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Schirru E, Rossino R, Jores RD, Corpino M, Muntoni S, Cucca F, Congia M. Clinical settings in which human leukocyte antigen typing is still useful in the diagnosis of celiac disease. World J Gastroenterol 2025; 31:104397. [PMID: 40248378 PMCID: PMC12001201 DOI: 10.3748/wjg.v31.i14.104397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/01/2025] [Accepted: 03/21/2025] [Indexed: 04/11/2025] Open
Abstract
Celiac disease (CD) is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals. It is characterized by intestinal histological damage and the production of specific autoantibodies. The latest European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2020 guidelines have excluded human leukocyte antigen (HLA) genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value, limited availability, and high cost in some countries. However, HLA genetic testing remains valuable in certain clinical contexts. This study provided practical indications for when to request and how to interpret HLA genotyping, emphasizing its continued relevance for CD diagnosis in specific cases. We also proposed a strategy for monitoring the risk of developing type 1 diabetes (T1D) in patients with CD, based on the risk stratification carried by different HLA genotypes. A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in 2012, when HLA genotyping became mandatory for the diagnosis of CD. We identified key clinical scenarios where HLA testing remains useful. Several high risk HLA-DQ genotypes strongly associated with CD were highlighted, including HLA-DQ2.5/HLA-DQ2.2 and HLA-DQ2.5/HLA-DQ2.5. Notably, while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD, it appears to confer protection against T1D. To support clinical practice, we presented a table clarifying commonly used HLA terminology, and another summarized the main clinical situations in which HLA genotyping should still be considered. These findings underscore the dual role of HLA testing: Not only can it help rule out CD in selected cases, but it also identifies patients with CD at risk for T1D, guiding personalized monitoring strategies.
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Affiliation(s)
- Enrico Schirru
- University Service Center for Animal Facility (CeSASt), University of Cagliari, Monserrato 09042, Sardinia, Italy
| | - Rossano Rossino
- Department of Medical Science and Public Health, University of Cagliari, Monserrato 09042, Sardegna, Italy
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
| | - Rita D Jores
- Department Outpatient Clinic, ASL8 Outpatient Clinic, Quartu Sant’Elena 09045, Sardegna, Italy
| | - Mara Corpino
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
| | - Sandro Muntoni
- Department of Biomedical Science, University of Cagliari, Monserrato 09042, Sardegna, Italy
| | - Francesco Cucca
- Department of Biomedical Science, University of Sassari, Sassari 07100, Sardegna, Italy
| | - Mauro Congia
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
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Theoretical Framework for the Study of Genetic Diseases Caused by Dominant Alleles. Life (Basel) 2023; 13:life13030733. [PMID: 36983888 PMCID: PMC10056381 DOI: 10.3390/life13030733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/08/2023] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
We propose a theoretical basis for analyzing several features of genetic diseases caused by dominant alleles, including: disease prevalence, genotype penetrance, and the relationship between causal genotype frequency and disease frequency. In addition, we provide a theoretical framework for accurate diagnosis and clinical approaches for disease study, including two examples in which inaccurate and incomplete diagnoses affect the estimates of disease prevalence: First, the disease iceberg effect shows that disease prevalence is often underestimated due to errors introduced by inaccurate diagnosis; second, because lifetime risk of disease is cumulative, and therefore an increasing function of age, measurements of prevalence are inaccurate if people of all ages are not included. Finally, we discuss the aggregation of genetic diseases. We identify theoretical and computational deficiencies associated with using the sibling recurrence-risk ratio as a measure of familial aggregation. We develop an alternative concept of aggregation and propose an associated measure that does not experience the deficiencies. Throughout, we provide clinicians and researchers practical implications of our theoretical framework.
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3
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Inflammatory auto-immune diseases of the intestine and their management by natural bioactive compounds. Biomed Pharmacother 2022; 151:113158. [PMID: 35644116 DOI: 10.1016/j.biopha.2022.113158] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 11/20/2022] Open
Abstract
Autoimmune diseases are caused by the overactivity of the immune system towards self-constituents. Risk factors of autoimmune diseases are multiple and include genetic, epigenetic, environmental, and psychological. Autoimmune chronic inflammatory bowel diseases, including celiac and inflammatory diseases (Crohn's disease and ulcerative colitis), constitute a significant health problem worldwide. Besides the complexity of the symptoms of these diseases, their treatments have only been palliative. Numerous investigations showed that natural phytochemicals could be promising strategies to fight against these autoimmune diseases. In this respect, plant-derived natural compounds such as flavonoids, phenolic acids, and terpenoids exhibited significant effects against three autoimmune diseases affecting the intestine, particularly bowel diseases. This review focuses on the role of natural compounds obtained from medicinal plants in modulating inflammatory auto-immune diseases of the intestine. It covers the most recent literature related to the effect of these natural compounds in the treatment and prevention of auto-immune diseases of the intestine.
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Horton RK, Hagen CE, Snyder MR. Pediatric Celiac Disease: A Review of Diagnostic Testing and Guideline Recommendations. J Appl Lab Med 2022; 7:294-304. [PMID: 34996069 DOI: 10.1093/jalm/jfab143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022]
Abstract
BACKGROUND The history of how our knowledge of celiac disease (CD) evolved points to its importance in children. Although it is now appreciated that CD can present at any age, it was originally thought to occur only in children and, if untreated, led to serious consequences. CONTENT This review includes a brief discussion of small bowel physiology and the pathogenesis of CD. Next, the varied clinical presentations of CD in children are reviewed, including both gastrointestinal and nongastrointestinal manifestations and how these contribute to the difficulty in diagnosis. In addition, information on specific conditions that are associated with CD is presented, particularly as it applies to diagnostic testing of apparently asymptomatic children. The review will also focus on diagnostic testing available for CD and their general performance characteristics. The review will end with a comparison between published guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition for diagnosis of pediatric CD. In particular, this review will focus on differences in the incorporation of serologic and genetic testing, and the role of biopsies in the pediatric population. SUMMARY It is important for laboratorians to understand the evolution of diagnostic guidelines for pediatric CD and how serologic and genetic testing are being applied to and interpreted in this particular patient group.
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Affiliation(s)
- Rachel K Horton
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Catherine E Hagen
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Melissa R Snyder
- Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
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Associations Between Subclass Profile of IgG Response to Gluten and the Gastrointestinal and Motor Symptoms in Children With Cerebral Palsy. J Pediatr Gastroenterol Nutr 2021; 73:367-375. [PMID: 34231978 PMCID: PMC8380641 DOI: 10.1097/mpg.0000000000003181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Gastrointestinal problems are often seen in children with cerebral palsy, although the etiology and underlying mechanisms are not fully understood. Recent data point to significantly elevated levels of IgG antibody to dietary gluten in cerebral palsy independent of celiac disease, a gluten-mediated autoimmune enteropathy. We aimed to further characterize this antibody response by examining its subclass distribution and target reactivity in the context of relevant patient symptom profile. METHODS Study participants included children with cerebral palsy (n = 70) and celiac disease (n = 85), as well as unaffected controls (n = 30). Serum IgG antibody to gluten was investigated for subclass distribution, pattern of reactivity towards target proteins, and relationship with gastrointestinal symptoms and motor function. RESULTS The anti-gluten IgG antibody response in the cerebral palsy cohort was constituted of all 4 subclasses. In comparison with celiac disease, however, IgG1, IgG2, and IgG3 subclasses were significantly lower, whereas the IgG4 response was significantly higher in cerebral palsy. Within the cohort of cerebral palsy patients, levels of anti-gluten IgG1, IgG3, and IgG4 were greater in those with gastrointestinal symptoms, and the IgG3 subclass antibody correlated inversely with gross motor function. The anti-gluten IgG antibodies targeted a broad range of gliadin and glutenin proteins. CONCLUSIONS These findings reveal an anti-gluten IgG subclass distribution in cerebral palsy that is significantly different from that in celiac disease. Furthermore, the observed association between IgG subclass and symptom profile is suggestive of a relationship between the immune response and disease pathophysiology that may indicate a role for defects in gut immune and barrier function in cerebral palsy.
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6
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Jang S, Lebwohl B, Abrams JA, Green PH, Freedberg DE, Alaedini A. Celiac disease serology and gut microbiome following proton pump inhibitor treatment. Medicine (Baltimore) 2020; 99:e21488. [PMID: 32871870 PMCID: PMC7458245 DOI: 10.1097/md.0000000000021488] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Celiac disease is an autoimmune enteropathy characterized by an aberrant immune response to ingested gluten in genetically predisposed individuals. Studies have pointed to a rising prevalence of celiac disease in recent decades. Changes in diet and use of medication that may impact the gut microbiome have been suggested as potential contributors. Exposure to proton pump inhibitors (PPIs) was recently found to be associated with an increased risk for subsequent diagnosis of celiac disease. We aimed to investigate potential mechanisms for this link by examining the relationship between PPI use and gluten-related immune responses in the context of changes in gut microbiome. METHODS We performed a post hoc analysis of blood and fecal samples from a recent randomized trial in order to assess the potential association between PPI use and development of celiac disease serology in conjunction with alterations in gastrointestinal microbial composition. The study included 12 healthy participants who were administered a PPI (Omeprazole; 40 mg twice daily) for 4 or 8 weeks. RESULTS The analysis did not reveal an overall significant change in levels of serologic markers of celiac disease for the study cohort in response to PPI treatment. However, one individual developed a marked increase in the celiac disease-specific autoantibody response to transglutaminase 2 in conjunction with enhanced immune reactivity to gluten during the trial. Genotyping revealed positivity for the celiac disease-associated HLA-DQ2 and -DQ8 alleles. Furthermore, the observed elevation in antibody responses was closely associated with a sharp increase in fecal abundance of bacteria of the order Actinomycetales. CONCLUSIONS The results of this exploratory analysis support further investigation of molecular mechanisms involved in the contribution of PPIs to celiac disease risk through the potential enhancement of gluten immunopathology and changes in gut microbial population.
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Affiliation(s)
- Sophie Jang
- Department of Medicine
- Institute of Human Nutrition
| | - Benjamin Lebwohl
- Department of Medicine
- Celiac Disease Center
- Department of Epidemiology, Columbia University Irving Medical Center
| | - Julian A. Abrams
- Department of Medicine
- Department of Epidemiology, Columbia University Irving Medical Center
| | | | | | - Armin Alaedini
- Department of Medicine
- Institute of Human Nutrition
- Celiac Disease Center
- Department of Medicine, New York Medical College, Valhalla, New York
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Escudero-Hernández C, Martín Á, de Pedro Andrés R, Fernández-Salazar L, Garrote JA, Bernardo D, Arranz E. Circulating Dendritic Cells from Celiac Disease Patients Display a Gut-Homing Profile and are Differentially Modulated by Different Gliadin-Derived Peptides. Mol Nutr Food Res 2020; 64:e1900989. [PMID: 31970917 DOI: 10.1002/mnfr.201900989] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 12/11/2019] [Indexed: 12/27/2022]
Abstract
SCOPE Circulating dendritic cell (DC) and monocyte subsets contribute to the pool of intestinal DC and macrophages in celiac disease (CeD), an autoimmune gut disorder triggered by dietary gluten. Here, this study aims to characterize these circulating subsets in CeD and assess the effect of different gliadin-derived peptides on conventional DC (cDC). METHODS AND RESULTS Flow cytometry profiling of peripheral blood mononuclear cells reveals a slight decrease in the proportion of plasmacytoid and type 1 cDC in gluten-free diet (GFD)-treated CeD patients. In comparison to healthy donors, DC and monocyte subsets from active and GFD-treated CeD patients display an increased gut-homing profile. Type 2 cDC (cDC2) are sorted and stimulated with the gliadin-derived peptides 8-mer, 19-mer, and 33-mer. All peptides induce cDC2 maturation, although the profile is different. While peptide 8-mer induces a Th1/Th17 pro-inflammatory cytokine profile in active CeD patients, cDC2 primed with peptide 33-mer displays a higher capacity to promote gut-homing CCR9+ expression onto autologous T-cells. CONCLUSION Distinct gliadin-derived peptides elicit different effects on cDC2 phenotype and function. This effect is compatible with a model where diverse gliadin peptides may cooperate to promote full cDC2 activation and the subsequent T-cell response in genetically predisposed individuals.
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Affiliation(s)
- Celia Escudero-Hernández
- Mucosal Immunology Laboratory, Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain.,Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Álvaro Martín
- Flow Cytometry facility. Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain
| | - Rodrigo de Pedro Andrés
- Mucosal Immunology Laboratory, Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain
| | - Luis Fernández-Salazar
- Digestive Disease Unit, Hospital Clínico Universitario de Valladolid, Avda Ramón y Cajal 3, 47003, Valladolid, Spain
| | - José Antonio Garrote
- Mucosal Immunology Laboratory, Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain.,Laboratory of Molecular Genetics, Hospital Universitario Río Hortega, C/ Dulzaina 2, 47012, Valladolid, Spain
| | - David Bernardo
- Mucosal Immunology Laboratory, Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain
| | - Eduardo Arranz
- Mucosal Immunology Laboratory, Instituto de Biología y Genética Molecular (IBGM), University of Valladolid-CSIC, C/ Sanz y Forés 3, 47003, Valladolid, Spain
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Clemente E, Efthymakis K, Carletti E, Capone V, Sperduti S, Bologna G, Marchisio M, Di Nicola M, Neri M, Sallese M. An explorative study identifies miRNA signatures for the diagnosis of non-celiac wheat sensitivity. PLoS One 2019; 14:e0226478. [PMID: 31834915 PMCID: PMC6910677 DOI: 10.1371/journal.pone.0226478] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023] Open
Abstract
Non-celiac wheat sensitivity (NCWS), also referred to as non-celiac gluten sensitivity, is a recently described disorder triggered by wheat/gluten ingestion. NCWS elicits a wide range of symptoms including diarrhoea, intestinal discomfort, and fatigue in analogy with other wheat/gluten-related disorders and celiac disease in particular. From the pathological standpoint, NCWS patients only have a slight increase of intraepithelial lymphocytes, while antibodies to tissue transglutaminase (tTG) and villous atrophy, otherwise diagnostic features of celiac disease, are absent. To date, the diagnosis of NCWS relies on symptoms and exclusion of confounding diseases, since biomarkers are not yet available. Here, the expression levels of selected miRNAs were examined in duodenal biopsies and peripheral blood leukocytes collected from newly diagnosed patients with NCWS and, as controls, from patients with celiac disease and gluten-independent gastrointestinal problems. We identified a few miRNAs whose expression is higher in the intestinal mucosa of patients affected by NCWS in comparison to control patients affect by gluten-independent dyspeptic symptoms (Helicobacter pylori-negative) and celiac disease. The present study provided the first evidence that NCWS patients have a characteristic miRNA expression patterns, such peculiarity could be exploited as a biomarker to the diagnosis of this disease.
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Affiliation(s)
- Emanuela Clemente
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Konstantinos Efthymakis
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Ageing Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
| | - Erminia Carletti
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Vanessa Capone
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Samantha Sperduti
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Giuseppina Bologna
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Ageing Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
| | - Marco Marchisio
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Ageing Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
| | - Marta Di Nicola
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
| | - Matteo Neri
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
- Department of Medicine and Ageing Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- * E-mail: (MS); (MN)
| | - Michele Sallese
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti–Pescara, Chieti, Italy
- Centre for Advanced Studies and Technology (CAST), “G. d'Annunzio” University of Chieti-Pescara, Chieti, Italy
- * E-mail: (MS); (MN)
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9
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Haghbin M, Rostami-Nejad M, Forouzesh F, Sadeghi A, Rostami K, Aghamohammadi E, Asadzadeh-Aghdaei H, Masotti A, Zali MR. The role of CXCR3 and its ligands CXCL10 and CXCL11 in the pathogenesis of celiac disease. Medicine (Baltimore) 2019; 98:e15949. [PMID: 31232926 PMCID: PMC6636963 DOI: 10.1097/md.0000000000015949] [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] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 03/30/2019] [Accepted: 05/15/2019] [Indexed: 01/28/2023] Open
Abstract
The chemokine receptor CXCR3 and its ligands CXCL10 and CXCL11 have been suggested to give rise to the most relevant chemokine axis able to facilitate the entrance of immune cells into inflamed tissues and be activated in different inflammatory disorders, such as celiac disease (CD).The aim of this study was to investigate the expression level of CXCR3, CXCL10, and CXCL11 genes in celiac patients compared to healthy controls. Both cohorts have been recruited from the Iranian population.In this case-control study, biopsy specimens were collected from 71 celiac patients (60.5% female) and 90 control subjects (57% female) during 2016. Total RNA was extracted and mRNA expression levels of CXCR3, CXCL10, and CXCL11 genes were investigated by SYBR green qPCR.Based on qPCR and relative quantification method, the mRNA expression levels of CXCR3, CXCL10, and CXCL11 were significantly higher in duodenal biopsies of celiac patients compared to healthy controls in the study population (P = .038, P = .021, and P = .012 respectively).The result of this study showed that CXCR3/CXCL10/CXCL11 signaling axis is overexpressed in the small intestinal mucosa of CD patients compared to controls. This finding might explain the specific enrollment of the main cell populations that infiltrate the epithelium.
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Affiliation(s)
- Mahrokh Haghbin
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Flora Forouzesh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamran Rostami
- Department of Gastroenterology MidCentral District Health Board, Palmerston North Hospital, New Zealand
| | - Elham Aghamohammadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andrea Masotti
- Bambino Gesù Children's Hospital-IRCCS, Research Laboratories, Rome, Italy
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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10
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Del Prete E, Facchiano A, Liò P. Bioinformatics methodologies for coeliac disease and its comorbidities. Brief Bioinform 2018; 21:355-367. [PMID: 30452543 DOI: 10.1093/bib/bby109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/01/2018] [Accepted: 10/11/2018] [Indexed: 12/30/2022] Open
Abstract
Coeliac disease (CD) is a complex, multifactorial pathology caused by different factors, such as nutrition, immunological response and genetic factors. Many autoimmune diseases are comorbidities for CD, and a comprehensive and integrated analysis with bioinformatics approaches can help in evaluating the interconnections among all the selected pathologies. We first performed a detailed survey of gene expression data available in public repositories on CD and less commonly considered comorbidities. Then we developed an innovative pipeline that integrates gene expression, cell-type data and online resources (e.g. a list of comorbidities from the literature), using bioinformatics methods such as gene set enrichment analysis and semantic similarity. Our pipeline is written in R language, available at the following link: http://bioinformatica.isa.cnr.it/COELIAC_DISEASE/SCRIPTS/. We found a list of common differential expressed genes, gene ontology terms and pathways among CD and comorbidities and the closeness among the selected pathologies by means of disease ontology terms. Physicians and other researchers, such as molecular biologists, systems biologists and pharmacologists can use it to analyze pathology in detail, from differential expressed genes to ontologies, performing a comparison with the pathology comorbidities or with other diseases.
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Affiliation(s)
- Eugenio Del Prete
- Department of Sciences, University of Basilicata,Via dell'Ateneo Lucano, Potenza, Italy.,National Research Council, Institute of Food Science (CNR-ISA),Via Roma 64, Avellino, Italy.,Computer Laboratory, University of Cambridge, JJ Thomson Ave., Cambridge, UK
| | - Angelo Facchiano
- National Research Council, Institute of Food Science (CNR-ISA),Via Roma 64, Avellino, Italy
| | - Pietro Liò
- Computer Laboratory, University of Cambridge, JJ Thomson Ave., Cambridge, UK
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11
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Savvateeva LV, Erdes SI, Antishin AS, Zamyatnin AA. Current Paediatric Coeliac Disease Screening Strategies and Relevance of Questionnaire Survey. Int Arch Allergy Immunol 2018; 177:370-380. [PMID: 30056445 DOI: 10.1159/000491496] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 06/25/2018] [Indexed: 12/12/2022] Open
Abstract
Coeliac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in genetically predisposed individuals. Identification of CD in clinical practice is often difficult due to the manifestation of non-specific symptoms and signs, so a relatively significant proportion of CD cases remain undiagnosed. Timely detection of the disease is necessary to provide an appropriate approach to control of the disease treatment, in order to avoid potential complications. This is even more important in the case of children and adolescents, to ensure their proper growth and development. In this review, we discuss the data on the current strategies for CD detection among paediatric populations and the role of questionnaire-based discovery of CD cases in the area of interest. We assume that mass screening is a preferable strategy for finding CD cases within the paediatric population because this could uncover symptomatic, oligosymptomatic, and asymptomatic CD cases. However, under conditions of limited financial resources, screening for CD in risk groups, members of which can be identified using questionnaires, is essential. The pros and cons of CD screening in paediatric populations are presented. These depend on a number of situational criteria (cost-effectiveness, lack of awareness), but screening is designed to improve the detection of the disease and therefore improve the quality of life of patients.
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Affiliation(s)
- Lyudmila V Savvateeva
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Svetlana I Erdes
- Faculty of Pediatrics, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Anton S Antishin
- Faculty of Pediatrics, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian .,Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian
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12
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Almeida FC, Gandolfi L, Costa KN, Picanço MRA, Almeida LM, Nóbrega YKM, Pratesi R, Pratesi CB, Selleski N. Frequency of HLA-DQ, susceptibility genotypes for celiac disease, in Brazilian newborns. Mol Genet Genomic Med 2018; 6:779-784. [PMID: 30014583 PMCID: PMC6160714 DOI: 10.1002/mgg3.444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/23/2018] [Accepted: 06/12/2018] [Indexed: 12/20/2022] Open
Abstract
Background The frequency of HLA‐DQ2 and DQ8 predisposing genotypes for celiac disease (CD) has shown significant variation among different world regions and has not been previously determined among the highly interbred Brazilian population. The aim of this study was to investigate the frequency of these genotypes among Brazilian newborns (NB). Methods We typed DQA1*05 ‐ DQB1*02 (DQ2.5) and DQA1*03 ‐ DQB1*03:02 (DQ8) alleles in 329 NB using qPCR technique. Subsequently we confirmed our results by PCR‐SSP using a reference kit which further identified DQ2.2 (DQA1*02:01 ‐ DQB1*02). Results Among the 329 NB, using qPCR technique: 5 (1.52%) carried both DQ2.5 and DQ8 variants; 58 (17.63%) carried only DQ2.5 (DQA1*05 and DQB1*02) and 47 (14.29%) carried only the DQ8 (DQA1*03 and DQB1*03:02) variant. The use of the PCR‐SSP method yielded further information; among the 329 samples: 34 (10.34%) tested positive for DQ2.2 and among the 47 previously DQ8 positives samples, we found 10 (3.04%) that also tested positives for DQ2.2. Conclusion 43.7% of the analyzed individual tested positive for at least one of the CD predisposing HLA‐DQ genotypes in our group of Brazilian NB. The highest frequency was found for DQ2.5 positive subjects (17.6%) followed by DQ8 (11.3%); DQ2.2 (10.3%); DQ8 and DQ2.2 (3.0%); DQ2.5 and DQ8 (1.5%). We found no positive sample for DQ2.5 associated with DQ2.2.
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Affiliation(s)
- Fernanda C Almeida
- Graduate Program in Medical Sciences, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Lenora Gandolfi
- Graduate Program in Medical Sciences, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, DF, Brazil.,Department of Pediatrics, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Karina N Costa
- Department of Pediatrics, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Marilucia R A Picanço
- Department of Pediatrics, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Lucas M Almeida
- Graduate Program in Medical Sciences, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Yanna K M Nóbrega
- Graduate Program in Medical Sciences, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brasilia, DF, Brazil
| | - Riccardo Pratesi
- Graduate Program in Medical Sciences, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, DF, Brazil.,Department of Pediatrics, School of Medicine, University of Brasilia, Brasilia, DF, Brazil
| | - Claudia B Pratesi
- Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, DF, Brazil
| | - Nicole Selleski
- Research Center for Celiac Disease, School of Medicine, University of Brasilia, Brasilia, DF, Brazil.,Graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, DF, Brazil
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14
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Thawani SP, Brannagan TH, Lebwohl B, Green PHR, Ludvigsson JF. Celiac disease and risk of myasthenia gravis - nationwide population-based study. BMC Neurol 2018; 18:28. [PMID: 29529996 PMCID: PMC5848580 DOI: 10.1186/s12883-018-1035-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/05/2018] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Case reports suggest there may be an association between celiac disease (CD) and myasthenia gravis (MG). METHODS We identified 29,086 individuals with CD in Sweden from 1969 to 2008. We compared these individuals with 144,480 matched controls. Hazard ratios (HRs) for future MG (identified through ICD codes) were estimated using Cox regression. RESULTS During 326,376 person-years of follow-up in CD patients, there were 7 MG cases (21/million person-years) compared to 22 MG cases in controls during 1,642,273 years of follow-up (14/million person-years) corresponding to a HR of 1.48 (95% CI = 0.64-3.41). HRs did not differ when stratifying for age, sex or calendar period. HRs were highest in the first year after follow-up, though insignificant. Individuals with CD were at no increased risk of MG more than 5 years after CD diagnosis (HR = 0.70; 95% CI = 0.16-3.09). CONCLUSION This study found no increased risk of MG in patients with CD.
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Affiliation(s)
- Sujata P Thawani
- Department of Neurology, New York University School of Medicine, New York, NY, USA
| | - Thomas H Brannagan
- Peripheral Neuropathy Center, Neurological Institute, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Benjamin Lebwohl
- Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Department Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Peter H R Green
- Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Jonas F Ludvigsson
- Department Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden.
- Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden.
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.
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15
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Dos Santos Domingues A, Selleski N, Uenishi RH, Medeiros Ribeiro de Magalhães C, Gandolfi L, Pratesi CB. The possible link between coeliac and Kawasaki diseases in Brazil: a cross-sectional study. BMJ Open 2018; 8:e018803. [PMID: 29444780 PMCID: PMC5829591 DOI: 10.1136/bmjopen-2017-018803] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Kawasaki disease (KD) is a self-limited acute systemic vasculitis of unknown aetiology that predominantly affects infants and young children eventually associated with immunological abnormalities. Coeliac disease (CD) is an inflammatory autoimmune disease characterised by a permanent gluten intolerance, which affects genetically susceptible individuals of any age group, and can cause intestinal and systemic symptoms. Association of CD with KD has been previously described in a single study that disclosed a surprisingly high prevalence of CD in children with a history of KD. OBJECTIVE To confirm the existence of a higher prevalence of CD among individuals with a history of KD, which would turn the screening for CD in patients with history of KD highly advisable. SETTING Children with history of KD, diagnosed and followed at the Rheumatology Clinic of the Children's Hospital of Brasilia (Brasilia, Brazil). PARTICIPANTS This study included 110 children with history of KD and a control group composed of 110 presumably healthy children. INTERVENTIONS Participants underwent anti-transglutaminase and anti-endomysial antibodies tests and genetic typing for the presence of CD predisposing alleles (HLA-DQ2 and DQ8). Jejunal biopsy was performed when necessary, according the European Society of Paediatric Gastroenterology, Hepatology and Nutrition guidelines. RESULTS Diagnosis of CD was confirmed in one (0.91%) patient with KD by positive serological tests, presence of predisposing alleles and CD typical lesions on duodenal biopsy. All serological tests were negative among the controls. The prevalence of CD predisposing alleles among patients with KD was 29.09%, similar to the prevalence found among controls, 33.64%. CONCLUSION The detected CD prevalence (0.91%) does not confirm the existence of an association between KD and CD since this prevalence is similar to that found in the general population (≃1%).
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Affiliation(s)
| | - Nicole Selleski
- Interdisciplinary Laboratory of Biosciences and Celiac Disease Research Center, School of Medicine, University of Brasilia, Brasilia, Brazil
- Post-graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, Brazil
| | - Rosa Harumi Uenishi
- Interdisciplinary Laboratory of Biosciences and Celiac Disease Research Center, School of Medicine, University of Brasilia, Brasilia, Brazil
- Post-graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, Brazil
| | | | - Lenora Gandolfi
- Interdisciplinary Laboratory of Biosciences and Celiac Disease Research Center, School of Medicine, University of Brasilia, Brasilia, Brazil
- Post-graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, Brazil
| | - Claudia B Pratesi
- Interdisciplinary Laboratory of Biosciences and Celiac Disease Research Center, School of Medicine, University of Brasilia, Brasilia, Brazil
- Post-graduate Program in Health Sciences, School of Health Sciences, University of Brasilia, Brasilia, Brazil
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Camerlengo F, Sestili F, Silvestri M, Colaprico G, Margiotta B, Ruggeri R, Lupi R, Masci S, Lafiandra D. Production and molecular characterization of bread wheat lines with reduced amount of α-type gliadins. BMC PLANT BIOLOGY 2017; 17:248. [PMID: 29258439 PMCID: PMC5738072 DOI: 10.1186/s12870-017-1211-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 12/08/2017] [Indexed: 05/24/2023]
Abstract
BACKGROUND Among wheat gluten proteins, the α-type gliadins are the major responsible for celiac disease, an autoimmune disorder that affects about 1% of the world population. In fact, these proteins contain several toxic and immunogenic epitopes that trigger the onset of the disease. The α-type gliadins are a multigene family, encoded by genes located at the complex Gli-2 loci. RESULTS Here, three bread wheat deletion lines (Gli-A2, Gli-D2 and Gli-A2/Gli-D2) at the Gli-2 loci were generated by the introgression in the bread wheat cultivar Pegaso of natural mutations, detected in different bread wheat cultivars. The molecular characterization of these lines allowed the isolation of 49 unique expressed genes coding α-type gliadins, that were assigned to each of the three Gli-2 loci. The number and the amount of α-type gliadin transcripts were drastically reduced in the deletion lines. In particular, the line Gli-A2/Gli-D2 contained only 12 active α-type gliadin genes (-75.6% respect to the cv. Pegaso) and a minor level of transcripts (-80% compared to cv. Pegaso). Compensatory pleiotropic effects were observed in the two other classes of gliadins (ω- and γ-gliadins) either at gene expression or protein levels. Although the comparative analysis of the deduced amino acid sequences highlighted the typical structural features of α-type gliadin proteins, substantial differences were displayed among the 49 proteins for the presence of toxic and immunogenic epitopes. CONCLUSION The deletion line Gli-A2/Gli-D2 did not contain the 33-mer peptide, one of the major epitopes triggering the celiac disease, representing an interesting material to develop less "toxic" wheat varieties.
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Affiliation(s)
- Francesco Camerlengo
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Francesco Sestili
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Marco Silvestri
- Institute of Biosciences and Bioresources, CNR, 70126 Bari, Italy
| | | | | | - Roberto Ruggeri
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Roberta Lupi
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Stefania Masci
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - Domenico Lafiandra
- Department of Agriculture and Forestry Sciences, University of Tuscia, 01100 Viterbo, Italy
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17
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Alaedini A, Lebwohl B, Wormser GP, Green PH, Ludvigsson JF. Borrelia infection and risk of celiac disease. BMC Med 2017; 15:169. [PMID: 28911326 PMCID: PMC5599869 DOI: 10.1186/s12916-017-0926-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 08/09/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease. METHODS Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease. RESULTS Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up. CONCLUSIONS Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease.
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Affiliation(s)
- Armin Alaedini
- Department of Medicine, Columbia University Medical Center, New York, NY, USA.
- Celiac Disease Center, Columbia University Medical Center, New York, NY, USA.
- Institute of Human Nutrition, Columbia University Medical Center, New York, NY, USA.
| | - Benjamin Lebwohl
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
- Celiac Disease Center, Columbia University Medical Center, New York, NY, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Gary P Wormser
- Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA
| | - Peter H Green
- Department of Medicine, Columbia University Medical Center, New York, NY, USA
- Celiac Disease Center, Columbia University Medical Center, New York, NY, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.
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Brietzke E, Cerqueira RO, Mansur RB, McIntyre RS. Gluten related illnesses and severe mental disorders: a comprehensive review. Neurosci Biobehav Rev 2017; 84:368-375. [PMID: 28830676 DOI: 10.1016/j.neubiorev.2017.08.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 08/02/2017] [Accepted: 08/14/2017] [Indexed: 12/22/2022]
Abstract
The putative role of gluten in the pathophysiology of severe mental illnesses remains uncertain and there is doubt about the possible benefit of gluten-free diets for individuals affected by psychosis and mood disorders. The objective of this review was to summarize the findings linking gluten related conditions to pathophysiological substrates implicated in schizophrenia and mood disorders and review the evidences of potential benefits of glute-free diets in these populations. A literature search was conducted within PubMed and Scielo databases including references from inception until March 1st 2017. The strategy search was to use the key words "gluten", "celiac disease", "wheat", "bipolar disorder", "mood disorders", "psychosis", "schizophrenia", "depression". In the review about the potential efficacy of gluten-free diets in severe mental illnesses, we included only studies with original data, including cross sectional and longitudinal studies and clinical trials. Book chapters, review articles and meta-analysis and republished data were excluded. Although the current available evidences suggest that people with celiac disease or gluten allergy could have a slightly higher risk of schizophrenia and mood disorders compared to the general population, the literature review reveals significant inaccuracies in the data. There is insufficient evidence to recommend gluten-free diets for populations with psychosis and mood disorders.
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Affiliation(s)
- Elisa Brietzke
- Research Group in Molecular and Behavioral Neuroscience of Bipolar Disorder, Federal University of São Paulo (Unifesp), São Paulo, Brazil; Mood Disorders Psychpharmachology Unit (MDPU), Toronto Western Hospital, University Health Network (UHN), University of Toronto, Toronto, Canada.
| | - Raphael O Cerqueira
- Research Group in Molecular and Behavioral Neuroscience of Bipolar Disorder, Federal University of São Paulo (Unifesp), São Paulo, Brazil
| | - Rodrigo B Mansur
- Mood Disorders Psychpharmachology Unit (MDPU), Toronto Western Hospital, University Health Network (UHN), University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada
| | - Roger S McIntyre
- Mood Disorders Psychpharmachology Unit (MDPU), Toronto Western Hospital, University Health Network (UHN), University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada
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Picascia S, Sidney J, Camarca A, Mazzarella G, Giardullo N, Greco L, Auricchio R, Auricchio S, Troncone R, Sette A, Gianfrani C. Gliadin-Specific CD8 + T Cell Responses Restricted by HLA Class I A*0101 and B*0801 Molecules in Celiac Disease Patients. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 198:1838-1845. [PMID: 28148736 DOI: 10.4049/jimmunol.1601208] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 01/03/2017] [Indexed: 12/20/2022]
Abstract
Initial studies associated the HLA class I A*01 and B*08 alleles with celiac disease (CD) susceptibility. Subsequent analyses showed a primary association with HLA class II alleles encoding for the HLA DQ2.5 molecule. Because of the strong linkage disequilibrium of A*01 and B*08 alleles with the DR3-DQ2.5 haplotype and a recent genome-wide association study indicating that B*08 and B*39 are predisposing genes, the etiologic role of HLA class I in CD pathogenesis needs to be addressed. We screened gliadin proteins (2α-, 2ω-, and 2γ-gliadin) using bioinformatic algorithms for the presence of peptides predicted to bind A*0101 and B*0801 molecules. The top 1% scoring 9- and 10-mer peptides (N = 97, total) were synthesized and tested in binding assays using purified A*0101 and B*0801 molecules. Twenty of ninety-seven peptides bound B*0801 and only 3 of 97 bound A*0101 with high affinity (IC50 < 500 nM). These 23 gliadin peptides were next assayed by IFN-γ ELISPOT for recognition in peripheral blood cells of CD patients and healthy controls carrying the A*0101 and/or B*0801 genes and in A*0101/B*0801- CD patients. Ten of the twenty-three peptides assayed recalled IFN-γ responses mediated by CD8+ T cells in A*0101/B*0801+ patients with CD. Two peptides were restricted by A*0101, and eight were restricted by B*0801. Of note, 50% (5/10) of CD8+ T cell epitopes mapped within the γ-gliadins. Our results highlight the value of predicted binding to HLA molecules for identifying gliadin epitopes and demonstrate that HLA class I molecules restrict the anti-gluten T cell response in CD patients.
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Affiliation(s)
- Stefania Picascia
- Institute of Protein Biochemistry-National Research Council, 80131 Naples, Italy
| | - John Sidney
- La Jolla Institute for Allergy and Immunology, La Jolla, CA 92130
| | - Alessandra Camarca
- Institute of Food Sciences-National Research Council, 83100 Avellino, Italy
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
| | | | | | - Luigi Greco
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
| | - Renata Auricchio
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
| | - Salvatore Auricchio
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
| | - Riccardo Troncone
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
| | - Alessandro Sette
- La Jolla Institute for Allergy and Immunology, La Jolla, CA 92130
| | - Carmen Gianfrani
- Institute of Protein Biochemistry-National Research Council, 80131 Naples, Italy;
- Department of Translational Medical Science and European Laboratory for Investigation and Food-Induced Diseases, University Federico II, 80131 Naples, Italy; and
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Overview of Celiac Disease in Russia: Regional Data and Estimated Prevalence. J Immunol Res 2017; 2017:2314813. [PMID: 28316996 PMCID: PMC5337843 DOI: 10.1155/2017/2314813] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/15/2017] [Accepted: 01/30/2017] [Indexed: 02/07/2023] Open
Abstract
Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of dietary gluten from some cereals mainly in individuals carrying the HLA-DQ2 and/or HLA-DQ8 haplotypes. As an autoimmune disease, CD is manifested in the small intestine in the form of a progressive and reversible inflammatory lesion due to immune response to self-antigens. Indeed, CD is one of the most challenging medicosocial problems in current gastroenterology. At present, the global CD prevalence is estimated at approximately 1% based on data sent from different locations and available CD screening strategies used. However, it is impossible to estimate global CD prevalence without all the data from the world, including Russia. In this review, we summarize the data on the incidence and prevalence of CD across geographically distinct regions of Russia, which are mostly present in local Russian scientific sources. Our conclusion is that the situation of CD prevalence in Russia is higher than is commonly believed and follows global tendencies that correspond to the epidemiologic situation in Europe, America, and Southwest Asia.
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Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, Verna EC, Volta U, Alaedini A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 2016; 65:1930-1937. [PMID: 27459152 PMCID: PMC5136710 DOI: 10.1136/gutjnl-2016-311964] [Citation(s) in RCA: 169] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/09/2016] [Accepted: 06/20/2016] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. DESIGN Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. RESULTS Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. CONCLUSIONS These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.
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Affiliation(s)
- Melanie Uhde
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Mary Ajamian
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Giacomo Caio
- Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Roberto De Giorgio
- Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Alyssa Indart
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Peter H Green
- Department of Medicine, Columbia University Medical Center, New York, New York, USA,CeliacDisease Center, Columbia University Medical Center, New York, New York, USA
| | - Elizabeth C Verna
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Umberto Volta
- Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Armin Alaedini
- Department of Medicine, Columbia University Medical Center, New York, New York, USA,CeliacDisease Center, Columbia University Medical Center, New York, New York, USA,Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA
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Singla S, Kumar P, Singh P, Kaur G, Rohtagi A, Choudhury M. HLA Profile of Celiac Disease among First-Degree Relatives from a Tertiary Care Center in North India. Indian J Pediatr 2016; 83:1248-1252. [PMID: 27264101 DOI: 10.1007/s12098-016-2146-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 05/05/2016] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To study the prevalence of Celiac disease (CD) in first-degree relatives (FDR) of CD children. METHODS This observational study was performed in FDR (parents and siblings) of consecutive newly diagnosed cases of CD enrolled from January 2011 through March 2012. Screening for CD in FDR was done using IgA tissue transglutaminase (tTG) levels in serum and the seropositive subset underwent upper gastrointestinal (UGI) endoscopy and biopsy to confirm the disease. In addition, HLA analysis for CD was performed in most of the index cases and FDR. RESULTS Of 202 FDR of the 64 index cases with CD, 17.3 % (35/202) were seropositive for IgA tTG while confirmed biopsy proven CD was diagnosed in 10.2 % (8/78) of children and 8.1 % (10/124) of adults. HLA DQ2/DQ8 was positive in 96.7 % of the index cases and all FDR with confirmed CD. CONCLUSIONS The prevalence of CD among FDR is 9 fold higher than the general population. High prevalence of CD in presence of anemia and short stature in seropositive FDR in index study indicates need of targeted screening of this subgroup for the presence of CD.CD is unlikely in the absence of HLADQ2/DQ8.
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Affiliation(s)
- Shilpy Singla
- Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, 110001, India
| | - Praveen Kumar
- Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, 110001, India.
| | - Preeti Singh
- Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, 110001, India
| | - Gurvinder Kaur
- Department of Transplant Immunology & Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Anurag Rohtagi
- Department of Medicine, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
| | - Monisha Choudhury
- Department of Pathology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
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23
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Francavilla R, Castellaneta S. Inverting the Diagnostic Pyramid in Celiac Disease: HLA Typing for Screening Suspects of Celiac Disease. J Pediatr Gastroenterol Nutr 2016; 63:e20. [PMID: 26863387 DOI: 10.1097/mpg.0000000000001162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Ruggiero Francavilla
- *Interdisciplinary Department of Medicine-Pediatric Section, University of Bari†Department of Pediatrics, San Paolo Hospital, Bari, Italy
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24
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Smigoc Schweiger D, Mendez A, Kunilo Jamnik S, Bratanic N, Bratina N, Battelino T, Brecelj J, Vidan-Jeras B. High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease. Autoimmunity 2016; 49:240-7. [PMID: 27138053 DOI: 10.3109/08916934.2016.1164144] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Shared susceptibility alleles in the HLA region contribute to the co-existence of type 1 diabetes (T1D) and celiac disease (CD). The aim of our study was to identify HLA genotype variations that influence co-occurrence of T1D and CD (T1D + CD) and the order of their onset. Totally 244 patients, 67 with T1D, 68 with CD and 69 with T1D + CD, (split into "T1D first" and "CD first"), were analyzed. Control group consisted of 130 healthy unrelated individuals. Two-tailed Fisher's exact test was used for statistical analysis. The genetic background of Slovenian CD patients resembled more northern than southern European populations with DR3-DQ2/DR3-DQ2 (odds ratio [OR] = 19.68) conferring the highest risk. The T1D + CD was associated with DR3-DQ2/DR3-DQ2 (OR = 45.53) and even more with DR3-DQ2/DR4-DQ8 (OR = 93.76). DR3-DQ2/DR7-DQ2 played a neutral role in susceptibility for T1D + CD. The order of the onset of T1D or CD in patients with co-occurring diseases was not influenced by HLA risk genotype profile. DR3-DQ2/DR3-DQ2 was associated with an increased risk for developing CD in patients with T1D, whereas patients with CD carrying DR3-DQ2/DR4-DQ8 were at higher risk for developing T1D. In addition to other genetic factors including HLA class I alleles present on DR3-DQ2 extended haplotype, the second extended haplotype may moderate the risk for T1D + CD conferred by DR3-DQ2. Our results suggested that individuals carrying high-risk genotypes DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4-DQ8 would more likely develop both T1D and CD than either disease alone.
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Affiliation(s)
- Darja Smigoc Schweiger
- a Department of Pediatric Endocrinology , Diabetes and Metabolic Diseases, UMC - University Children's Hospital , Ljubljana , Slovenia
| | - Andrijana Mendez
- b Blood Transfusion Center of Slovenia, Tissue Typing Centre , Ljubljana , Slovenia
| | - Sabina Kunilo Jamnik
- b Blood Transfusion Center of Slovenia, Tissue Typing Centre , Ljubljana , Slovenia
| | - Nina Bratanic
- a Department of Pediatric Endocrinology , Diabetes and Metabolic Diseases, UMC - University Children's Hospital , Ljubljana , Slovenia
| | - Natasa Bratina
- a Department of Pediatric Endocrinology , Diabetes and Metabolic Diseases, UMC - University Children's Hospital , Ljubljana , Slovenia
| | - Tadej Battelino
- a Department of Pediatric Endocrinology , Diabetes and Metabolic Diseases, UMC - University Children's Hospital , Ljubljana , Slovenia .,c Faculty of Medicine , University of Ljubljana , Ljubljana , Slovenia , and
| | - Jernej Brecelj
- c Faculty of Medicine , University of Ljubljana , Ljubljana , Slovenia , and.,d Department of Gastroenterology , Hepatology and Nutrition, UMC - University Children's Hospital , Ljubljana , Slovenia
| | - Blanka Vidan-Jeras
- b Blood Transfusion Center of Slovenia, Tissue Typing Centre , Ljubljana , Slovenia
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25
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Mitchell RT, Sun A, Mayo A, Forgan M, Comrie A, Gillett PM. Coeliac screening in a Scottish cohort of children with type 1 diabetes mellitus: is DQ typing the way forward? Arch Dis Child 2016; 101:230-3. [PMID: 26718815 PMCID: PMC4789707 DOI: 10.1136/archdischild-2015-309754] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 11/23/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Children with type 1 diabetes mellitus (T1DM) are at increased risk of coeliac disease (CD). Recent guidelines indicate coeliac screening should include HLA typing for CD predisposing (DQ2/DQ8) alleles and those negative for these alleles require no further coeliac screening. METHODS Children (n=176) with T1DM attending clinics across two Scottish regions were screened for HLA DQ2/DQ8 as part of routine screening. Data collected included the frequency of DQ2/DQ8 genotypes and the additional cost of HLA screening. RESULTS Overall, DQ2/DQ8 alleles were identified in 94% of patients. The additional cost of HLA typing was £3699.52 (£21.02 per patient). All patients with known CD (11/176) were positive for DQ2/DQ8 and all were diagnosed with CD within 5 years of T1DM diagnosis. CONCLUSIONS The vast majority of children with T1DM have CD-predisposing HLA genotypes limiting the number of patients that can be excluded from further screening. We conclude that HLA genotyping is not currently indicated for CD screening in this population.
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Affiliation(s)
- R T Mitchell
- MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh,Edinburgh, UK,Departments of Paediatric Diabetes (RTM) and Paediatric Gastroenterology (PMG), Royal Hospital for Sick Children, Edinburgh, UK
| | - A Sun
- Departments of Paediatric Diabetes, Royal Aberdeen Children's Hospital, Aberdeen, UK
| | - A Mayo
- Departments of Paediatric Diabetes, Royal Aberdeen Children's Hospital, Aberdeen, UK
| | - M Forgan
- BTS Tissue Typing, Ninewells Hospital, Dundee, UK
| | - A Comrie
- BTS Tissue Typing, Ninewells Hospital, Dundee, UK
| | - P M Gillett
- Departments of Paediatric Diabetes (RTM) and Paediatric Gastroenterology (PMG), Royal Hospital for Sick Children, Edinburgh, UK
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26
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Abstract
PURPOSE OF REVIEW The duodenal biopsy is the gold standard for the diagnosis of celiac disease. However, given improvements in the performance of serological testing, the possibility of accurately diagnosing celiac disease without the need of a biopsy has attracted interest. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has revised its recommendations to include a diagnostic algorithm that includes sequential serological testing and human leukocyte antigen genotyping for symptomatic children which would enable a diagnosis of celiac disease to be made in the absence of a confirmatory intestinal biopsy. RECENT FINDINGS Recent studies have evaluated the ESPGHAN guidelines and have mostly corroborated that celiac disease can be accurately diagnosed in specific pediatric patient populations without the need of a biopsy. However, two cautionary points have been raised that warrant further consideration - the success of this approach is highly dependent targeting a population with a high pretest probability of celiac disease, as well, the performance of serology assays must be established and the appropriate use of cutoffs is essential. SUMMARY The duodenal biopsy will remain the gold standard for diagnosing celiac disease in a majority of patients. However, as serology assays evolve and as a greater understanding of the genetic risk factors of celiac disease is achieved, more patients may be accurately diagnosed without the need for a biopsy.
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27
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Zajacova M, Kotrbova-Kozak A, Cepek P, Cerna M. Differences in promoter DNA methylation and mRNA expression of individual alleles of the HLA class II DQA1 gene. Immunol Lett 2015; 167:147-54. [DOI: 10.1016/j.imlet.2015.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 08/07/2015] [Accepted: 08/12/2015] [Indexed: 12/11/2022]
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SELLESKI N, ALMEIDA LM, ALMEIDA FCD, GANDOLFI L, PRATESI R, NÓBREGA YKDM. SIMPLIFYING CELIAC DISEASE PREDISPOSING HLA-DQ ALLELES DETERMINATION BY THE REAL TIME PCR METHOD. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52:143-6. [DOI: 10.1590/s0004-28032015000200013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 10/23/2014] [Indexed: 11/22/2022]
Abstract
Background Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Genetic susceptibility is associated with two sets of alleles, DQA1*05 - DQB1*02 and DQA1*03 - DQB1*03:02, which code for class II MHC DQ2 and DQ8 molecules, respectively. Approximately 90%-95% of celiac patients are HLA-DQ2 positive, and half of the remaining patients are HLA-DQ8 positive. In fact, during a celiac disease diagnostic workup, the absence of these specific DQA and DQB alleles has a near perfect negative predictive value. Objective Improve the detection of celiac disease predisposing alleles by combining the simplicity and sensitivity of real-time PCR (qPCR) and melting curve analysis with the specificity of sequence-specific primers (SSP). Methods Amplifications of sequence-specific primers for DQA1*05 (DQ2), DQB1*02 (DQ2), and DQA1*03 (DQ8) were performed by the real time PCR method to determine the presence of each allele in independent reactions. Primers for Human Growth Hormone were used as an internal control. A parallel PCR-SSP protocol was used as a reference method to validate our results. Results Both techniques yielded equal results. From a total of 329 samples the presence of HLA predisposing alleles was determined in 187 (56.8%). One hundred fourteen samples (61%) were positive for a single allele, 68 (36.3%) for two alleles, and only 5 (2.7%) for three alleles. Conclusion Results obtained by qPCR technique were highly reliable with no discordant results when compared with those obtained using PCR-SSP.
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Affiliation(s)
- Nicole SELLESKI
- School of Health Sciences, Brazil; Universidade de Brasilia (UnB), Brazil
| | | | | | - Lenora GANDOLFI
- School of Health Sciences, Brazil; School of Medicine, Brazil; School of Medicine, Brazil; Universidade de Brasilia (UnB), Brazil
| | - Riccardo PRATESI
- School of Health Sciences, Brazil; School of Medicine, Brazil; School of Medicine, Brazil; Universidade de Brasilia (UnB), Brazil
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29
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Rubicz R, Yolken R, Alaedini A, Drigalenko E, Charlesworth JC, Carless MA, Severance EG, Krivogorsky B, Dyer TD, Kent JW, Curran JE, Johnson MP, Cole SA, Almasy L, Moses EK, Blangero J, Göring HHH. Genome-wide genetic and transcriptomic investigation of variation in antibody response to dietary antigens. Genet Epidemiol 2015; 38:439-46. [PMID: 24962563 DOI: 10.1002/gepi.21817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 04/24/2014] [Accepted: 04/24/2014] [Indexed: 11/11/2022]
Abstract
Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here, we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1,300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h(2) ), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (P = 8.57 × 10(-8) ), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with antigliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved.
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Affiliation(s)
- Rohina Rubicz
- Departent of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America; Division of Public Health Sciences, Fred Hutchinson Cancer Research Institute, Seattle, Washington, United States of America
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30
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Leonard MM, Serena G, Sturgeon C, Fasano A. Genetics and celiac disease: the importance of screening. Expert Rev Gastroenterol Hepatol 2015; 9:209-15. [PMID: 25294637 DOI: 10.1586/17474124.2014.945915] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The prevalence of celiac disease (CD) is increasing. Despite an increased awareness and an improvement in diagnostic testing, the majority of individuals with CD remain undiagnosed. Currently, genetic testing in screening for CD is used only to exclude a diagnosis or reinforce a strong clinical suspicion. In this paper, we review the most current literature regarding genetic testing in CD. In response to important data revealing that an individual's HLA haplotype is one of the strongest known predictors of CD, we propose genetic screening for at-risk infants to stratify individuals based on genetic risk to ultimately create genetic specific screening algorithms.
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Affiliation(s)
- Maureen M Leonard
- Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, 165 Cambridge St, Boston MA 02111, USA
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31
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Abadie V, Jabri B. Immunopathology of Celiac Disease. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00080-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Interleukin-18 gene promoter polymorphisms and celiac disease in Italian patients. Mol Biol Rep 2014; 42:525-33. [PMID: 25374428 DOI: 10.1007/s11033-014-3796-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 10/14/2014] [Indexed: 01/05/2023]
Abstract
Celiac disease (CD) is the most common food-sensitive enteropathy in genetically susceptible individuals. The major genetic risk factors known are specific human leukocyte antigen (HLA)-DQ haplotypes, but other genetic factors are supposed to be involved. Interleukin-18 (IL-18) is a pro-inflammatory cytokine that has an important role in the immune defense and it has the potential to influence inflammatory disorders. IL-18 is able to promote Th1 cell development and it is expressed in the mucosa of the small intestine in celiac patients. Given the IL-18 biological role, and since a few studies have previously suggested its involvement in CD, in order to investigate the role of IL18 gene in the susceptibility to CD we have performed a case-control study, analyzing two IL18 gene promoter polymorphisms, previously reported to impair the transcriptional activity of the gene, (-137G > C and -607C > A, rs187238 and rs1946518 respectively). A total of 556 CD Italian patients and 582 controls, further stratified for HLA class II (DQ) CD risk haplotypes were enrolled. The -607A > C A allele and A/A genotype, as well as the combination of this allele with the -137G allele in the AG haplotype, were associated with an increased risk towards CD development, in particular in HLA-DQ2.2 patients. Although the association was very moderate, our results indicate the possible involvement of IL18 gene in the susceptibility to CD, and for this reason we do think it should deserve further investigation.
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Smigoc Schweiger D, Mendez A, Kunilo Jamnik S, Bratanic N, Bratina N, Battelino T, Brecelj J, Vidan-Jeras B. Genetic risk for co-occurrence of type 1 diabetes and celiac disease is modified by HLA-C and killer immunoglobulin-like receptors. ACTA ACUST UNITED AC 2014; 84:471-8. [DOI: 10.1111/tan.12450] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 09/06/2014] [Accepted: 09/12/2014] [Indexed: 01/13/2023]
Affiliation(s)
- D. Smigoc Schweiger
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases; University Medical Centre - University Children's Hospital; Ljubljana Slovenia
| | - A. Mendez
- Blood Transfusion Center of Slovenia; Tissue Typing Centre; Ljubljana Slovenia
| | - S. Kunilo Jamnik
- Blood Transfusion Center of Slovenia; Tissue Typing Centre; Ljubljana Slovenia
| | - N. Bratanic
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases; University Medical Centre - University Children's Hospital; Ljubljana Slovenia
| | - N. Bratina
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases; University Medical Centre - University Children's Hospital; Ljubljana Slovenia
| | - T. Battelino
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases; University Medical Centre - University Children's Hospital; Ljubljana Slovenia
- Faculty of Medicine; University of Ljubljana; Ljubljana Slovenia
| | - J. Brecelj
- Department of Gastroenterology, Hepatology and Nutrition; University Medical Centre - University Children's Hospital; Ljubljana Slovenia
| | - B. Vidan-Jeras
- Blood Transfusion Center of Slovenia; Tissue Typing Centre; Ljubljana Slovenia
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Moeller S, Canetta PA, Taylor AK, Arguelles-Grande C, Snyder H, Green PH, Kiryluk K, Alaedini A. Lack of serologic evidence to link IgA nephropathy with celiac disease or immune reactivity to gluten. PLoS One 2014; 9:e94677. [PMID: 24732864 PMCID: PMC3986214 DOI: 10.1371/journal.pone.0094677] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 03/18/2014] [Indexed: 12/21/2022] Open
Abstract
IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infections and food antigens, including wheat gluten, have been proposed as potential contributing environmental factors. Increased immune reactivity to gluten and/or association with celiac disease, an autoimmune disorder triggered by ingestion of gluten, have been reported in IgA nephropathy. However, studies are inconsistent about this association. We aimed to evaluate the proposed link between IgA nephropathy and celiac disease or immune reactivity to gluten by conducting a comprehensive analysis of associated serologic markers in cohorts of well-characterized patients and controls. Study participants included patients with biopsy-proven IgA nephropathy (n = 99), unaffected controls of similar age, gender, and race (n = 96), and patients with biopsy-proven celiac disease (n = 30). All serum specimens were tested for IgG and IgA antibodies to native gliadin and deamidated gliadin, as well as IgA antibody to transglutaminase 2 (TG2). Anti-TG2 antibody-positive nephropathy patients and unaffected controls were subsequently tested for IgA anti-endomysial antibody and genotyped for celiac disease-associated HLA-DQ2 and -DQ8 alleles. In comparison to unaffected controls, there was not a statistically significant increase in IgA or IgG antibody reactivity to gliadin in individuals with IgA nephropathy. In addition, the levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between IgA nephropathy patients and unaffected controls. Results of the additional anti-endomysial antibody testing and HLA genotyping were corroborative. The data from this case-control study do not reveal any evidence to suggest a significant role for celiac disease or immune reactivity to gluten in IgA nephropathy.
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Affiliation(s)
- Sina Moeller
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
- Celiac Disease Center, Columbia University Medical Center, New York, New York, United States of America
| | - Pietro A. Canetta
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
| | - Annette K. Taylor
- Esoterix, Inc., Laboratory Corporation of America Holdings, Englewood, Colorado, United States of America
| | - Carolina Arguelles-Grande
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
- Celiac Disease Center, Columbia University Medical Center, New York, New York, United States of America
| | - Holly Snyder
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
| | - Peter H. Green
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
- Celiac Disease Center, Columbia University Medical Center, New York, New York, United States of America
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
| | - Armin Alaedini
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
- Celiac Disease Center, Columbia University Medical Center, New York, New York, United States of America
- Institute of Human Nutrition, Columbia University Medical Center, New York, New York, United States of America
- * E-mail:
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35
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Castillo NE, Leffler DA. Celiac Disease as a Model Disorder for Testing Novel Autoimmune Therapeutics. THE VALUE OF BCG AND TNF IN AUTOIMMUNITY 2014:126-139. [DOI: 10.1016/b978-0-12-799964-7.00008-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Romanos J, Rybak A, Wijmenga C, Wapenaar MC. Molecular diagnosis of celiac disease: are we there yet? ACTA ACUST UNITED AC 2013; 2:399-416. [PMID: 23495707 DOI: 10.1517/17530059.2.4.399] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Celiac disease (CD) is a complex genetic disorder of the small intestine resulting from aberrant cellular responses to gluten peptides. It may affect as much as 1% of the Western population and the only treatment is a lifelong gluten-free diet. Allelic variants of the HLA-DQ locus, coding for the HLA-DQ2 and HLA-DQ8 molecules, contribute to ∼ 40% of CD etiology, whereas other genes, such as MYO9B, CTLA4, IL2, IL21, PARD3 and MAGI2, have only a modest effect. Most of these genes have shown varied association among different populations and an overlap with other autoimmune or inflammatory disorders, indicating that such disorders may share common pathways. OBJECTIVES In this review, a molecular approach into diagnostics of celiac disease is shown. CONCLUSIONS Genome-wide association studies will allow more genes to be identified, and knowing how risk variants combine will help to predict better the risk for the individual. HLA typing can already be used to identify high-risk individuals.
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Affiliation(s)
- Jihane Romanos
- PhD student University of Groningen, University Medical Center Groningen, Department of Genetics, PO Box 30001, 9700 RB Groningen, The Netherlands
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Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci 2013; 70:631-59. [PMID: 22782113 PMCID: PMC11113843 DOI: 10.1007/s00018-012-1070-x] [Citation(s) in RCA: 949] [Impact Index Per Article: 79.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 06/19/2012] [Accepted: 06/21/2012] [Indexed: 12/13/2022]
Abstract
The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.
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Affiliation(s)
- Takuya Suzuki
- Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima, 739-8528, Japan.
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38
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Guarene M, Capittini C, De Silvestri A, Pasi A, Badulli C, Sbarsi I, Cremaschi AL, Garlaschelli F, Pizzochero C, Monti MC, Montecucco C, Corazza GR, Larizza D, Bianchi PE, Salvaneschi L, Martinetti M. Targeting the immunogenetic diseases with the appropriate HLA molecular typing: critical appraisal on 2666 patients typed in one single centre. BIOMED RESEARCH INTERNATIONAL 2013; 2013:904247. [PMID: 23509798 PMCID: PMC3581126 DOI: 10.1155/2013/904247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 12/20/2012] [Indexed: 11/18/2022]
Abstract
We compared the immunogenetic data from 2666 patients affected by HLA-related autoimmune diseases with those from 4389 ethnically matched controls (3157 cord blood donors CBD, 1232 adult bone marrow donors BMD), to verify the appropriateness of HLA typing requests received in the past decade. The frequency of HLA-B∗27 phenotype was 10.50% in 724 ankylosing spondylitis, 16.80% in 125 uveitis (3.41% BMD, 4.24% CBD, P < 0.0001); HLA-B∗51 allele was 15.57% in 212 Behçet's disease (12.91% BMD, 9.88% CBD, P < 0.0001); the HLA-DRB1-rheumatoid arthritis (RA) shared epitope was 13.72% in 554 RA (10.85% BMD, 13.48% CBD, P = 0.016); the carriers of almost one of HLA-DQB1 susceptibility alleles were 84.91% in 795 celiac disease (CD) and 59.37% in 256 insulin-dependent diabetes mellitus (IDDM) (46.06% in 875 CBD, 42.75% in 662 BMD P < 0.0001). Overall, our results show that the HLA marker frequencies were higher in patients than controls, but lower than expected from the literature data (excluding CD and IDDM) and demonstrate that, in complex immunogenetic conditions, a substantial number of genetic analyses are redundant and inappropriate, burdening to the public health costs. For this reason, we suggest the Italian Scientific Society of Immunogenetics to establish guidelines to improve the appropriateness of typing requests.
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Affiliation(s)
- M. Guarene
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - C. Capittini
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - A. De Silvestri
- Unità di Biometria, Direzione Scientifica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - A. Pasi
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - C. Badulli
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - I. Sbarsi
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - A. L. Cremaschi
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - F. Garlaschelli
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - C. Pizzochero
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - M. C. Monti
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - C. Montecucco
- Clinica Reumatologica, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, 27100 Pavia, Italy
| | - G. R. Corazza
- Clinica Medica I, Centro per lo Studio e la Cura delle Malattie Infiammatorie Croniche Intestinali, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, 27100 Pavia, Italy
| | - D. Larizza
- Clinica Pediatrica, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, 27100 Pavia, Italy
| | - P. E. Bianchi
- Clinica Oculistica, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, 27100 Pavia, Italy
| | - L. Salvaneschi
- Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, 27100 Pavia, Italy
| | - M. Martinetti
- Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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39
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Lavant EH, Carlson J. HLA DR-DQ genotyping by capillary electrophoresis for risk assessment for celiac disease. Methods Mol Biol 2013; 919:297-307. [PMID: 22976110 DOI: 10.1007/978-1-62703-029-8_26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The risk for celiac disease (CD) is clearly related to specific HLA DQA1 and DQB1 alleles, but HLA -typing is often considered too costly for frequent use.Here we present a method using sequence-specific primed PCR (PCR-SSP) for HLA-DR-DQ genotyping optimized for capillary electrophoresis on Applied Biosystems 3130xl Genetic Analyzer. Requiring a total of three PCR reactions and a single electrophoretic step, this method reduces the reagent expenses and technical time for directed HLA typing to distinguish risk alleles for CD, with a sufficient throughput for large-scale screening projects.
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Affiliation(s)
- Ewa H Lavant
- Department of Biomedical Laboratory Science, Malmö University, Malmö, Sweden.
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Taler I, Phillip M, Lebenthal Y, de Vries L, Shamir R, Shalitin S. Growth and metabolic control in patients with type 1 diabetes and celiac disease: a longitudinal observational case-control study. Pediatr Diabetes 2012; 13:597-606. [PMID: 22564209 DOI: 10.1111/j.1399-5448.2012.00878.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Revised: 04/02/2012] [Accepted: 04/12/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The occurrence of celiac disease (CD) in patients with type 1 diabetes (T1D) is increasing. OBJECTIVE To determine the effect of CD on growth and glycemic control in patients with T1D, and the effects of adherence to gluten-free diet (GFD) on these parameters. PATIENTS AND METHODS A longitudinal retrospective case-control design was used. The medical files of 68 patients with T1D and duodenal-biopsy-confirmed CD were reviewed for data on weight, height, hemoglobin A1c (HbA1c), frequency of diabetic ketoacidosis (DKA), and severe hypoglycemic events before and after diagnosis and treatment of CD. Findings were compared with 131 patients with T1D only matched for age, gender, and duration of diabetes. RESULTS CD was diagnosed in 5.5% of all patients with T1D attending our center during the study period; 26% of the patients with CD were symptomatic. There were no significant differences in glycemic control or frequency of severe hypoglycemia or DKA events between the study and control groups. Body mass index-standard deviation score (SDS), height-SDS, and HbA1c values were marginally but not significantly higher in the control than the study group and similar in subjects with CD with good or fair/poor adherence to a GFD throughout follow-up. CONCLUSIONS Patients with T1D and CD treated with GFD have growth and measures of metabolic control similar to those with T1D without CD. The decision whether asymptomatic celiac patients should be put on a GFD or only symptomatic patients has to be weighed against possible short- and long-term consequences of no intervention, and should be based on more evidence from larger randomized studies.
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Affiliation(s)
- Irit Taler
- Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
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41
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HLA class II high-resolution genotyping in Greek children with celiac disease and impact on disease susceptibility. Pediatr Res 2012; 72:625-30. [PMID: 23041663 DOI: 10.1038/pr.2012.133] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Celiac disease (CD) has been associated with HLA class II heterodimers. This study aimed at determining the HLA genotypic and allelic distribution in Greek children with CD as compared with the general population. METHODS A total of 118 children with CD and 120 healthy individuals serving as controls were included in the study. RESULTS Higher frequencies for HLA-DQB1*02:01 (40.25 vs. 9.58%, P < 0.001) and DQB1*02:02 (20.34 vs. 5.42%, P < 0.001) were observed in patients with CD, whereas HLA-DQB1*03:01 (16.53 vs. 30.42%, P < 0.001), DQB1*05:01 (0.85 vs. 10%, P < 0.001), and DQB1*05:02 (5.51 vs. 17.92%, P < 0.001) were significantly lower, as compared with the controls. DQA1*02:01 (patients with CD vs. controls: 20.76 vs. 6.67%, P < 0.001) and DQA1*05:01 (40.25 vs. 9.58%, P < 0.001) were significantly more frequent in patients. The frequencies of HLA-DQA1* 01:01, *01:02, *01:04, and *05:05 were significantly lower in patients (P < 0.001). The haplotype mainly associated with CD was DRB1*03-DQB1*02:01-DQA1*05:01; patients with CD vs. controls: 39.83 vs. 9.58%, P < 0.001. In total, 84.75% of patients carried DQ2 (vs. 21.67% in controls, P < 0.001), whereas 11.02% were DQ8 positive/DQ2 negative. CONCLUSION This study confirms the existing data and provides additional evidence supporting a strong genetic predisposition for CD associated with the class II alleles DQB1*02 and DQA1*05 encoding the serological specificity DQ2.
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Abstract
Gluten sensitivity has been best recognized and understood in the context of two conditions, celiac disease and wheat allergy. However, some individuals complain of symptoms in response to ingestion of "gluten," without histologic or serologic evidence of celiac disease or wheat allergy. The term non-celiac gluten sensitivity (NCGS) has been suggested for this condition, although a role for gluten proteins as the sole trigger of the associated symptoms remains to be established. This article reviews the available information regarding symptomatology, epidemiology and genetics, serology and histology, and in vitro and in vivo experimental data on the pathophysiology of NCGS.
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Affiliation(s)
- Knut E A Lundin
- Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Center for Immune Regulation, University of Oslo, Oslo, Norway.
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43
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Newton KP, Singer SA. Celiac disease in children and adolescents: special considerations. Semin Immunopathol 2012; 34:479-496. [PMID: 22549889 DOI: 10.1007/s00281-012-0313-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 04/10/2012] [Indexed: 02/06/2023]
Abstract
Although there are many commonalities between adult and pediatric celiac disease (CD), special considerations must be taken into account when working with children and adolescents. In this patient population, there are unique aspects of the epidemiology, pathogenesis, presentation, diagnosis, and management of CD. In terms of management, early and timely recognition of CD can maximize childhood and adolescent development and prevent complications. This requires insight into the unique presentations of CD in the pediatric population. Furthermore, health care providers must use proper screening methods and continue surveillance of at-risk individuals throughout childhood. Potential interventions for primary prevention of CD in children, although not completely understood, may offer some benefit. The goals of this article are to discuss in detail these special considerations when dealing with pediatric CD.
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Affiliation(s)
- Kimberly P Newton
- Rady Childrens Hospital, 3020 Children's Way MC5030, San Diego, CA 92123, USA.
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44
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Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol 2012; 34:551-66. [PMID: 22660791 DOI: 10.1007/s00281-012-0316-x] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 04/16/2012] [Indexed: 12/21/2022]
Abstract
Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.
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Affiliation(s)
- Valérie Abadie
- Sainte-Justine Hospital Research Centre, Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1C5, Canada.
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45
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Catamo E, Segat L, Lenarduzzi S, Petix V, Morgutti M, Crovella S. CD14 polymorphisms correlate with an augmented risk for celiac disease in Italian patients. Genes Immun 2012; 13:489-95. [DOI: 10.1038/gene.2012.23] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Beni V, Zewdu T, Joda H, Katakis I, O'Sullivan CK. Gold nanoparticle fluorescent molecular beacon for low-resolution DQ2 gene HLA typing. Anal Bioanal Chem 2011; 402:1001-9. [PMID: 22086396 DOI: 10.1007/s00216-011-5493-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 10/05/2011] [Accepted: 10/10/2011] [Indexed: 11/26/2022]
Abstract
Coeliac disease is an inflammation of the small intestine triggered by gluten ingestion. We present a fluorescent genosensor, exploiting molecular-beacon-functionalized gold nanoparticles, for the identification of human leukocyte antigen (HLA) DQ2 gene, a key genetic factor in coeliac disease. Optimization of sensor performance was achieved by tuning the composition of the oligonucleotide monolayer immobilized on the gold nanoparticle and the molecular beacon design. Co-immobilization of the molecular beacon with a spacing oligonucleotide (thiolated ten-thymine oligonucleotide) in the presence of ten-adenine oligonucleotides resulted in a significant increase of the sensor response owing to improved spacing of the molecular beacons and extension of the distance from the nanoparticle surface, which renders them more available for recognition. Further increase in the response (approximately 40%) was shown to be achievable when the recognition sequence of the molecular beacon was incorporated in the stem. Improvement of the specificity of the molecular beacons was also achieved by the incorporation within their recognition sequence of a one-base mismatch. Finally, gold nanoparticles functionalized with two molecular beacons targeting the DQA1*05* and DQB1*02* alleles allowed the low-resolution typing of the DQ2 gene at the nanomolar level.
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Affiliation(s)
- Valerio Beni
- Nanobiotechnology and Bioanalysis Group, Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Av. Pasos Catalans, 26, 43007 Tarragona, Spain.
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Dias MDCS, Castro LCGD, Gandolfi L, Almeida RCD, Córdoba MS, Pratesi R. Screening for celiac disease among patients with Turner syndrome in Brasília, DF, midwest region of Brazil. ARQUIVOS DE GASTROENTEROLOGIA 2011; 47:246-9. [PMID: 21140084 DOI: 10.1590/s0004-28032010000300007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2009] [Accepted: 12/18/2009] [Indexed: 01/15/2023]
Abstract
CONTEXT Several studies have demonstrated a higher prevalence of celiac disease (CD) among females with Turner syndrome when compared to the general population. Nevertheless, there is no record in literature concerning this investigation among Brazilian patients. OBJECTIVE To assess the prevalence of CD among a group of Brazilian patients with Turner syndrome. METHODS Fifty-six females with Turner syndrome and on gluten-containing diet were screened for CD utilizing immunoglobulin A antiendomysium (IgA-EMA) and immunoglobulin A anti-tissue transglutaminase (IgA-tTG) antibody assays. Additionally, they were genotyped for CD human leukocyte antigen (CD-HLA) predisposing alleles. Patients showing positivity in serological testing were offered to perform small intestine biopsy for histological confirmation. RESULTS Mean age at diagnosis of Turner syndrome was 5.5 ± 4.4 years; mean age at screening for CD was 17.0 ± 9.3 years (from 10 months of age to 52 years). Two girls were positive for IgA-EMA and IgA-tTG, presented predisposing HLA-DQ2 alleles and both had the diagnosis of CD confirmed by jejunal biopsy. CONCLUSION The 3.6% prevalence of biopsy-proven CD among this group of females with Turner syndrome is 10 times higher than the one among females from the general population of the same geographical area. This result provides additional support to an association between these two disorders and restates that girls and women with Turner syndrome represent a high risk population for developing CD.
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Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 2011; 29:493-525. [PMID: 21219178 DOI: 10.1146/annurev-immunol-040210-092915] [Citation(s) in RCA: 353] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Celiac disease (CD) is a gluten-sensitive enteropathy that develops in genetically susceptible individuals by exposure to cereal gluten proteins. This review integrates insights from immunological studies with results of recent genetic genome-wide association studies into a disease model. Genetic data, among others, suggest that viral infections are implicated and that natural killer effector pathways are important in the pathogenesis of CD, but most prominently these data converge with existing immunological findings that CD is primarily a T cell-mediated immune disorder in which CD4(+) T cells that recognize gluten peptides in the context of major histocompatibility class II molecules play a central role. Comparison of genetic pathways as well as genetic susceptibility loci between CD and other autoimmune and inflammatory disorders reveals that CD bears stronger resemblance to T cell-mediated organ-specific autoimmune than to inflammatory diseases. Finally, we present evidence suggesting that the high prevalence of CD in modern societies may be the by-product of past selection for increased immune responses to combat infections in populations in which agriculture and cereals were introduced early on in the post-Neolithic period.
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Affiliation(s)
- Valérie Abadie
- Department of Medicine, University of Chicago, Illinois 60637, USA
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Vatta S, Fabris A, Segat L, Not T, Crovella S. Tag–single nucleotide polymorphism–based human leukocyte antigen genotyping in celiac disease patients from northeastern Italy. Hum Immunol 2011; 72:499-502. [DOI: 10.1016/j.humimm.2011.03.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 03/15/2011] [Accepted: 03/31/2011] [Indexed: 11/16/2022]
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Roujon P, Guidicelli G, Moreau JF, Taupin JL. [Immunogenetics of celiac disease]. PATHOLOGIE-BIOLOGIE 2011; 61:e5-11. [PMID: 21616607 DOI: 10.1016/j.patbio.2011.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 03/23/2011] [Indexed: 01/31/2023]
Abstract
Celiac disease is an auto-immune enteropathy involving genetic factors. It is associated in almost all the patients, to specific susceptibility alleles encoding histocompatibility antigens (HLA for human leucocyte antigen), specifically certain variants of the HLA-DQ2, and the HLA-DQ8 HLA class II molecules. Its estimated prevalence is 1% in the european and north-american populations. However, although these alleles represent the main genetic factor for this disease, they do not explain it on their own, as they are expressed by up to 30% of the population. Recent immunological advances allowed identifying the immunodominant epitopes of gluten, to establish the role of tissue transglutaminase in the disease and to define at the atomic level the presentation of these antigens by the HLA-DQ molecule. It is noteworthy that the HLA susceptibility alleles only account for 40% of the whole genetic risk, and the challenge is now to explain the remaining 60%. Genome-wide association studies using the DNA arrays technology to screen single nucleotide polymorphisms to pinpoint candidate regions and genes, have started to provide answers, but contradictory results sometimes still persist. Most of the genes emerging as statistically significantly associated with celiac disease are involved in the immune response, and suggest that the situation is complex.
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Affiliation(s)
- P Roujon
- Laboratoire d'immunologie et d'immunogénétique, hôpital Pellegrin, CHU de Bordeaux, place Amélie-Raba-Léon,33076 Bordeaux cedex, France
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