biomarker for the Differential Diagnosis between Celiac Disease and Non-Celiac Gluten Sensitivity in Patients under Gluten Free Diet. Nutrients 2024; 16:2294. [PMID: 39064736 PMCID: PMC11279444 DOI: 10.3390/nu16142294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND The differential diagnosis between patients with celiac disease (CD) and non-celiac gluten sensitivity (NCGS) is difficult when a gluten-free diet (GFD) has been initiated before the diagnostic work-up. Isolated increases in TCRγδ+ and celiac lymphogram (increased TCRγδ+ plus decreased CD3-) may enable differential diagnosis in this challenging clinical setting. This study evaluated: (1) the accuracy of %TCRγδ+ and celiac lymphogram for diagnosing CD before and after GFD and for differentiation with NCGS; (2) TCRγδ+ kinetics at baseline and after starting GFD in both CD and NCGS. METHODS The inclusion criteria were patients with CD (n = 104), NCGS (n = 37), and healthy volunteers (n = 18). An intestinal biopsy for intraepithelial lymphogram by flow cytometry was performed at baseline and after GFD. The optimal cutoff for CD diagnostic accuracy was established by maximizing the Youden index and via logistic regression. RESULTS %TCRγδ+ showed better diagnostic accuracy than celiac lymphogram for identifying CD before and after GFD initiation. With a cutoff > 13.31, the accuracy for diagnosing CD in patients under GFD was 0.88 [0.80-0.93], whereas the accuracy for diagnosing NCGS (%TCRγδ+ ≤ 13.31) was 0.84 [0.76-0.89]. The percentage of TCRγδ+ cells showed differential kinetics between CD (baseline 22.7% [IQR, 16.4-33.6] vs. after GFD 26.4% [IQR, 17.8-36.8]; p = 0.026) and NCGS (baseline 9.4% [IQR, 4.1-14.6] vs. after GFD 6.4% [IQR, 3.2-11]; p = 0.022). CONCLUSION TCRγδ+ T cell assessment accurately diagnoses CD before and after a GFD. Increased TCRγδ+ was maintained in the long term after GFD in CD but not in NCGS. Altogether, this suggests the potential usefulness of this marker for the differential diagnosis of these two entities in patients on a GFD.
Collapse
Affiliation(s)
- Albert Martín-Cardona
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Anna Carrasco
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Beatriz Arau
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Judith Vidal
- Department of Flow Cytometry, Catlab, 08232 Viladecavalls, Spain;
| | - Eva Tristán
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carme Ferrer
- Pathology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain;
| | - Gerardo Gonzalez-Puglia
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
| | - Natàlia Pallarès
- Biostatistics Support and Research Unit, Germans Trias i Pujol Research Institute and Hospital (IGTP), 08916 Badalona, Spain; (N.P.); (C.T.)
| | - Cristian Tebé
- Biostatistics Support and Research Unit, Germans Trias i Pujol Research Institute and Hospital (IGTP), 08916 Badalona, Spain; (N.P.); (C.T.)
| | - Sergio Farrais
- Gastroenterology Department, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain;
| | - Concepción Núñez
- Laboratorio de Investigación en Genética de Enfermedades Complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain;
| | - Fernando Fernández-Bañares
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria Esteve
- Gastroenterology Department, Hospital Universitari Mútua Terrassa, University of Barcelona, 08221 Terrassa, Spain; (A.M.-C.); (A.C.); (B.A.); (E.T.); (G.G.-P.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| |
Collapse
|
|
4
|
Silvester JA, Elli L, Khosla C, Tye-Din JA. Past, Present, and Future of Noninvasive Tests to Assess Gluten Exposure, Celiac Disease Activity, and End-Organ Damage. Gastroenterology 2024; 167:159-171. [PMID: 38670279 PMCID: PMC11235091 DOI: 10.1053/j.gastro.2024.01.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/02/2024] [Accepted: 01/04/2024] [Indexed: 04/28/2024]
Abstract
Although many biomarkers have been proposed, and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity, or end-organ damage in treated patients with celiac disease. Challenges to developing and evaluating better biomarkers include significant interindividual variability-related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current "gold standard" for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is a better reflection of the "ground truth" may indeed appear to perform poorly. The goal of this review was to analyze past and present efforts to establish robust noninvasive tools for monitoring treated patients with celiac disease and to highlight emerging tools that may prove to be useful in clinical practice.
Collapse
Affiliation(s)
- Jocelyn A Silvester
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts.
| | - Luca Elli
- Center for Prevention and Diagnosis of Celiac Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Chaitan Khosla
- Sarafan ChEM-H, Departments of Chemistry and Chemical Engineering, Stanford University, Stanford, California
| | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
| |
Collapse
|
|
5
|
Gómez-Aguililla S, Núñez C, Rubio M, Corzo M. Isolation and cryopreservation of peripheral blood mononuclear cells. Methods Cell Biol 2023; 179:127-141. [PMID: 37625870 DOI: 10.1016/bs.mcb.2023.01.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
The study of peripheral blood mononuclear cells (PBMCs) in immune-mediated diseases, such as celiac disease (CD), is important to uncover pathogenesis, find new biomarkers and discover and evaluate new treatments. Many studies have been published about the use and value of PBMCs in CD such as those including enzyme-linked immunospot (ELISPOT) assays, flow cytometry, peptide-MHC tetramers, genetic and proteomic analyses, and in vitro and proliferation assays. We present here and easy and efficient method for isolation of PBMCs using density gradient centrifugation. We also describe a simple way to freeze PBMCs in order to preserve their number and viability and a thawing procedure leading to high rates of viability of the cryopreserved cells to be used in subsequent applications.
Collapse
Affiliation(s)
- Sara Gómez-Aguililla
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Concepción Núñez
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Mercedes Rubio
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - María Corzo
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| |
Collapse
|
|
6
|
Anderson RP. Review article: Diagnosis of coeliac disease: a perspective on current and future approaches. Aliment Pharmacol Ther 2022; 56 Suppl 1:S18-S37. [PMID: 35815826 DOI: 10.1111/apt.16840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/09/2022]
Abstract
Diagnostics will play a central role in addressing the ongoing dramatic rise in global prevalence of coeliac disease, and in deploying new non-dietary therapeutics. Clearer understanding of the immunopathogenesis of coeliac disease and the utility of serology has led to partial acceptance of non-biopsy diagnosis in selected cases. Non-biopsy diagnosis may expand further because research methods for measuring gluten-specific CD4+ T cells and the acute recall response to gluten ingestion in patients is now relatively straightforward. This perspective on diagnosis in the context of the immunopathogenesis of coeliac disease sets out to highlight current consensus, limitations of current practices, gluten food challenge for diagnosis and the potential for diagnostics that measure the underlying cause for coeliac disease, gluten-specific immunity.
Collapse
|
|
7
|
Söderström H, Rehn J, Cervin M, Ahlstermark C, Bybrant MC, Carlsson A. Compliance to a Gluten-Free Diet in Swedish Children with Type 1 Diabetes and Celiac Disease. Nutrients 2021; 13:nu13124444. [PMID: 34959996 PMCID: PMC8709103 DOI: 10.3390/nu13124444] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/01/2021] [Accepted: 12/09/2021] [Indexed: 12/25/2022] Open
Abstract
Children with type 1 diabetes (T1D) are at increased risk of celiac disease (CD). The replacement of insulin in T1D, and the exclusion of gluten in CD, are lifelong, burdensome treatments. Compliance to a gluten-free diet (GFD) in children with CD is reported to be high, while compliance in children with both diseases has scarcely been studied. To examine compliance to a GFD in children with both T1D and CD, we analyzed tissue transglutaminase IgA-antibodies (tTGA). Moreover, associations between compliance and age, sex, glycemic control, ketoacidosis (DKA), body mass index (BMI), and time of CD diagnosis were investigated. Of the 743 children diagnosed with T1D in southern Sweden between 2005 and 2012, 9% were also diagnosed with CD. Of these, 68% showed good compliance to a GFD, 18% showed intermediate compliance, and 14% were classified as non-compliant. Higher age, poorer HbA1c, and more DKAs were significantly (p < 0.05) associated with poorer compliance. In conclusion, we found that compliance to a GFD in children with T1D and CD is likely be lower than in children with CD only. Our results indicate that children with both T1D and CD could need intensified dietary support and that older children and children with poor metabolic control are especially vulnerable subgroups.
Collapse
Affiliation(s)
- Hanna Söderström
- Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden; (J.R.); (M.C.); (A.C.)
- Skåne University Hospital, 221 85 Lund, Sweden;
- Correspondence:
| | - Julia Rehn
- Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden; (J.R.); (M.C.); (A.C.)
| | - Matti Cervin
- Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden; (J.R.); (M.C.); (A.C.)
| | | | - Mara Cerqueiro Bybrant
- Department of Women’s and Children’s Health, Division of Pediatric Endocrinology, Karolinska Institutet, 171 76 Stockholm, Sweden;
| | - Annelie Carlsson
- Department of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden; (J.R.); (M.C.); (A.C.)
- Skåne University Hospital, 221 85 Lund, Sweden;
| |
Collapse
|
|
8
|
Anderson RP. Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis. Expert Rev Clin Immunol 2021; 18:75-91. [PMID: 34767744 DOI: 10.1080/1744666x.2021.2006636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. AREAS COVERED The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. EXPERT OPINION Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.
Collapse
|
|
9
|
Fernández-Bañares F, López-Palacios N, Corzo M, Arau B, Rubio M, Fernández-Prieto M, Tristán E, Pujals M, Farrais S, Horta S, Hernández JM, Gomez-Perosanz M, Reche PA, Esteve M, Núñez C. Activated gut-homing CD8 + T cells for coeliac disease diagnosis on a gluten-free diet. BMC Med 2021; 19:237. [PMID: 34610833 PMCID: PMC8493675 DOI: 10.1186/s12916-021-02116-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/01/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The diagnosis of coeliac disease (CD) in individuals that have started a gluten-free diet (GFD) without an adequate previous diagnostic work-out is a challenge. Several immunological assays such as IFN-γ ELISPOT have been developed to avoid the need of prolonged gluten challenge to induce the intestinal damage. We aimed to evaluate the diagnostic accuracy of activated gut-homing CD8+ and TCRγδ+ T cells in blood after a 3-day gluten challenge and to compare it with the performance of IFN-γ ELISPOT in a HLA-DQ2.5 subsample. METHODS A total of 22 CD patients and 48 non-CD subjects, all of them following a GFD, underwent a 3-day 10-g gluten challenge. The percentage of two T cell subsets (CD8+ CD103+ β7hi CD38+/total CD8+ and TCRγδ+ CD103+ β7hi CD38+/total TCRγδ+) in fresh peripheral blood drawn baseline and 6 days after the challenge was determined by flow cytometry. IFN-γ ELISPOT assays were also performed in HLA-DQ2.5 participants. ROC curve analysis was used to assess the diagnostic performance of the CD8+ T cell response and IFN-γ ELISPOT. RESULTS Significant differences between the percentage of the two studied subsets of CD8+ and TCRγδ+ cells at days 0 and 6 were found only when considering CD patients (p < 10-3 vs. non-CD subjects). Measuring activated CD8+ T cells provided accurate CD diagnosis with 95% specificity and 97% sensitivity, offering similar results than IFN-γ ELISPOT. CONCLUSIONS The results provide a highly accurate blood test for CD diagnosis in patients on a GFD of easy implementation in daily clinical practice.
Collapse
Affiliation(s)
- Fernando Fernández-Bañares
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Natalia López-Palacios
- Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain
| | - María Corzo
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain
| | - Beatriz Arau
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Mercedes Rubio
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain
| | - Marta Fernández-Prieto
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain
| | - Eva Tristán
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Mar Pujals
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain
| | - Sergio Farrais
- Servicio de Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, 28040, Madrid, Spain
| | - Saúl Horta
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain
| | - Juana María Hernández
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain
| | - Marta Gomez-Perosanz
- Facultad de Medicina, Laboratorio de Inmunomedicina, Departamento de Inmunología, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Pedro A Reche
- Facultad de Medicina, Laboratorio de Inmunomedicina, Departamento de Inmunología, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - María Esteve
- Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Concepción Núñez
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain.
| |
Collapse
|
|
10
|
Cárdenas-Torres FI, Cabrera-Chávez F, Figueroa-Salcido OG, Ontiveros N. Non-Celiac Gluten Sensitivity: An Update. ACTA ACUST UNITED AC 2021; 57:medicina57060526. [PMID: 34073654 PMCID: PMC8224613 DOI: 10.3390/medicina57060526] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022]
Abstract
Non-celiac gluten sensitivity (NCGS) is a clinical entity characterized by the absence of celiac disease and wheat allergy in patients that trigger reproducible symptomatic responses to gluten-containing foods consumption. Due to the lack of sensitive and reproducible biomarkers for NCGS diagnosis, placebo-controlled gluten challenges must be carried out for its diagnosis. The gluten challenges can be either double- or single-blind, for research or clinical practice purposes, respectively. For improving our understanding about the magnitude and relevance of NCGS in different populations, epidemiological studies based on self-report have been carried out. However, the gluten challenge-based prevalence of NCGS remains to be estimated. Since NCGS was recently recognized as a clinical entity, more studies are needed to delve into NCGS pathogenesis, for instance, the molecular interactions between the suspected cereal grain components that trigger NCGS, such as fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) and amylase and trypsin inhibitors, and the immune system remains to be elucidated. Although still under debate, NCGS patients can be susceptible to only one or more than one of the NCGS triggers. The treatment of NCGS involves the dietary restriction of the suspected triggers of the disease, but there is controversial data about the effectiveness of different dietary interventions such as the gluten-free diet and low-FODMAP diet. Certainly, our understanding of NCGS is improving quickly due to the constant availability of new scientific information on this topic. Thus, the aim of the present narrative review is to present an up-to-date overview on NCGS from epidemiology to current therapy.
Collapse
Affiliation(s)
- Feliznando Isidro Cárdenas-Torres
- Doctorate Program in Nutrition Science, Faculty of Nutrition Sciences, University of Sinaloa, Culiacán 80019, Mexico; (F.I.C.-T.); (F.C.-C.)
| | - Francisco Cabrera-Chávez
- Doctorate Program in Nutrition Science, Faculty of Nutrition Sciences, University of Sinaloa, Culiacán 80019, Mexico; (F.I.C.-T.); (F.C.-C.)
| | - Oscar Gerardo Figueroa-Salcido
- Postgraduate in Health Sciences, Division of Biological and Health Sciences, University of Sonora, Hermosillo 83000, Mexico
- Correspondence: (O.G.F.-S.); (N.O.)
| | - Noé Ontiveros
- Clinical and Research Laboratory (LACIUS, URS), Department of Chemical, Biological, and Agricultural Sciences (DC-QB), Division of Sciences and Engineering, University of Sonora, Navojoa 85880, Mexico
- Correspondence: (O.G.F.-S.); (N.O.)
| |
Collapse
|
|
11
|
Hardy MY, Goel G, Russell AK, Chen Yi Mei SLG, Brown GJE, Wang S, Szymczak E, Zhang R, Goldstein KE, Neff KM, Williams LJ, Truitt KE, Dzuris JL, Tye-Din JA, Anderson RP. A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease. Front Immunol 2021; 12:661622. [PMID: 34093551 PMCID: PMC8171185 DOI: 10.3389/fimmu.2021.661622] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/04/2021] [Indexed: 12/16/2022] Open
Abstract
Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
Collapse
Affiliation(s)
- Melinda Y Hardy
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gautam Goel
- ImmusanT, Inc., Cambridge, MA, United States
| | - Amy K Russell
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | | | - Gregor J E Brown
- Department of Gastroenterology, Alfred Hospital, Prahran, VIC, Australia
| | - Suyue Wang
- ImmusanT, Inc., Cambridge, MA, United States
| | | | - Ruan Zhang
- ImmusanT, Inc., Cambridge, MA, United States
| | | | | | | | | | | | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | | |
Collapse
|
|
12
|
Smithson G, Siegelman J, Oki T, Maxwell JR, Leffler DA. The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development. Front Immunol 2021; 12:665756. [PMID: 33897715 PMCID: PMC8060282 DOI: 10.3389/fimmu.2021.665756] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.
Collapse
Affiliation(s)
- Glennda Smithson
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Jenifer Siegelman
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Toshihiko Oki
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Joseph R Maxwell
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Daniel A Leffler
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States.,Celiac Disease Research Program, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
13
|
Kurki A, Kemppainen E, Laurikka P, Kaukinen K, Lindfors K. The use of peripheral blood mononuclear cells in celiac disease diagnosis and treatment. Expert Rev Gastroenterol Hepatol 2021; 15:305-316. [PMID: 33176106 DOI: 10.1080/17474124.2021.1850262] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Celiac disease is characterized by an abnormal immune activation driven by the ingestion of gluten from wheat, barley, and rye. Gluten-specific CD4+ T cells play an important role in disease pathogenesis and are detectable among peripheral blood mononuclear cells (PBMCs). Areas covered: This review summarizes the use of celiac disease patient PBMCs in clinical applications focusing on their exploitation in the development of diagnostic approaches and novel drugs to replace or complement gluten-free diet. Expert opinion: The most used PBMC-based methods applied in celiac disease research include ELISpot and HLA-DQ:gluten tetramer technology. ELISpot has been utilized particularly in research aiming to develop a celiac disease vaccine and in studies addressing the toxicity of different grains in celiac disease. HLA-DQ:gluten tetramer technology on the other hand initially focused on improving current diagnostics but in combination with additional markers it is also a useful outcome measure in clinical trials to monitor the efficacy of drug candidates. In addition, the technology serves well in the more detailed characterization of celiac disease-specific T cells, thereby possibly revealing novel therapeutic targets. Future studies may also reveal clinical applications for PBMC microRNAs and/or dendritic cells or monocytes present among PBMCs.
Collapse
Affiliation(s)
- Alma Kurki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University , Tampere, Finland
| | - Esko Kemppainen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University , Tampere, Finland
| | - Pilvi Laurikka
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University , Tampere, Finland
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University , Tampere, Finland.,Department of Internal Medicine, Tampere University Hospital , Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University , Tampere, Finland
| |
Collapse
|
|
14
|
Anderson RP, Goel G, Hardy MY, Russell AK, Wang S, Szymczak E, Zhang R, Goldstein KE, Neff K, Truitt KE, Williams LJ, Dzuris JL, Tye-Din JA. Whole blood interleukin-2 release test to detect and characterize rare circulating gluten-specific T cell responses in coeliac disease. Clin Exp Immunol 2021; 204:321-334. [PMID: 33469922 DOI: 10.1111/cei.13578] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 02/07/2023] Open
Abstract
Whole blood cytokine release assays (CRA) assessing cellular immunity to gluten could simplify the diagnosis and monitoring of coeliac disease (CD). We aimed to determine the effectiveness of electrochemiluminescence CRA to detect responses to immunodominant gliadin peptides. HLA-DQ2·5+ CD adults (cohort 1, n = 6; cohort 2, n = 12) and unaffected controls (cohort 3, n = 9) were enrolled. Cohort 1 had 3-day gluten challenge (GC). Blood was collected at baseline, and for cohort 1 also at 3 h, 6 h and 6 days after commencing 3-day GC. Gliadin peptide-stimulated proliferation, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and 14- and 3-plex electrochemiluminescence CRA were performed. Poisson distribution analysis was used to estimate responding cell frequencies. In cohort 1, interleukin (IL)-2 dominated the gliadin peptide-stimulated cytokine release profile in whole blood. GC caused systemic IL-2 release acutely and increased gliadin peptide-stimulated IFN-γ ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL-2, but also included IFN-γ, C-X-C motif chemokine ligand 10/IFN-γ-induced protein 10 (CXCL10/IP-10), CXCL9/monokine induced by IFN-γ (MIG), IL-10, chemokine (C-C motif) ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP-1α), TNF-α and IL-8/CXCL8. In cohorts 2 and 3, gliadin peptide-stimulated whole blood IL-2 release was 100% specific and 92% sensitive for CD patients on a gluten-free diet; the estimated frequency of cells in CD blood secreting IL-2 to α-gliadin peptide was 0·5 to 11 per ml. Whole blood IL-2 release successfully mapped human leucocyte antigen (HLA)-DQ2·5-restricted epitopes in an α-gliadin peptide library using CD blood before and after GC. Whole blood IL-2 release assay using electrochemiluminescence is a sensitive test for rare gliadin-specific T cells in CD, and could aid in monitoring and diagnosis. Larger studies and validation with tetramer-based assays are warranted.
Collapse
Affiliation(s)
| | - G Goel
- ImmusanT, Inc., Cambridge, MA, USA
| | - M Y Hardy
- Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,University of Melbourne, Parkville, VIC, Australia
| | - A K Russell
- Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,University of Melbourne, Parkville, VIC, Australia
| | - S Wang
- ImmusanT, Inc., Cambridge, MA, USA
| | | | - R Zhang
- ImmusanT, Inc., Cambridge, MA, USA
| | | | - K Neff
- ImmusanT, Inc., Cambridge, MA, USA
| | | | | | | | - J A Tye-Din
- Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| |
Collapse
|
|
15
|
Leonard MM, Silvester JA, Leffler D, Fasano A, Kelly CP, Lewis SK, Goldsmith JD, Greenblatt E, Kwok WW, McAuliffe WJ, Galinsky K, Siegelman J, Chow IT, Wagner JA, Sapone A, Smithson G. Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial. Gastroenterology 2021; 160:720-733.e8. [PMID: 33130104 PMCID: PMC7878429 DOI: 10.1053/j.gastro.2020.10.040] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/15/2020] [Accepted: 10/25/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology. METHODS In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence. RESULTS All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. CONCLUSIONS Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.
Collapse
Affiliation(s)
- Maureen M Leonard
- Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, Massachusetts; Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts
| | - Jocelyn A Silvester
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Daniel Leffler
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts; Takeda Pharmaceuticals Inc Co, Cambridge, Massachusetts
| | - Alessio Fasano
- Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, Massachusetts; Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts
| | - Ciarán P Kelly
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts; Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Suzanne K Lewis
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Jeffrey D Goldsmith
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts; Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | | | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, Washington
| | | | | | | | - I-Ting Chow
- Benaroya Research Institute at Virginia Mason, Seattle, Washington
| | - John A Wagner
- Takeda Pharmaceuticals Inc Co, Cambridge, Massachusetts
| | - Anna Sapone
- Takeda Pharmaceuticals Inc Co, Cambridge, Massachusetts
| | | |
Collapse
|
|
16
|
Mendo-Lopez R, Yoosuf S, Leffler D. Gluten Challenge in Gluten-Associated Disorders. DIAGNOSIS AND MANAGEMENT OF GLUTEN-ASSOCIATED DISORDERS 2021:65-88. [DOI: 10.1007/978-3-030-56722-4_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
17
|
Asri N, Rostami-Nejad M, Barzegar M, Nikzamir A, Rezaei-Tavirani M, Razzaghi M, Zali MR. Suppressive Mechanisms Induced by Tregs in Celiac Disease. IRANIAN BIOMEDICAL JOURNAL 2020; 24:140-147. [PMID: 31952431 PMCID: PMC7275623 DOI: 10.29252/ibj.24.3.140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 08/06/2019] [Indexed: 12/03/2022]
Abstract
Celiac disease (CD) is a systemic immune-mediated disorder caused by the dietary gluten in individuals who are genetically susceptible to the disease. In fact, CD is a T cell-mediated immune disease in which gluten-derived peptides activate the lamina propria CD4+ Teff cells, and these T-cell subsets can cause the intestinal tissue damages. Also, there are additional subsets of CD4+ T cells with suppressor functions. These subsets express the master transcription factor, FOXP3, and include Tr1 cells and CD4+CD25+ regulatory T cells (Tregs), which are the main population involved in maintaining the peripheral tolerance, preventing the autoimmune diseases and limiting the chronic inflammatory diseases such as CD. The suppressive function of Tregs is important to maintain the immune homeostasis. This paper examined the features and the basic mechanisms used by Tregs to mediate the suppression in CD.
Collapse
Affiliation(s)
- Nastaran Asri
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of MedicalSciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Barzegar
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolrahim Nikzamir
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of MedicalSciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
18
|
Charlesworth RPG. Diagnosing coeliac disease: Out with the old and in with the new? World J Gastroenterol 2020; 26:1-10. [PMID: 31933510 PMCID: PMC6952296 DOI: 10.3748/wjg.v26.i1.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/05/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023] Open
Abstract
Coeliac disease (CD) is a complex condition resulting from an interplay between genetic and environmental factors. When diagnosing the condition, serological testing and genotyping are useful in excluding CD, although the gold standard of testing is currently histopathological examination of the small intestine. There are drawbacks associated with this form of testing however and because of this, novel forms of testing are currently under investigation. Before we develop completely novel tests though, it is important to ask whether or not we can simply use the data we gather from coeliac patients more effectively and build a more accurate snapshot of CD through statistical analysis of combined metrics. It is clear that not one single test can accurately diagnose CD and it is also clear that CD patients can no longer be defined by discrete classifications, the continuum of patient presentation needs to be recognised and correctly captured to improve diagnostic accuracy. This review will discuss the current diagnostics for CD and then outline novel diagnostics under investigation for the condition. Finally, improvements to current protocols will be discussed with the need for a holistic "snapshot" of CD using a number of metrics simultaneously.
Collapse
|
|
19
|
Sánchez-León S, Giménez MJ, Comino I, Sousa C, López Casado MÁ, Torres MI, Barro F. Stimulatory Response of Celiac Disease Peripheral Blood Mononuclear Cells Induced by RNAi Wheat Lines Differing in Grain Protein Composition. Nutrients 2019; 11:nu11122933. [PMID: 31816892 PMCID: PMC6950052 DOI: 10.3390/nu11122933] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/27/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Wheat gluten proteins are responsible for the bread-making properties of the dough but also for triggering important gastrointestinal disorders. Celiac disease (CD) affects approximately 1% of the population in Western countries. The only treatment available is the strict avoidance of gluten in the diet. Interference RNA (RNAi) is an excellent approach for the down-regulation of genes coding for immunogenic proteins related to celiac disease, providing an alternative for the development of cereals suitable for CD patients. In the present work, we report a comparative study of the stimulatory capacity of seven low-gluten RNAi lines differing in grain gluten and non-gluten protein composition, relevant for CD and other gluten pathologies. Peripheral blood mononuclear cells (PBMCs) of 35 patients with active CD were included in this study to assess the stimulatory response induced by protein extracts from the RNAi lines. Analysis of the proliferative response and interferon-gamma (INF-γ) release of PBMCs demonstrated impaired stimulation in response to all RNAi lines. The lower response was provided by lines with a very low content of α- and γ-gliadins, and low or almost devoid of DQ2.5 and p31-43 α-gliadin epitopes. The non-gluten protein seems not to play a key role in PBMC stimulation.
Collapse
Affiliation(s)
- Susana Sánchez-León
- Departamento de Mejora Genética Vegetal, Instituto de Agricultura Sostenible, 14004 Córdoba, Spain; (S.S.-L.); (M.J.G.)
| | - María José Giménez
- Departamento de Mejora Genética Vegetal, Instituto de Agricultura Sostenible, 14004 Córdoba, Spain; (S.S.-L.); (M.J.G.)
| | - Isabel Comino
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain; (I.C.); (C.S.)
| | - Carolina Sousa
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain; (I.C.); (C.S.)
| | | | - María Isabel Torres
- Departamento de Biología Experimental, Campus Universitario Las Lagunillas, 23071 Jaén, Spain;
| | - Francisco Barro
- Departamento de Mejora Genética Vegetal, Instituto de Agricultura Sostenible, 14004 Córdoba, Spain; (S.S.-L.); (M.J.G.)
- Correspondence:
| |
Collapse
|
|
20
|
Fernández-Prieto M, Fernández-Aceñero MJ, López-Palacios N, Bodas A, Farrais S, Cuevas D, Pascual V, Cerón-Nieto MÁ, Horta-Herrera S, Espino-Paisán L, Salazar I, Núñez C. CX3CL1-CX3CR1 Axis: A New Player in Coeliac Disease Pathogenesis. Nutrients 2019; 11:2551. [PMID: 31652730 PMCID: PMC6893425 DOI: 10.3390/nu11112551] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The CX3CL1-CX3CR1 axis has been related to numerous diseases. The aim of our study was to investigate its involvement in coeliac disease (CD) pathogenesis, particularly in the early phase of the disease. METHODS We collected peripheral blood from CD patients and controls, enrolled in a 3-day gluten challenge, to study soluble CX3CL1, I-TAC and MIG by Luminex, CX3CL1 and CX3CR1 gene expression by qPCR, and CX3CR1 protein expression in monocytes and CD8+, CD4+ and γδ+ T cells, by flow cytometry. We also analysed the expression of the CX3CL1 and CX3CR1 mRNA and protein in the duodenal biopsies of CD patients with active and treated disease, and in non-CD control individuals, by qPCR and immunohistochemistry. RESULTS After the gluten challenge, increased levels of CX3CL1, I-TAC and MIG proteins were observed in the peripheral blood of CD patients, with no changes in CX3CL1 mRNA, or CX3CR1 mRNA and protein. Regarding duodenal tissue, CX3CL1 was absent or barely present in the superficial and basal epithelium of CD patients, contrasting with the moderate to high levels present in controls. CONCLUSIONS CX3CL1 seems to be involved in the appearance and progression of CD, and it appears to be a potential diagnostic biomarker. Its use as an alternative therapeutic target in CD deserves further research.
Collapse
Affiliation(s)
- Marta Fernández-Prieto
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - María Jesús Fernández-Aceñero
- Servicio de Anatomía Patológica, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Natalia López-Palacios
- Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Andrés Bodas
- Servicio de Pediatría, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Sergio Farrais
- Servicio de Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain.
| | - David Cuevas
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Virginia Pascual
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - M Ángeles Cerón-Nieto
- Servicio de Anatomía Patológica, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Saúl Horta-Herrera
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Laura Espino-Paisán
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Isabel Salazar
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Concepción Núñez
- Laboratorio de Investigación en Genética de enfermedades complejas, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
| |
Collapse
|
|
21
|
Goel G, Daveson AJM, Hooi CE, Tye-Din JA, Wang S, Szymczak E, Williams LJ, Dzuris JL, Neff KM, Truitt KE, Anderson RP. Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease. Clin Exp Immunol 2019; 199:68-78. [PMID: 31505020 DOI: 10.1111/cei.13369] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2019] [Indexed: 12/14/2022] Open
Abstract
Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)-2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten-mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free-diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high-sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL-2, chemokine (C-C motif) ligand 20 (CCL20), IL-6, chemokine (C-X-C motif) ligand (CXCL)9, CXCL8, interferon (IFN)-γ, IL-10, IL-22, IL-17A, tumour necrosis factor (TNF)-α, CCL2 and amphiregulin. IL-2 and IL-17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL-2 increased most (median 57-fold), then CCL20 (median 10-fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL-2, IL-17A, IL-22 and IFN-γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.
Collapse
Affiliation(s)
- G Goel
- ImmusanT, Inc., Cambridge, MA,, USA
| | - A J M Daveson
- Faculty of Medicine, University of Queensland, 288 Herston Rd, Herston, 4006, QLD, Australia
| | - C E Hooi
- Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - J A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - S Wang
- ImmusanT, Inc., Cambridge, MA,, USA
| | | | | | | | - K M Neff
- ImmusanT, Inc., Cambridge, MA,, USA
| | | | | |
Collapse
|
|
22
|
Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond. Trends Mol Med 2019; 25:836-852. [DOI: 10.1016/j.molmed.2019.05.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/13/2022]
|
|
23
|
Cabanillas B. Gluten-related disorders: Celiac disease, wheat allergy, and nonceliac gluten sensitivity. Crit Rev Food Sci Nutr 2019; 60:2606-2621. [PMID: 31402697 DOI: 10.1080/10408398.2019.1651689] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The consumption of gluten-free products is becoming an increased alimentary habit in the general population. The scientific unfounded perception suggesting that the avoidance of gluten would improve health or that gluten could be toxic for humans are fostering medically unjustified adherences to a gluten-free diet. Currently, only patients diagnosed with celiac disease are advised to follow a strict lifelong gluten-free diet. In the same way, patients diagnosed with IgE-mediated wheat allergy must avoid exposure to wheat in any form. In that context, a third disorder, called nonceliac gluten sensitivity, characterized by distress after gluten consumption and in which neither celiac disease nor IgE-mediated allergy plays a role, has gained increased attention in the last years. Although important scientific advances have been made in the understanding of the pathologic mechanisms behind nonceliac gluten sensitivity, this disorder is still a matter of active debate in the scientific community. In the present review, the most recent advances in the immunopathology, diagnostic biomarkers and susceptibility determinants of gluten-related diseases are summarized and discussed. Furthermore, an updated overview of the new potential therapies that are currently underway for the treatment of gluten-related disorders is also provided.
Collapse
Affiliation(s)
- Beatriz Cabanillas
- Department of Dermatology and Allergy, University of Bonn Medical Center, Bonn, Germany
| |
Collapse
|
|
24
|
Vorobjova T, Tagoma A, Oras A, Alnek K, Kisand K, Talja I, Uibo O, Uibo R. Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa. J Immunol Res 2019; 2019:6179243. [PMID: 31214623 PMCID: PMC6535873 DOI: 10.1155/2019/6179243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/08/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023] Open
Abstract
Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.
Collapse
Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Aili Tagoma
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Astrid Oras
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kristi Alnek
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kalle Kisand
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Ija Talja
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Oivi Uibo
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Estonia
- Children's Clinic, Tartu University Hospital, Tartu, Estonia
| | - Raivo Uibo
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| |
Collapse
|
|
25
|
Figueroa-Salcido OG, Ontiveros N, Cabrera-Chavez F. Gluten Vehicle and Placebo for Non-Celiac Gluten Sensitivity Assessment. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E117. [PMID: 31035487 PMCID: PMC6572297 DOI: 10.3390/medicina55050117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 04/20/2019] [Accepted: 04/23/2019] [Indexed: 12/13/2022]
Abstract
Non-celiac gluten sensitivity (NCGS) is a syndrome characterized by gastrointestinal and extraintestinal manifestations triggered after gluten ingestion in the absence of celiac disease and wheat allergy. Because of the lack of biomarkers for NCGS diagnosis, the cornerstone for its assessment is a single- or double-blind placebo-controlled (DBPC) gluten challenge. However, there are some non-standardized points in the diagnostic approach proposed by the experts. This complicate comparisons among the results published by different research groups. The gluten vehicle and placebo must be indistinguishable from each other, which entails sensory and technological evaluations of the designed gluten vehicle and placebo products. At the moment, there is no standardized method for the preparation of the gluten vehicle and placebo for carrying out DBPC gluten challenges for NCGS assessment. This review focuses on the challenges that researchers have to face, either for the development of an accepted gluten vehicle and placebo or for identifying NCGS cases on the basis of DBPC gluten challenges.
Collapse
Affiliation(s)
- Oscar Gerardo Figueroa-Salcido
- Nutrition Sciences Academic Unit, Autonomous University of Sinaloa, Cedros y Calle Sauces S/N, Fraccionamiento Los Fresnos, Culiacán 80019, Sinaloa, Mexico.
| | - Noé Ontiveros
- Division of Sciences and Engineering, Department of Chemical, Biological, and Agricultural Sciences (DC-QB), University of Sonora, Navojoa 85880, Sonora, Mexico.
| | - Francisco Cabrera-Chavez
- Nutrition Sciences Academic Unit, Autonomous University of Sinaloa, Cedros y Calle Sauces S/N, Fraccionamiento Los Fresnos, Culiacán 80019, Sinaloa, Mexico.
| |
Collapse
|
|
26
|
López-Palacios N, Pascual V, Castaño M, Bodas A, Fernández-Prieto M, Espino-Paisán L, Martínez-Ojinaga E, Salazar I, Martínez-Curiel R, Rey E, Estrada L, Molero-Abraham M, Reche PA, Dieli-Crimi R, Núñez C. Evaluation of T cells in blood after a short gluten challenge for coeliac disease diagnosis. Dig Liver Dis 2018; 50:1183-1188. [PMID: 29903545 DOI: 10.1016/j.dld.2018.04.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 04/06/2018] [Accepted: 04/19/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM To diagnose coeliac disease (CD) in individuals on a gluten free diet (GFD), we aimed to assess the utility of detecting activated γδ and CD8 T cells expressing gut-homing receptors after a short gluten challenge. METHODS We studied 15 CD patients and 35 non-CD controls, all exposed to three days of gluten when following a GFD. Peripheral blood was collected before and six days after starting gluten consumption, and the expression of CD103, β7 and CD38 in γδ and CD8 T cells was assessed by flow cytometry. Determination of IFN-γ and IP-10 was performed by means of ELISPOT and/or Luminex technology. RESULTS We observed both γδ and CD8 T cells coexpressing CD103, β7hi and CD38 in every patient with CD on day six, but only in one control. The studied CD8 T subpopulation was easier to detect than the γδ subpopulation. Increased IFN-γ and IP-10 levels after challenge were observed in patients with CD, but not in controls. CONCLUSION A short three-day gluten challenge elicits the activation of CD103+ β7hi CD8+ T cells in CD. These cells can be detected by flow cytometry in peripheral blood, opening new possibilities for CD diagnosis in individuals on a GFD.
Collapse
Affiliation(s)
- Natalia López-Palacios
- Department of Gastroenterology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Virginia Pascual
- Laboratory of research in Complex Disease Genetics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Mercedes Castaño
- Laboratory of research in Complex Disease Genetics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Andrés Bodas
- Department of Pediatrics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Marta Fernández-Prieto
- Laboratory of research in Complex Disease Genetics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Laura Espino-Paisán
- Laboratory of research in Complex Disease Genetics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Eva Martínez-Ojinaga
- Department of Pediatric Gastroenterology and Nutrition, Hospital Universitario La Paz, Madrid, Spain
| | - Isabel Salazar
- Department of Animal Production, Faculty of Veterinary, Complutense University of Madrid, Madrid, Spain
| | - Raquel Martínez-Curiel
- Laboratory of research in Complex Disease Genetics, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Enrique Rey
- Department of Gastroenterology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Lourdes Estrada
- Department of Pathology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Magdalena Molero-Abraham
- Immunomedicine Laboratory, Department of Immunology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Pedro A Reche
- Immunomedicine Laboratory, Department of Immunology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Romina Dieli-Crimi
- Department of Gastroenterology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| | - Concepción Núñez
- Department of Gastroenterology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
| |
Collapse
|
|
27
|
Ludvigsson JF, Ciacci C, Green PH, Kaukinen K, Korponay-Szabo IR, Kurppa K, Murray JA, Lundin KEA, Maki MJ, Popp A, Reilly NR, Rodriguez-Herrera A, Sanders DS, Schuppan D, Sleet S, Taavela J, Voorhees K, Walker MM, Leffler DA. Outcome measures in coeliac disease trials: the Tampere recommendations. Gut 2018; 67:1410-1424. [PMID: 29440464 PMCID: PMC6204961 DOI: 10.1136/gutjnl-2017-314853] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 12/19/2017] [Accepted: 01/08/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. DESIGN Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. RESULTS We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. CONCLUSION Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.
Collapse
Affiliation(s)
- Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
| | - Carolina Ciacci
- Coeliac Center at Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, Salerno, Italy
| | - Peter Hr Green
- Celiac Disease Center at Columbia University, New York, USA
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Ilma R Korponay-Szabo
- Coeliac Disease Centre, Heim Pál Children's Hospital, Budapest, Hungary
- Department of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- Department of Paediatrics, Tampere University Hospital, Tampere, Finland
| | | | - Knut Erik Aslaksen Lundin
- Institute of Clinical Medicine and K.G. Jebsen Coeliac Disease Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
| | - Markku J Maki
- Science Center, Tampere University Hospital, Tampere, Finland
- Tampere Centre for Child Health Research, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
| | - Alina Popp
- Institute for Mother and Child Health Bucharest, University of Medicine and Pharmacy 'Carol Davila', Bucharest, Romania
- Tampere Centre for Child Health Research, University of Tampere, Tampere University Hospital, Tampere, Finland
| | - Norelle R Reilly
- Division of Pediatric Gastroenterology, Columbia University Medical Center, New York, USA
- Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, USA
| | | | - David S Sanders
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK
| | - Detlef Schuppan
- Celiac Center, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Juha Taavela
- Tampere Centre for Child Health Research, University of Tampere, Tampere University Hospital, Tampere, Finland
| | | | - Marjorie M Walker
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
| | - Daniel A Leffler
- Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
28
|
Addressing Barriers for Patients with Celiac Disease When Assessing for Gluten in Medications. J Acad Nutr Diet 2018; 118:1365-1369. [DOI: 10.1016/j.jand.2018.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 03/28/2018] [Indexed: 11/23/2022]
|
|
29
|
Sarna VK, Lundin KEA, Mørkrid L, Qiao SW, Sollid LM, Christophersen A. HLA-DQ-Gluten Tetramer Blood Test Accurately Identifies Patients With and Without Celiac Disease in Absence of Gluten Consumption. Gastroenterology 2018; 154:886-896.e6. [PMID: 29146521 DOI: 10.1053/j.gastro.2017.11.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/22/2017] [Accepted: 11/03/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Celiac disease is characterized by HLA-DQ2/8-restricted responses of CD4+ T cells to cereal gluten proteins. A diagnosis of celiac disease based on serologic and histologic evidence requires patients to be on gluten-containing diets. The growing number of individuals adhering to a gluten-free diet (GFD) without exclusion of celiac disease complicates its detection. HLA-DQ-gluten tetramers can be used to detect gluten-specific T cells in blood of patients with celiac disease, even if they are on a GFD. We investigated whether an HLA-DQ-gluten tetramer-based assay accurately identifies patients with celiac disease. METHODS We produced HLA-DQ-gluten tetramers and added them to peripheral blood mononuclear cells isolated from 143 HLA-DQ2.5+ subjects (62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]). T cells that bound HLA-DQ-gluten tetramers were quantified by flow cytometry. Laboratory tests and flow cytometry gating analyses were performed by researchers blinded to sample type, except for samples from subjects with celiac disease on a gluten-containing diet. Test precision analyses were performed using samples from 10 subjects. RESULTS For the HLA-DQ-gluten tetramer-based assay, we combined flow-cytometry variables in a multiple regression model that identified individuals with celiac disease on a GFD with an area under the receiver operating characteristic curve value of 0.96 (95% confidence interval [CI] 0.89-1.00) vs subjects without celiac disease on a GFD. The assay detected individuals with celiac disease on a gluten-containing diet vs controls with an area under the receiver operating characteristic curve value of 0.95 (95% CI 0.90-1.00). Optimized cutoff values identified subjects with celiac disease on a GFD with 97% sensitivity (95% CI 0.92-1.00) and 95% specificity (95% CI 0.84-1.00) vs subjects without celiac disease on a GFD. The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI 1.00-1.00]) and 90% specificity (95% CI 0.83-0.98) vs controls. In an analysis of 4 controls with positive results from the HLA-DQ-gluten tetramer test, 2 had unrecognized celiac disease and the remaining 2 had T cells that proliferated in response to gluten antigen in vitro. CONCLUSIONS An HLA-DQ-gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD. This test would allow individuals with suspected celiac disease to avoid gluten challenge and duodenal biopsy, but requires validation in a larger study. Clinicaltrials.gov no: NCT02442219.
Collapse
Affiliation(s)
- Vikas K Sarna
- Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.
| | - Knut E A Lundin
- KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway; Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Lars Mørkrid
- Department of Medical Biochemistry, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Shuo-Wang Qiao
- Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway; Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway
| | - Ludvig M Sollid
- Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway; Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and University of Oslo, Oslo, Norway
| | - Asbjørn Christophersen
- Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
| |
Collapse
|
|
30
|
Tye-Din JA, Galipeau HJ, Agardh D. Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies. Front Pediatr 2018; 6:350. [PMID: 30519552 PMCID: PMC6258800 DOI: 10.3389/fped.2018.00350] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/29/2018] [Indexed: 12/14/2022] Open
Abstract
Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.
Collapse
Affiliation(s)
- Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia.,Centre for Food & Allergy Research, Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Daniel Agardh
- The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.,Unit of Endocrinology and Gastroenterology, Department of Pediatrics, Skåne University Hospital, Malmö, Sweden
| |
Collapse
|
|
31
|
Hindryckx P, Levesque BG, Holvoet T, Durand S, Tang CM, Parker C, Khanna R, Shackelton LM, D'Haens G, Sandborn WJ, Feagan BG, Lebwohl B, Leffler DA, Jairath V. Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials. Gut 2018; 67:61-69. [PMID: 27799282 DOI: 10.1136/gutjnl-2016-312762] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/06/2016] [Accepted: 10/10/2016] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials. DESIGN MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA). RESULTS Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy. CONCLUSIONS Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.
Collapse
Affiliation(s)
- Pieter Hindryckx
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Department of Gastroenterology, University of Ghent, Ghent, Belgium
| | - Barrett G Levesque
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Tom Holvoet
- Department of Gastroenterology, University of Ghent, Ghent, Belgium
| | - Serina Durand
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Ceen-Ming Tang
- Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK.,Oxford University Clinical Academic Graduate School, John Radcliffe Hospital, Oxford, UK
| | - Claire Parker
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada
| | - Reena Khanna
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Lisa M Shackelton
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada
| | - Geert D'Haens
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands
| | - William J Sandborn
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Brian G Feagan
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Department of Medicine, University of Western Ontario, London, Ontario, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada
| | - Benjamin Lebwohl
- Celiac Disease Center, Columbia University, New York, New York, USA
| | - Daniel A Leffler
- The Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Vipul Jairath
- Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.,Department of Medicine, University of Western Ontario, London, Ontario, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada
| |
Collapse
|
|
32
|
Abstract
Celiac disease has advanced from a medical rarity to a highly prevalent disorder. Patients with the disease show varying degrees of chronic inflammation within the small intestine due to an aberrant immune response to the digestion of gliadin found in wheat. As a result, cytokines and antibodies are produced in celiac patients that can be used as specific biomarkers for developing diagnostic tests. This review paper describes celiac disease in terms of its etiological cause, pathological effects, current diagnostic tests based on mucosal biopsy, and the genetic basis for the disease. In addition, it discusses the use of gliadin-induced cytokines, antibodies and autoantibodies as a diagnostic tool for celiac disease. Despite good initial results in terms of sensitivity and specificity, when these immunological tests were used on a large scale, even in combination with genetic testing, the results showed lower predictive value. This review addresses that issue and ends with an outlook on future work required to develop diagnostic tests with greater accuracy in predicting celiac disease in the general public, thus avoiding the need for endoscopy and mucosal biopsy.
Collapse
Affiliation(s)
- Anantdeep Kaur
- Institute for Biomedical Materials and Devices (IBMD), The University of Technology Sydney, Broadway, PO Box 123, Sydney, NSW, 2007, Australia
| | - Olga Shimoni
- Institute for Biomedical Materials and Devices (IBMD), The University of Technology Sydney, Broadway, PO Box 123, Sydney, NSW, 2007, Australia.
| | - Michael Wallach
- School of Life Sciences, The University of Technology Sydney, Broadway, PO Box 123, Sydney, NSW, 2007, Australia
| |
Collapse
|
|
33
|
Presymptomatic Diagnosis of Celiac Disease in Predisposed Children: The Role of Gene Expression Profile. J Pediatr Gastroenterol Nutr 2017; 65:314-320. [PMID: 28827480 DOI: 10.1097/mpg.0000000000001519] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The prevalence of celiac disease (CD) has increased significantly in recent years, and risk prediction and early diagnosis have become imperative especially in at-risk families. In a previous study, we identified individuals with CD based on the expression profile of a set of candidate genes in peripheral blood monocytes. Here we evaluated the expression of a panel of CD candidate genes in peripheral blood mononuclear cells from at-risk infants long time before any symptom or production of antibodies. METHODS We analyzed the gene expression of a set of 9 candidate genes, associated with CD, in 22 human leukocyte antigen predisposed children from at-risk families for CD, studied from birth to 6 years of age. Nine of them developed CD (patients) and 13 did not (controls). We analyzed gene expression at 3 different time points (age matched in the 2 groups): 4-19 months before diagnosis, at the time of CD diagnosis, and after at least 1 year of a gluten-free diet. At similar age points, controls were also evaluated. RESULTS Three genes (KIAA, TAGAP [T-cell Activation GTPase Activating Protein], and SH2B3 [SH2B Adaptor Protein 3]) were overexpressed in patients, compared with controls, at least 9 months before CD diagnosis. At a stepwise discriminant analysis, 4 genes (RGS1 [Regulator of G-protein signaling 1], TAGAP, TNFSF14 [Tumor Necrosis Factor (Ligand) Superfamily member 14], and SH2B3) differentiate patients from controls before serum antibodies production and clinical symptoms. Multivariate equation correctly classified CD from non-CD children in 95.5% of patients. CONCLUSIONS The expression of a small set of candidate genes in peripheral blood mononuclear cells can predict CD at least 9 months before the appearance of any clinical and serological signs of the disease.
Collapse
|
|
34
|
Goel G, King T, Daveson AJ, Andrews JM, Krishnarajah J, Krause R, Brown GJE, Fogel R, Barish CF, Epstein R, Kinney TP, Miner PB, Tye-Din JA, Girardin A, Taavela J, Popp A, Sidney J, Mäki M, Goldstein KE, Griffin PH, Wang S, Dzuris JL, Williams LJ, Sette A, Xavier RJ, Sollid LM, Jabri B, Anderson RP. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet Gastroenterol Hepatol 2017; 2:479-493. [PMID: 28506538 PMCID: PMC5676538 DOI: 10.1016/s2468-1253(17)30110-3] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet. METHODS We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. FINDINGS Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 μg and three to placebo (first cohort), nine were allocated to Nexvax2 90 μg and four to placebo (second cohort), eight were allocated to Nexvax2 150 μg and four to placebo (third cohort), and three were allocated to Nexvax2 150 μg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 μg and four to placebo (first cohort), ten were allocated to Nexvax2 300 μg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 μg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 μg because of transient, acute gastrointestinal adverse events with onset 2-5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 μg, seven (78%) of nine who received Nexvax2 90 μg, and five (63%) of eight who received Nexvax2 150 μg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 μg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 μg, and all ten (100%) who received Nexvax2 300 μg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 μg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 μg, five (63%) of eight who received Nexvax2 90 μg, and six (100%) of six who received Nexvax2 150 μg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 μg (p=0·021). INTERPRETATION The MTD of Nexvax2 was 150 μg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease. FUNDING ImmusanT.
Collapse
Affiliation(s)
- Gautam Goel
- Division of Gastroenterology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tim King
- Department of Gastroenterology, Auckland City Hospital, Auckland, New Zealand
| | - A James Daveson
- School of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Jane M Andrews
- Department of Gastroenterology & Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia
| | | | | | - Gregor J E Brown
- Department of Gastroenterology, Alfred Hospital, Prahran, VIC, Australia
| | - Ronald Fogel
- Clinical Research Institute of Michigan, Chesterfield, MI, USA
| | - Charles F Barish
- University of North Carolina School of Medicine, Chapel Hill, NC, USA; Wake Gastroenterology and Wake Research Associates, Raleigh, NC, USA
| | | | | | - Philip B Miner
- Oklahoma Foundation for Digestive Research, Oklahoma City, OK, USA
| | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Murdoch Children's Research Institute and Department of Gastroenterology, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Adam Girardin
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Juha Taavela
- Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland
| | - Alina Popp
- Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland; Alfred Rusescu Institute for Mother and Child Care and Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - John Sidney
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Markku Mäki
- Tampere Center for Child Health Research and Department of Pediatrics, University of Tampere Faculty of Medicine and Life Sciences and Tampere University Hospital, Tampere, Finland
| | | | | | | | | | | | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Ramnik J Xavier
- Division of Gastroenterology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ludvig M Sollid
- Centre for Immune Regulation, KG Jebsen Coeliac Disease Research Centre, and Department of Immunology, University of Oslo, Oslo, Norway; Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Bana Jabri
- Department of Pediatrics, Department of Medicine, University of Chicago, Chicago, IL, USA
| | | |
Collapse
|
|
35
|
Cook L, Munier CML, Seddiki N, van Bockel D, Ontiveros N, Hardy MY, Gillies JK, Levings MK, Reid HH, Petersen J, Rossjohn J, Anderson RP, Zaunders JJ, Tye-Din JA, Kelleher AD. Circulating gluten-specific FOXP3 +CD39 + regulatory T cells have impaired suppressive function in patients with celiac disease. J Allergy Clin Immunol 2017; 140:1592-1603.e8. [PMID: 28283419 DOI: 10.1016/j.jaci.2017.02.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 02/03/2017] [Accepted: 02/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. OBJECTIVE We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells. METHODS Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). RESULTS Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 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. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. CONCLUSION This study provides the first estimation of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of patients with celiac disease. FOXP3+CD39+ Treg cells comprised a major proportion of all circulating gluten-specific CD4+ T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis.
Collapse
Affiliation(s)
- Laura Cook
- 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.
| | - C Mee Ling Munier
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia
| | - Nabila Seddiki
- 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
| | - David van Bockel
- Immunovirology and Pathogenesis Program, The Kirby Institute, UNSW Sydney, Sydney, Australia
| | - Noé Ontiveros
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Melinda Y Hardy
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Jana K Gillies
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hugh H Reid
- 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
| | - Jan Petersen
- 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
| | - Jamie Rossjohn
- 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; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
| | - Robert P Anderson
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; ImmusanT, Cambridge, Mass
| | - John J Zaunders
- 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
| | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Australia
| | - Anthony D Kelleher
- 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
| |
Collapse
|
|
36
|
Schumann M, Siegmund B, Schulzke JD, Fromm M. Celiac Disease: Role of the Epithelial Barrier. Cell Mol Gastroenterol Hepatol 2017; 3:150-162. [PMID: 28275682 PMCID: PMC5331784 DOI: 10.1016/j.jcmgh.2016.12.006] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022]
Abstract
In celiac disease (CD) a T-cell-mediated response to gluten is mounted in genetically predisposed individuals, resulting in a malabsorptive enteropathy histologically highlighted by villous atrophy and crypt hyperplasia. Recent data point to the epithelial layer as an under-rated hot spot in celiac pathophysiology to date. This overview summarizes current functional and genetic evidence on the role of the epithelial barrier in CD, consisting of the cell membranes and the apical junctional complex comprising sealing as well as ion and water channel-forming tight junction proteins and the adherens junction. Moreover, the underlying mechanisms are discussed, including apoptosis of intestinal epithelial cells, biology of intestinal stem cells, alterations in the apical junctional complex, transcytotic uptake of gluten peptides, and possible implications of a defective epithelial polarity. Current research is directed toward new treatment options for CD that are alternatives or complementary therapeutics to a gluten-free diet. Thus, strategies to target an altered epithelial barrier therapeutically also are discussed.
Collapse
Key Words
- Bmp, bone morphogenetic protein
- CBC, crypt base columnar cell
- CD, celiac disease
- Celiac Sprue
- EGF, epidermal growth factor
- Epithelial Polarity
- GFD, gluten-free diet
- GI, gastrointestinal
- GWAS, genome-wide association studies
- Gluten-Sensitive Enteropathy
- IEC, intestinal epithelial cell
- IL, interleukin
- MIC-A, major histocompatibility complex class I chain–related gene-A
- Partitioning-Defective Proteins
- SNP, single-nucleotide polymorphism
- TJ, tight junction
- Tight Junction
- ZO, zonula occludens
- aPKC, atypical protein kinase C
- α-Gliadin 33mer
Collapse
Affiliation(s)
- Michael Schumann
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Jörg D. Schulzke
- Institute of Clinical Physiology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Fromm
- Institute of Clinical Physiology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
37
|
Hardy MY, Tye-Din JA. Coeliac disease: a unique model for investigating broken tolerance in autoimmunity. Clin Transl Immunology 2016; 5:e112. [PMID: 27990287 PMCID: PMC5133362 DOI: 10.1038/cti.2016.58] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/12/2016] [Accepted: 09/12/2016] [Indexed: 01/06/2023] Open
Abstract
Coeliac disease, a prevalent immune-mediated enteropathy driven by dietary gluten, provides an exceptional human model to dissect the genetic, environmental and immunologic factors operating in autoimmunity. Despite the causative antigen being an exogenous food protein, coeliac disease has many features in common with autoimmune disease including a strong HLA class II association and the presence of pathogenic CD4+ T cells and autoantibodies. CD8+ intraepithelial lymphocytes specifically target and destroy intestinal epithelium in response to stress signals and not a specific antigen. A unique feature of coeliac disease is the ability to remove gluten to induce disease remission and reintroduce it to trigger a memory response. This provides an unparalleled opportunity to study disease-relevant CD4+ T cells that have been expanded in vivo. As a result, the causative peptides have been characterised at a level unprecedented for any autoimmune disease. Despite the complexity of the gluten proteome, resistance to gastrointestinal proteolysis and susceptibility to post-translational modification by transglutaminase help shape a restricted repertoire of immunogenic gluten peptides that have high affinity for disease-associated HLA. The critical steps in coeliac disease pathogenesis have been broadly elucidated and provide the basis for experimental therapies in pre-clinical or clinical development. However, little is known about how and why tolerance to gluten sometimes breaks or fails to develop. Understanding the interactions between genes, the environment, gluten immunity and the microbiome may provide novel approaches for the prevention and treatment of disease.
Collapse
Affiliation(s)
- Melinda Y Hardy
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Centre of Food and Allergy Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| |
Collapse
|
|
38
|
Losurdo G, Giorgio F, Piscitelli D, Montenegro L, Covelli C, Fiore MG, Giangaspero A, Iannone A, Principi M, Amoruso A, Barone M, Di Leo A, Ierardi E. May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis? World J Gastroenterol 2016; 22:8017-8025. [PMID: 27672296 PMCID: PMC5028815 DOI: 10.3748/wjg.v22.i35.8017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME). METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni's test. The χ(2) test was used for categorical variables. Pearson's test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS. RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels (6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD88 levels similarly to non gluten-related causes of DL (7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count (15-25 and more than 25/100 enterocytes) strongly correlated with mRNA levels of all tested molecules (P < 0.0001). CONCLUSION Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of tTG and IFNγ mRNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. MyD88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value.
Collapse
|
|
39
|
Hardy MY, Anderson RP, Tye-Din JA. Reply. Gastroenterology 2016; 150:779-80. [PMID: 26826377 DOI: 10.1053/j.gastro.2016.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Melinda Y Hardy
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | | | - Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| |
Collapse
|
|
40
|
Li W, Jiang W, Dai S, Wang L. Multiplexed Detection of Cytokines Based on Dual Bar-Code Strategy and Single-Molecule Counting. Anal Chem 2016; 88:1578-84. [DOI: 10.1021/acs.analchem.5b03043] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Wei Li
- Key
Laboratory of Natural Products Chemical Biology, Ministry of Education,
School of Pharmacy, Shandong University, Jinan, 250012, P. R. China
| | - Wei Jiang
- School
of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China
| | - Shuang Dai
- Key
Laboratory of Natural Products Chemical Biology, Ministry of Education,
School of Pharmacy, Shandong University, Jinan, 250012, P. R. China
| | - Lei Wang
- Key
Laboratory of Natural Products Chemical Biology, Ministry of Education,
School of Pharmacy, Shandong University, Jinan, 250012, P. R. China
| |
Collapse
|
|
41
|
De Giorgio R, Volta U, Gibson PR. Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction? Gut 2016; 65:169-78. [PMID: 26078292 DOI: 10.1136/gutjnl-2015-309757] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 05/29/2015] [Indexed: 12/11/2022]
Abstract
IBS is one of the most common types of functional bowel disorder. Increasing attention has been paid to the causative role of food in IBS. Food ingestion precipitates or exacerbates symptoms, such as abdominal pain and bloating in patients with IBS through different hypothesised mechanisms including immune and mast cell activation, mechanoreceptor stimulation and chemosensory activation. Wheat is regarded as one of the most relevant IBS triggers, although which component(s) of this cereal is/are involved remain(s) unknown. Gluten, other wheat proteins, for example, amylase-trypsin inhibitors, and fructans (the latter belonging to fermentable oligo-di-mono-saccharides and polyols (FODMAPs)), have been identified as possible factors for symptom generation/exacerbation. This uncertainty on the true culprit(s) opened a scenario of semantic definitions favoured by the discordant results of double-blind placebo-controlled trials, which have generated various terms ranging from non-coeliac gluten sensitivity to the broader one of non-coeliac wheat or wheat protein sensitivity or, even, FODMAP sensitivity. The role of FODMAPs in eliciting the clinical picture of IBS goes further since these short-chain carbohydrates are found in many other dietary components, including vegetables and fruits. In this review, we assessed current literature in order to unravel whether gluten/wheat/FODMAP sensitivity represent 'facts' and not 'fiction' in IBS symptoms. This knowledge is expected to promote standardisation in dietary strategies (gluten/wheat-free and low FODMAP) as effective measures for the management of IBS symptoms.
Collapse
Affiliation(s)
- Roberto De Giorgio
- Department of Medical and Surgical Sciences, Centro di Ricerca Bio-Medica Applicata (C.R.B.A.) and Digestive System, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, Centro di Ricerca Bio-Medica Applicata (C.R.B.A.) and Digestive System, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Peter R Gibson
- Department of Gastroenterology Alfred Hospital, Monash University, Melbourne, Australia
| |
Collapse
|
|
42
|
Picascia S, Mandile R, Auricchio R, Troncone R, Gianfrani C. Gliadin-Specific T-Cells Mobilized in the Peripheral Blood of Coeliac Patients by Short Oral Gluten Challenge: Clinical Applications. Nutrients 2015; 7:10020-31. [PMID: 26633487 PMCID: PMC4690067 DOI: 10.3390/nu7125515] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/17/2015] [Accepted: 11/26/2015] [Indexed: 12/20/2022] Open
Abstract
Celiac disease (CD) is a common lifelong food intolerance triggered by dietary gluten affecting 1% of the general population. Gliadin-specific T-cell lines and T-cell clones obtained from intestinal biopsies have provided great support in the investigation of immuno-pathogenesis of CD. In the early 2000 a new in vivo, less invasive, approach was established aimed to evaluate the adaptive gliadin-specific T-cell response in peripheral blood of celiac patients on a gluten free diet. In fact, it has been demonstrated that three days of ingestion of wheat-containing food induces the mobilization of memory T lymphocytes reactive against gliadin from gut-associated lymphoid tissue into peripheral blood of CD patients. Such antigen-specific T-cells releasing interferon-γ can be transiently detected by using the enzyme-linked immunospot (ELISPOT) assays or by flow cytometry tetramer technology. This paper discusses the suitability of this in vivo tool to investigate the repertoire of gluten pathogenic peptides, to support CD diagnosis, and to assess the efficacy of novel therapeutic strategies. A systematic review of all potential applications of short oral gluten challenge is provided.
Collapse
Affiliation(s)
- Stefania Picascia
- Institute of Protein Biochemistry-CNR, Via Pietro Castellino 111, Naples 80131, Italy.
| | - Roberta Mandile
- Department of Translational Medical Science (DISMET), Section of Pediatrics, University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
| | - Renata Auricchio
- Department of Translational Medical Science (DISMET), Section of Pediatrics, University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
- European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
| | - Riccardo Troncone
- Department of Translational Medical Science (DISMET), Section of Pediatrics, University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
- European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
| | - Carmen Gianfrani
- Institute of Protein Biochemistry-CNR, Via Pietro Castellino 111, Naples 80131, Italy.
- European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University of Naples Federico II, Via S Pansini 5, Naples 80131, Italy.
| |
Collapse
|
|
43
|
Ierardi E, Amoruso A, Giorgio F, Principi M, Losurdo G, Piscitelli D, Buffelli F, Fiore MG, Mongelli A, Castellaneta NM, Giangaspero A, De Francesco V, Montenegro L, Di Leo A. Mucosal molecular pattern of tissue transglutaminase and interferon gamma in suspected seronegative celiac disease at marsh 1 and 0 stages. Saudi J Gastroenterol 2015; 21:379-385. [PMID: 26655133 PMCID: PMC4707806 DOI: 10.4103/1319-3767.167189] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 05/23/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIM In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNα). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNα-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). MATERIALS AND METHODS Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 μm sections were used for the extraction and assay of tTG and IFNα coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. RESULTS Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15-25 (26 patients: group B), and 0-15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNα-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4. CONCLUSIONS Our results suggest that tTG- and IFNγmRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15-25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.
Collapse
Affiliation(s)
- Enzo Ierardi
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Annacinzia Amoruso
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Floriana Giorgio
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Mariabeatrice Principi
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Giuseppe Losurdo
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | | | | | - Maria G. Fiore
- Department of Pathology Section, University of Bari, Bari, Italy
| | - Antonio Mongelli
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Nicola M. Castellaneta
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Antonio Giangaspero
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Vincenzo De Francesco
- Department of Gastroenterology Department of Medical Sciences Unit, Ospedali Riuniti, Foggia, Italy
| | - Lucia Montenegro
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| | - Alfredo Di Leo
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari, Bari, Italy
| |
Collapse
|
|
44
|
Hardy MY, Girardin A, Pizzey C, Cameron DJ, Watson KA, Picascia S, Auricchio R, Greco L, Gianfrani C, La Gruta NL, Anderson RP, Tye-Din JA. Consistency in polyclonal T-cell responses to gluten between children and adults with celiac disease. Gastroenterology 2015; 149:1541-1552.e2. [PMID: 26226573 DOI: 10.1053/j.gastro.2015.07.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/15/2015] [Accepted: 07/18/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Developing antigen-specific approaches for diagnosis and treatment of celiac disease requires a detailed understanding of the specificity of T cells for gluten. The existing paradigm is that T-cell lines and clones from children differ from those of adults in the hierarchy and diversity of peptide recognition. We aimed to characterize the T-cell response to gluten in children vs adults with celiac disease. METHODS Forty-one children with biopsy-proven celiac disease (median age, 9 years old; 17 male), who had been on strict gluten-free diets for at least 3 months, were given a 3-day challenge with wheat; blood samples were collected and gluten-specific T cells were measured. We analyzed responses of T cells from these children and from 4 adults with celiac disease to a peptide library and measured T-cell receptor bias. We isolated T-cell clones that recognized dominant peptides and assessed whether gluten peptide recognition was similar between T-cell clones from children and adults. RESULTS We detected gluten-specific responses by T cells from 30 of the children with celiac disease (73%). T cells from the children recognized the same peptides that were immunogenic to adults with celiac disease; deamidation of peptides increased these responses. Age and time since diagnosis did not affect the magnitude of T-cell responses to dominant peptides. T-cell clones specific for dominant α- or ω-gliadin peptides from children with celiac disease had comparable levels of reactivity to wheat, rye, and barley peptides as T-cell clones from adults with celiac disease. The α-gliadin-specific T cells from children had biases in T-cell receptor usage similar to those in adults. CONCLUSIONS T cells from children with celiac disease recognize similar gluten peptides as T cells from adults with celiac disease. The findings indicate that peptide-based diagnostics and therapeutics for adults may also be used for children.
Collapse
Affiliation(s)
- Melinda Y Hardy
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Adam Girardin
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Catherine Pizzey
- Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Donald J Cameron
- Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Katherine A Watson
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Renata Auricchio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy
| | - Luigi Greco
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy
| | | | - Nicole L La Gruta
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
| |
Collapse
|
|
45
|
Ontiveros N, López-Gallardo JA, Vergara-Jiménez MJ, Cabrera-Chávez F. Self-Reported Prevalence of Symptomatic Adverse Reactions to Gluten and Adherence to Gluten-Free Diet in an Adult Mexican Population. Nutrients 2015. [PMID: 26197336 PMCID: PMC4517044 DOI: 10.3390/nu7075267] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The prevalence of symptomatic adverse reactions to gluten and adherence to gluten-free diet in Latin American countries is unknown. These measurements are strongly linked to gluten-related disorders. This work aimed to estimate the prevalence of adverse reactions to oral gluten and the adherence to gluten-free diet in the adult Mexican population. To reach this aim, a self-administered questionnaire was designed and tested for clarity/comprehension and reproducibility. Then, a self-administered questionnaire-based cross-sectional study was conducted in the Mexican population. The estimated prevalence rates were (95% CI): 11.9% (9.9–13.5) and 7.8 (6.4–9.4) for adverse and recurrent adverse reactions to gluten respectively; adherence to gluten-free diet 3.7% (2.7–4.8), wheat allergy 0.72% (0.38–1.37); celiac disease 0.08% (0.01–0.45), and NCGS 0.97% (0.55–1.68). Estimated pooled prevalence of self-reported physician-diagnosis of gluten-related disorders was 0.88% (0.49–1.5), and 93.3% respondents reported adherence to gluten-free diet without a physician-diagnosis of gluten-related disorders. Symptom comparisons between those who reported recurrent adverse reactions to gluten and other foods showed statistically significant differences for bloating, constipation, and tiredness (p < 0.05). Gluten-related disorders may be underdiagnosed in the Mexican population and most people adhering to a gluten-free diet are doing it without proper diagnostic work-up of these disorders, and probably without medical/dietician advice.
Collapse
Affiliation(s)
- Noe Ontiveros
- Regional Program for PhD in Biotechnology, FCQB, University of Sinaloa, Culiacán, Sinaloa 80019, México; E-Mail:
| | - Jesús A. López-Gallardo
- Nutrition Sciences Academic Unit, University of Sinaloa, Culiacán, Sinaloa 80019, México; E-Mails: (J.A.L.-G.); (M.J.V.-J.)
| | - Marcela J. Vergara-Jiménez
- Nutrition Sciences Academic Unit, University of Sinaloa, Culiacán, Sinaloa 80019, México; E-Mails: (J.A.L.-G.); (M.J.V.-J.)
| | - Francisco Cabrera-Chávez
- Nutrition Sciences Academic Unit, University of Sinaloa, Culiacán, Sinaloa 80019, México; E-Mails: (J.A.L.-G.); (M.J.V.-J.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +52-667-753-5454
| |
Collapse
|
|
46
|
Korponay-Szabó IR, Troncone R, Discepolo V. Adaptive diagnosis of coeliac disease. Best Pract Res Clin Gastroenterol 2015; 29:381-98. [PMID: 26060104 DOI: 10.1016/j.bpg.2015.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 04/24/2015] [Accepted: 05/07/2015] [Indexed: 01/31/2023]
Abstract
Coeliac disease has for a long time simply been regarded as a gluten-dependent enteropathy and a duodenal biopsy was required in all patients for the diagnosis. It is now accepted that autoimmunity against transglutaminase 2 is an earlier, more universal and more specific feature of coeliac disease than histologic lesions. Moreover, high serum levels of combined anti-transglutaminase 2 and anti-endomysium antibody positivity have excellent predictive value for the presence of enteropathy with villous atrophy. This makes the histology evaluation of the gut no longer necessary in well defined symptomatic paediatric patients with compatible HLA-DQ2 and/or DQ8 background. The biopsy-sparing diagnostic route is not yet recommended by gastroenterologists for adults, and certain clinical circumstances (immunodeficiency conditions, extraintestinal manifestations, type-1 diabetes mellitus, age less than 2 years) may require modified diagnostic approaches. Coeliac patients with preserved duodenal villous structure do exist and these need a more extended evaluation by immunologic and molecular biology tools.
Collapse
Affiliation(s)
- Ilma R Korponay-Szabó
- Department of Paediatrics, University of Debrecen Medical School, Nagyerdei krt 98, Debrecen 4032, Hungary; Coeliac Disease Centre, Heim Pál Children's Hospital, Üllöi út 86, Budapest 1089, Hungary.
| | - Riccardo Troncone
- University of Naples Federico II, Department of Medical Translational Sciences, Section of Pediatrics, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Valentina Discepolo
- University of Naples Federico II, Department of Medical Translational Sciences, Section of Pediatrics, Via Sergio Pansini 5, 80131 Napoli, Italy; University of Chicago, Department of Medicine and the University of Chicago Celiac Disease Center, Chicago 900 E 57th Street, 60615 Chicago, IL, USA
| |
Collapse
|
|
47
|
Assessing of Celiac Disease and Nonceliac Gluten Sensitivity. Gastroenterol Res Pract 2015; 2015:723954. [PMID: 26064097 PMCID: PMC4429206 DOI: 10.1155/2015/723954] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 04/15/2015] [Indexed: 12/17/2022] Open
Abstract
The publication of papers on the topic of gluten related disorders has substantially increased over the last few years. This has motivated healthcare professionals to pay attention not only to celiac disease and wheat allergy but also to a condition termed nonceliac gluten sensitivity (NCGS). Until now this condition has been diagnosed clinically on the basis of exclusion criteria and clinical response to gluten withdrawal. In addition, recent research in this field has shown that other food components distinct from gluten are implicated in NCGS cases, thereby changing our general understanding of NCGS diagnosis in either individuals on gluten containing diets or those already following a gluten-free diet with no proper diagnostic work-up of celiac disease. With this in mind, the assessment of NCGS will require extensive knowledge of celiac disease manifestations and the laboratory tests commonly performed during diagnosis of celiac disease.
Collapse
|
|
48
|
Abstract
BACKGROUND While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. KEY MESSAGES Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non-starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re-challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of 'non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed. CONCLUSIONS Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world.
Collapse
|
|
49
|
Tye-Din JA, Cameron DJS, Daveson AJ, Day AS, Dellsperger P, Hogan C, Newnham ED, Shepherd SJ, Steele RH, Wienholt L, Varney MD. Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective. Intern Med J 2015; 45:441-450. [PMID: 25827511 PMCID: PMC4405087 DOI: 10.1111/imj.12716] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/08/2015] [Indexed: 12/25/2022]
Abstract
The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results.
Collapse
Affiliation(s)
- J A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, Australia
- Departments of Medical Biology, The University of MelbourneMelbourne, Victoria, Australia
- Department of Gastroenterology, The Royal Melbourne HospitalMelbourne, Victoria, Australia
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
| | - D J S Cameron
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Gastroenterology, Monash Children's Hospital, The Royal Children's HospitalMelbourne, Victoria, Australia
- Department of Paediatrics, Monash UniversityMelbourne, Victoria, Australia
| | - A J Daveson
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Gastroenterology, Queen Elizabeth II Jubilee Hospital, Brisbane and School of Medicine, University of QueenslandBrisbane, Australia
| | - A S Day
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Paediatrics Department, University of OtagoChristchurch, New Zealand
| | - P Dellsperger
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Coeliac New South WalesNew South Wales, Australia
| | - C Hogan
- General Practice, The University of MelbourneMelbourne, Victoria, Australia
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
| | - E D Newnham
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Eastern Health Clinical School, Monash UniversityMelbourne, Victoria, Australia
- Department of Gastroenterology, Box Hill HospitalMelbourne, Victoria, Australia
| | - S J Shepherd
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Dietetics and Human Nutrition, La Trobe UniversityMelbourne, Victoria, Australia
| | - R H Steele
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Immunology, Wellington HospitalWellington, New Zealand
| | - L Wienholt
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Clinical Immunology, Royal Prince Alfred HospitalSydney, Australia
| | - M D Varney
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood ServiceMelbourne, Victoria, Australia
| |
Collapse
|
|
50
|
Björck S, Lindehammer SR, Fex M, Agardh D. Serum cytokine pattern in young children with screening detected coeliac disease. Clin Exp Immunol 2015; 179:230-5. [PMID: 25212572 PMCID: PMC4298400 DOI: 10.1111/cei.12454] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2014] [Indexed: 12/12/2022] Open
Abstract
Coeliac disease is an autoimmune disease characterized by inflammation localized to the small bowel, but less is known about systemic signs of inflammation. The aim was to measure cytokines of the T helper 1 (Th1) and T helper 2 (Th2) cell patterns in children with screening-detected coeliac disease before and after treatment with a gluten-free diet. Serum samples selected before and after the start of a gluten-free diet from 26 3-year-old children diagnosed with biopsy-proven coeliac disease and from 52 matched controls were assayed in an multiplex enzyme-linked immunosorbent assay (ELISA) for the 10 cytokines: interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13 and tumour necrosis factor (TNF)-α. Among Th1 cytokines, IFN-γ and IL-12p70 were elevated significantly in children with coeliac disease compared to controls (P < 0·001 and P = 0·001, respectively). Similar findings were demonstrated for the Th2 cytokines IL-5 (P < 0·001), IL-10 (P = 0·001) and IL-13 (P = 0·002). No difference in cytokine levels between the two groups was found for TNF-α, IL-1β, IL-2, IL-4 and IL-8. After gluten-free diet, levels of IL-5, IL-12 and IL-10 decreased significantly (P < 0·001, P = 0·002 and P = 0·007) and IFN-γ levels were reduced (P = 0·059). Young children with coeliac disease detected by screening demonstrate elevated levels of serum cytokines at time of diagnosis. A prolonged systemic inflammation may, in turn, contribute to long-term complications known to be associated with untreated coeliac disease.
Collapse
Affiliation(s)
- S Björck
- Department of Pediatrics, Skåne University Hospital, Malmö, Sweden; Unit of Diabetes and Celiac Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | | | | | | |
Collapse
|