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Özkan A, Merry GE, Chou DB, Posey RR, Stejskalova A, Calderon K, Sperry M, Horvath V, Ferri LE, Carlotti E, McDonald SAC, Winton DJ, Riccardi R, Bordeianou L, Hall S, Goyal G, Ingber DE. Human Organ Chips Reveal New Inflammatory Bowel Disease Drivers. RESEARCH SQUARE 2025:rs.3.rs-5627712. [PMID: 39975910 PMCID: PMC11838723 DOI: 10.21203/rs.3.rs-5627712/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma, sex hormones, and peristalsis-associated mechanical deformations play a key role in driving inflammation, fibrosis, and disease progression in male and female IBD patients.
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Affiliation(s)
- Alican Özkan
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Gwenn E. Merry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - David B. Chou
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Ryan R. Posey
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Anna Stejskalova
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Karina Calderon
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Megan Sperry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Viktor Horvath
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Entact Bio, Watertown, MA
| | - Lorenzo E. Ferri
- Thoracic and Upper GI Cancer Research Laboratories, Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Department of Experimental Surgery and Department of Surgery, McGill University, Montreal, QC, Canada
| | - Emanuela Carlotti
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Stuart A. C. McDonald
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Douglas J. Winton
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom
| | - Rocco Riccardi
- Department of Surgery, Massachusetts General Hospital, Boston, MA
| | | | - Sean Hall
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Iovance Therapeutics, Tampa, FL
| | - Girija Goyal
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Donald E. Ingber
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA
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Özkan A, Merry G, Chou DB, Posey RR, Stejskalova A, Calderon K, Sperry M, Horvath V, Ferri LE, Carlotti E, McDonald SAC, Winton DJ, Riccardi R, Bordeianou L, Hall S, Goyal G, Ingber DE. Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.12.05.24318563. [PMID: 39677416 PMCID: PMC11643285 DOI: 10.1101/2024.12.05.24318563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma and peristalsis-associated mechanical deformations play a key role in driving inflammation and disease progression in male and female IBD patients.
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Affiliation(s)
- Alican Özkan
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Gwenn Merry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - David B. Chou
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Ryan R. Posey
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Anna Stejskalova
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Karina Calderon
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Megan Sperry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Viktor Horvath
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Entact Bio, Watertown, MA
| | - Lorenzo E. Ferri
- Thoracic and Upper GI Cancer Research Laboratories, Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Department of Experimental Surgery and Department of Surgery, McGill University, Montreal, QC, Canada
| | - Emanuela Carlotti
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Stuart A. C. McDonald
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Douglas J. Winton
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom
| | - Rocco Riccardi
- Department of Surgery, Massachusetts General Hospital, Boston, MA
| | | | - Sean Hall
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Iovance Therapeutics, Tampa, FL
| | - Girija Goyal
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Donald E. Ingber
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA
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Chen H, Li Q, Gao T, Wang Y, Ren X, Liu S, Zhang S, Zhou P, Lyu J, Bai H, Wang Y. Causal role of immune cells in inflammatory bowel disease: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e37537. [PMID: 38579066 PMCID: PMC10994490 DOI: 10.1097/md.0000000000037537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 02/16/2024] [Indexed: 04/07/2024] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by an inflammatory response closely related to the immune system, but the relationship between inflammation and IBD remains unclear. We performed a comprehensive 2-sample Mendelian randomization (MR) analysis to determine the causal relationship between immune cell characteristics and IBD. Using publicly available genetic data, we explored the relationship between 731 immune cell characteristics and IBD risk. Inverse-variance weighting was the primary analytical method. To test the robustness of the results, we used the weighted median-based, MR-Egger, simple mode, and mode-based methods. Finally, we performed a reverse MR analysis to assess the possibility of reverse causality. We identified suggestive associations between 2 immune cell traits and IBD risk (P = 4.18 × 10-5 for human leukocyte antigen-DR on CD14+ monocytes, OR: 0.902; 95% CI: 0.859-0.947; for CD39+ CD4+ T cells, P = 6.24 × 10-5; OR: 1.042; 95% CI: 1.021-1.063). Sensitivity analysis results of these immune cell traits were consistent. In reverse MR analysis, we found no statistically significant association between IBD and these 2 cell traits. Our study demonstrates the close connection between immune cells and IBD using MR, providing guidance for future clinical and basic research.
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Affiliation(s)
- Haoyu Chen
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Qi Li
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Tianyu Gao
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Yuhua Wang
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Xuetong Ren
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Shaowei Liu
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
| | - Shixiong Zhang
- School of Graduate, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Pingping Zhou
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, China
| | - Jingjing Lyu
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, China
| | - Haiyan Bai
- Department of Gastroenterology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, China
| | - Yangang Wang
- School of Graduate, Hebei University of Chinese Medicine, Hebei, Shijiazhuang, China
- Department of Gastroenterology, Beijing University of Chinese Medicine, Third Affiliated Hospital, Beijing, China
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Kulski JK, Suzuki S, Shiina T, Pfaff AL, Kõks S. Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson's disease. Front Immunol 2024; 15:1349030. [PMID: 38590523 PMCID: PMC10999589 DOI: 10.3389/fimmu.2024.1349030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/06/2024] [Indexed: 04/10/2024] Open
Abstract
Introduction Parkinson's disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson's Progression Markers Initiative (PPMI) cohort. Aims and methods In the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as DRA and the DRB3/4/5 haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes. Results Significant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at p<0.05 by the Fisher's exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%). Conclusions These data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.
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Affiliation(s)
- Jerzy K. Kulski
- Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
- Health and Medical Science, Division of Immunology and Microbiology, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Shingo Suzuki
- Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Takashi Shiina
- Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Abigail L. Pfaff
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
| | - Sulev Kõks
- Perron Institute for Neurological and Translational Science, Perth, WA, Australia
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
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Boles JS, Krueger ME, Jernigan JE, Cole CL, Neighbarger NK, Uriarte Huarte O, Tansey MG. A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis. Brain Behav Immun 2024; 117:473-492. [PMID: 38341052 DOI: 10.1016/j.bbi.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 01/23/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024] Open
Abstract
The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.
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Affiliation(s)
- Jake Sondag Boles
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
| | - Maeve E Krueger
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Janna E Jernigan
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Cassandra L Cole
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Noelle K Neighbarger
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Oihane Uriarte Huarte
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Malú Gámez Tansey
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
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Baumdick ME, Niehrs A, Degenhardt F, Schwerk M, Hinrichs O, Jordan-Paiz A, Padoan B, Wegner LHM, Schloer S, Zecher BF, Malsy J, Joshi VR, Illig C, Schröder-Schwarz J, Möller KJ, Martin MP, Yuki Y, Ozawa M, Sauter J, Schmidt AH, Perez D, Giannou AD, Carrington M, Davis RS, Schumacher U, Sauter G, Huber S, Puelles VG, Melling N, Franke A, Altfeld M, Bunders MJ. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44 + Natural Killer Cells in Ulcerative Colitis. Gastroenterology 2023; 165:946-962.e13. [PMID: 37454979 PMCID: PMC10529779 DOI: 10.1053/j.gastro.2023.06.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 05/25/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND & AIMS Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. METHODS HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. RESULTS These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. CONCLUSIONS We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.
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Affiliation(s)
- Martin E Baumdick
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Annika Niehrs
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Maria Schwerk
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ole Hinrichs
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Ana Jordan-Paiz
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Benedetta Padoan
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Lucy H M Wegner
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Sebastian Schloer
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and Cells in Motion Interfaculty Center, University of Münster, Münster, Germany
| | - Britta F Zecher
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Malsy
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems, Germany
| | - Vinita R Joshi
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Christin Illig
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Jennifer Schröder-Schwarz
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kimberly J Möller
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Maureen P Martin
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Yuko Yuki
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | | | | | - Daniel Perez
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasios D Giannou
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mary Carrington
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts
| | - Randall S Davis
- Departments of Medicine, Microbiology, and Biochemistry and Molecular Genetics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Victor G Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Marcus Altfeld
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany
| | - Madeleine J Bunders
- Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Section of Regenerative Medicine and Immunology, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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7
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Wang MH, Friton JJ, Rebert N, Monroe K, Nix BD, Fiocchi C, Raffals LE, Leighton JA, Pasha SF, Picco MF, Newberry RD, Achkar JP, Faubion WA. Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis. Clin Transl Gastroenterol 2023; 14:e00615. [PMID: 37440754 PMCID: PMC10522100 DOI: 10.14309/ctg.0000000000000615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.
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Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Gastroenterology, Mayo Clinic Health System, Southwest Minnesota Region, Mankato, Minnesota, USA
| | - Jessica J. Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nancy Rebert
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Billy D. Nix
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jonathan A. Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Shabana F. Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Michael F. Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Rodney D. Newberry
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Jean-Paul Achkar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - William A. Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
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8
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Boles JS, Krueger ME, Jernigan JE, Cole CL, Neighbarger NK, Huarte OU, Tansey MG. A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.10.552488. [PMID: 37609290 PMCID: PMC10441416 DOI: 10.1101/2023.08.10.552488] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.
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Affiliation(s)
- Jake Sondag Boles
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Maeve E. Krueger
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Janna E. Jernigan
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Cassandra L. Cole
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Noelle K. Neighbarger
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Oihane Uriarte Huarte
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Malú Gámez Tansey
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
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9
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Abed A, Law N, Calapre L, Lo J, Bhat V, Bowyer S, Millward M, Gray ES. Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy. Eur J Cancer 2022; 172:98-106. [PMID: 35759816 DOI: 10.1016/j.ejca.2022.05.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 03/23/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Biomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments. METHODS We carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). RESULTS Homozygosity at one or more HLA-I loci, but not HLA-II, was associated with a reduced risk of irAE (relative risk (RR) = 0.61, 95% CI 0.33-0.95, P = 0.035) especially pneumonitis or any grade 3 toxicity. Patients with HLA-A03 supertype had a higher risk of developing irAE (RR = 1.42, 95% CI 1.02-2.01, P = 0.039). The occurrence of any irAE was significantly associated with improved CBR (RR = 1.48, P < 0.0001), PFS (HR = 0.45, P = 0.0003) and OS (HR = 0.34, P < 0.0001). CONCLUSIONS Homozygosity at one or more HLA-I loci may serve as biomarker to predict patients who are unlikely to experience severe irAEs among patients with NSCLC and treated with anti-PD1/PDL1, but less likely to derive clinical benefit. Patients with HLA-I homozygous might benefit from additional therapy.
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Affiliation(s)
- Afaf Abed
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia; Linear Clinical Research, Nedlands, WA, Australia; School of Medicine, University of Western Australia, Nedlands, Australia.
| | - Ngie Law
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
| | - Leslie Calapre
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
| | - Johnny Lo
- School of Sciences, Edith Cowan University, Joondalup, WA, Australia; Centre for Artificial Intelligence and Machine Learning, Edith Cowan University, Joondalup, WA, Australia.
| | - Vikas Bhat
- School of Medicine, University of Western Australia, Nedlands, Australia.
| | - Samantha Bowyer
- Linear Clinical Research, Nedlands, WA, Australia; School of Medicine, University of Western Australia, Nedlands, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
| | - Michael Millward
- Linear Clinical Research, Nedlands, WA, Australia; School of Medicine, University of Western Australia, Nedlands, Australia.
| | - Elin S Gray
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia; Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
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10
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Brooks-Warburton J, Modos D, Sudhakar P, Madgwick M, Thomas JP, Bohar B, Fazekas D, Zoufir A, Kapuy O, Szalay-Beko M, Verstockt B, Hall LJ, Watson A, Tremelling M, Parkes M, Vermeire S, Bender A, Carding SR, Korcsmaros T. A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis. Nat Commun 2022; 13:2299. [PMID: 35484353 PMCID: PMC9051123 DOI: 10.1038/s41467-022-29998-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 04/06/2022] [Indexed: 12/11/2022] Open
Abstract
We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.
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Affiliation(s)
- Johanne Brooks-Warburton
- Earlham Institute, Norwich Research Park, Norwich, UK
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
- Department of Clinical, Pharmaceutical and Biological Sciences, University of Hertfordshire, Hertford, UK
- Gastroenterology Department, Lister Hospital, Stevenage, UK
| | - Dezso Modos
- Earlham Institute, Norwich Research Park, Norwich, UK
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
- Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
| | - Padhmanand Sudhakar
- Earlham Institute, Norwich Research Park, Norwich, UK
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
- KU Leuven, Department of Chronic diseases, Metabolism and Ageing, Leuven, Belgium
| | - Matthew Madgwick
- Earlham Institute, Norwich Research Park, Norwich, UK
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - John P Thomas
- Earlham Institute, Norwich Research Park, Norwich, UK
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
- Department of Gastroenterology, Norfolk and Norwich University Hospitals, Norwich, UK
| | - Balazs Bohar
- Earlham Institute, Norwich Research Park, Norwich, UK
- Department of Genetics, Eötvös Loránd University, Budapest, Hungary
| | - David Fazekas
- Earlham Institute, Norwich Research Park, Norwich, UK
- Department of Genetics, Eötvös Loránd University, Budapest, Hungary
| | - Azedine Zoufir
- Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
| | - Orsolya Kapuy
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | | | - Bram Verstockt
- KU Leuven, Department of Chronic diseases, Metabolism and Ageing, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Lindsay J Hall
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
- Norwich Medical School, University of East Anglia, Norwich, UK
- School of Life Sciences, ZIEL - Institute for Food & Health, Technical University of Munich, 80333, Freising, Germany
| | - Alastair Watson
- Department of Gastroenterology, Norfolk and Norwich University Hospitals, Norwich, UK
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Mark Tremelling
- Department of Gastroenterology, Norfolk and Norwich University Hospitals, Norwich, UK
| | - Miles Parkes
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Severine Vermeire
- KU Leuven, Department of Chronic diseases, Metabolism and Ageing, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Andreas Bender
- Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK
| | - Simon R Carding
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.
- Norwich Medical School, University of East Anglia, Norwich, UK.
| | - Tamas Korcsmaros
- Earlham Institute, Norwich Research Park, Norwich, UK.
- Gut Microbes and Health Programme, The Quadram Institute Bioscience, Norwich Research Park, Norwich, UK.
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11
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Ceballos D, Hernández-Camba A, Ramos L. Diet and microbiome in the beginning of the sequence of gut inflammation. World J Clin Cases 2021; 9:11122-11147. [PMID: 35071544 PMCID: PMC8717522 DOI: 10.12998/wjcc.v9.i36.11122] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/26/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract due, at least partially, to an aberrant and excessive mucosal immune response to gut bacteria in genetically-predisposed individuals under certain environmental factors. The incidence of IBD is rising in western and newly industrialized countries, paralleling the increase of westernized dietary patterns, through new antigens, epithelial function and permeability, epigenetic mechanisms (e.g., DNA methylation), and alteration of the gut microbiome. Alteration in the composition and functionality of the gut microbiome (including bacteria, viruses and fungi) seems to be a nuclear pathogenic factor. The microbiome itself is dynamic, and the changes in food quality, dietary habits, living conditions and hygiene of these western societies, could interact in a complex manner as modulators of dysbiosis, thereby influencing the activation of immune cells' promoting inflammation. The microbiome produces diverse small molecules via several metabolic ways, with the fiber-derived short-chain fatty acids (i.e., butyrate) as main elements and having anti-inflammatory effects. These metabolites and some micronutrients of the diet (i.e., vitamins, folic acid, beta carotene and trace elements) are regulators of innate and adaptive intestinal immune homeostasis. An excessive and unhealthy consumption of sugar, animal fat and a low-vegetable and -fiber diet are risk factors for IBD appearance. Furthermore, metabolism of nutrients in intestinal epithelium and in gut microbiota is altered by inflammation, changing the demand for nutrients needed for homeostasis. This role of food and a reduced gut microbial diversity in causing IBD might also have a prophylactic or therapeutic role for IBD. The relationship between dietary intake, symptoms, and bowel inflammation could lead to dietary and lifestyle recommendations, including diets with abundant fruits, vegetables, olive oil and oily fish, which have anti-inflammatory effects and could prevent dysbiosis and IBD. Dietary modulation and appropriate exclusion diets might be a new complementary management for treatment at disease flares and in refractory patients, even reducing complications, hospitalizations and surgery, through modifying the luminal intestinal environment.
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Affiliation(s)
- Daniel Ceballos
- Department of Gastroenterology, Hospital Universitario de Gran Canaria Doctor Negrin, Las Palmas 35019, Canarias, Spain
| | - A Hernández-Camba
- Department of Gastroenterology, Hospital Universitario Nuestra Señora de La Candelaria, Santa Cruz de Tenerife 38010, Canarias, Spain
| | - Laura Ramos
- Department of Gastroenterology, Hospital Universitario de Canarias, San Cristóbal de La Laguna 38320, Canarias, Spain
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12
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Taylor HB, Klaeger S, Clauser KR, Sarkizova S, Weingarten-Gabbay S, Graham DB, Carr SA, Abelin JG. MS-Based HLA-II Peptidomics Combined With Multiomics Will Aid the Development of Future Immunotherapies. Mol Cell Proteomics 2021; 20:100116. [PMID: 34146720 PMCID: PMC8327157 DOI: 10.1016/j.mcpro.2021.100116] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/25/2022] Open
Abstract
Immunotherapies have emerged to treat diseases by selectively modulating a patient's immune response. Although the roles of T and B cells in adaptive immunity have been well studied, it remains difficult to select targets for immunotherapeutic strategies. Because human leukocyte antigen class II (HLA-II) peptides activate CD4+ T cells and regulate B cell activation, proliferation, and differentiation, these peptide antigens represent a class of potential immunotherapy targets and biomarkers. To better understand the molecular basis of how HLA-II antigen presentation is involved in disease progression and treatment, systematic HLA-II peptidomics combined with multiomic analyses of diverse cell types in healthy and diseased states is required. For this reason, MS-based innovations that facilitate investigations into the interplay between disease pathologies and the presentation of HLA-II peptides to CD4+ T cells will aid in the development of patient-focused immunotherapies.
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Affiliation(s)
- Hannah B Taylor
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Susan Klaeger
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Karl R Clauser
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | | | - Shira Weingarten-Gabbay
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Daniel B Graham
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Steven A Carr
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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13
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Nakazawa M, Miyamae J, Okano M, Kanemoto H, Katakura F, Shiina T, Ohno K, Tsujimoto H, Moritomo T, Watari T. Dog leukocyte antigen (DLA) class II genotypes associated with chronic enteropathy in French bulldogs and miniature dachshunds. Vet Immunol Immunopathol 2021; 237:110271. [PMID: 34044267 DOI: 10.1016/j.vetimm.2021.110271] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/01/2021] [Accepted: 05/19/2021] [Indexed: 01/02/2023]
Abstract
Canine chronic enteropathy (CE) is a group of immunogenetic disorders of unclear etiology characterized by chronic or recurrent gastrointestinal signs and inflammation. Diagnosis of CE subtypes by treatment response is a lengthy and challenging process, particularly in refractory cases of the disease. Given known association of dog leukocyte antigen (DLA) class II genotype and various immunogenetic disorders between and across breeds, this study was designed to examine the potential of determining susceptibility to refractory CE through identification of risk and protective genotypes in French bulldogs and miniature dachshunds-two popular dog breeds in Japan. Sequence-based genotyping of three DLA class II genes in 29 French bulldogs and 30 miniature dachshunds with refractory CE revealed a protective haplotype DLA-DRB1*002:01-DQA1*009:01-DQB1*001:01 against CE in French bulldogs (OR 0.09, 95 % CI 0.01-0.71, p = 0.0084). No statistical difference was noted between miniature dachshund cases and controls. These findings, largely disparate from a previous study on German shepherd dogs in the UK, were taken as possible indication of etiological differences in the refractory CE noted between and within breeds, and by extension, the potential of identifying such disease heterogeneity by DLA typing. The DLA-DQA1/DQB1 haplotype, protective against CE in our French bulldogs, has been reported as protective in various immune-mediated disorders such as Doberman hepatitis (Dyggve et al., 2011). Likewise, the DLA-DRB1*006:01 risk allele for Doberman hepatitis was noted in more French bulldogs with CE compared to controls, in line with reports on genotypes associated with both risk and protection being shared across various autoimmune diseases and breeds. These findings support an immunogenetic basis to the French bulldog-CE in our analysis, calling for further DLA studies working with larger samples and different breeds towards phenotypic clarification that may aid in early diagnosis, treatment, and prophylaxis through epigenetic approaches and breeding.
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Affiliation(s)
- Meg Nakazawa
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Jiro Miyamae
- Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoino-oka, Imabari, Ehime, 794-8555, Japan
| | - Masaharu Okano
- Department of Legal Medicine, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-Ku, Tokyo, 101-8310, Japan
| | - Hideyuki Kanemoto
- DVMs Animal Medical Center Yokohama, 966-5 Kawamuko, Tsuzuki, Yokohama, Kanagawa, 224-0044, Japan; Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Fumihiko Katakura
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Takashi Shiina
- Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Koichi Ohno
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Hajime Tsujimoto
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Tadaaki Moritomo
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Toshihiro Watari
- Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan.
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14
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Tarhini AA, Kang N, Lee SJ, Hodi FS, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis. J Immunother Cancer 2021; 9:jitc-2021-002535. [PMID: 33963015 PMCID: PMC8108687 DOI: 10.1136/jitc-2021-002535] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2021] [Indexed: 01/30/2023] Open
Abstract
Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1–2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1–2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1–2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1–2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1–2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3–4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3–4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1–2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3–4 irAEs.
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Affiliation(s)
- Ahmad A Tarhini
- Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA
| | - Ni Kang
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Sandra J Lee
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - F Stephen Hodi
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Gary I Cohen
- Greater Baltimore Medical Center, Baltimore, Maryland, USA
| | - Omid Hamid
- The Angeles Clinic & Research Institute, A Cedars Sinai Affiliate, Los Angeles, California, USA
| | - Laura F Hutchins
- Department of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA
| | - Jeffrey A Sosman
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Harriet M Kluger
- Department of Medicine, Yale University, New Haven, Connecticut, USA
| | - Zeynep Eroglu
- Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA
| | - Henry B Koon
- Case Western Reserve University, Cleveland, Ohio, USA
| | | | | | - David R Minor
- Sutter-California Pacific Medical Center, San Francisco, California, USA
| | - Carrie B Lee
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - Lawrence E Flaherty
- Wayne State University and Karmanos Cancer Institute, Detroit, Michigan, USA
| | | | | | - Vernon K Sondak
- Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA
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15
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Angeletti A, Arrigo S, Madeo A, Molteni M, Vietti E, Arcuri L, Coccia MC, Gandullia P, Ghiggeri GM. Different renal manifestations associated with very early onset pediatric inflammatory bowel disease: case report and review of literature. BMC Nephrol 2021; 22:146. [PMID: 33888087 PMCID: PMC8061217 DOI: 10.1186/s12882-021-02358-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/14/2021] [Indexed: 01/10/2023] Open
Abstract
Background Inflammatory bowel diseases are characterized by chronic inflammation of the gastrointestinal tract. In particular, Crohn disease and ulcerative colitis represent the two most common types of clinical manifestations. Extraintestinal manifestations of inflammatory bowel diseases represent a common complications, probably reflecting the systemic inflammation. Renal involvement is reported in 4–23% of cases. However, available data are limited to few case series and retrospective analysis, therefore the real impact of renal involvement is not well defined. Case presentation We report the case of a 10-years old male affected by very early onset unclassified-Inflammatory bowel diseases since he was 1-year old, presenting with a flare of inflammatory bowel diseases associated with acute kidney injury due to granulomatous interstitial nephritis. Of interest, at 7-year-old, he was treated for IgA nephropathy. To our knowledge, no previous reports have described a relapse of renal manifestation in inflammatory bowel diseases, characterized by two different clinical and histological phenotypes. Conclusions The link between the onset of kidney injuries with flares of intestinal inflammation suggest that nephritis maybe considered an extra-intestinal manifestation correlated with active inflammatory bowel disease. However, if granulomatous interstitial nephritis represents a cell-mediated hypersensitivity reaction than a true extraintestinal manifestation of inflammatory bowel diseases is still not clarified. We suggest as these renal manifestations here described may be interpreted as extraintestinal disorder and also considered as systemic signal of under treatment of the intestinal disease.
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Affiliation(s)
- A Angeletti
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
| | - S Arrigo
- Pediatric Gastroenterology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - A Madeo
- Pediatric Gastroenterology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - M Molteni
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - E Vietti
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - L Arcuri
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - M C Coccia
- Department of Pathology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - P Gandullia
- Pediatric Gastroenterology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - G M Ghiggeri
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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16
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Degenhardt F, Mayr G, Wendorff M, Boucher G, Ellinghaus E, Ellinghaus D, ElAbd H, Rosati E, Hübenthal M, Juzenas S, Abedian S, Vahedi H, Thelma BK, Yang SK, Ye BD, Cheon JH, Datta LW, Daryani NE, Ellul P, Esaki M, Fuyuno Y, McGovern DPB, Haritunians T, Hong M, Juyal G, Jung ES, Kubo M, Kugathasan S, Lenz TL, Leslie S, Malekzadeh R, Midha V, Motyer A, Ng SC, Okou DT, Raychaudhuri S, Schembri J, Schreiber S, Song K, Sood A, Takahashi A, Torres EA, Umeno J, Alizadeh BZ, Weersma RK, Wong SH, Yamazaki K, Karlsen TH, Rioux JD, Brant SR, Franke A. Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations. Hum Mol Genet 2021; 30:356-369. [PMID: 33555323 PMCID: PMC8098114 DOI: 10.1093/hmg/ddab017] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/27/2020] [Accepted: 12/23/2020] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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Affiliation(s)
- Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Gabriele Mayr
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Mareike Wendorff
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Gabrielle Boucher
- Research Center, Montréal Heart Institute, Université de Montréal and the Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada
| | - Eva Ellinghaus
- K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway
| | - Hesham ElAbd
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Elisa Rosati
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Matthias Hübenthal
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Simonas Juzenas
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Shifteh Abedian
- Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, The Netherlands.,Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - Homayon Vahedi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - B K Thelma
- Department of Genetics, University of Delhi South Campus, New Delhi, Delhi 110021, India
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Lisa Wu Datta
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Naser Ebrahim Daryani
- Department of Gastroenterology, Emam Hospital, Tehran University of Medical Sciences, Tehran 1419733141, Iran
| | - Pierre Ellul
- Department of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Motohiro Esaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yuta Fuyuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama 351-0198, Japan
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Myhunghee Hong
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701 Korea
| | - Garima Juyal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, Delhi 110067, India
| | - Eun Suk Jung
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, 351-0198, Japan
| | - Subra Kugathasan
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.,Pediatric Institute, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Tobias L Lenz
- Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany
| | - Stephen Leslie
- Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia
| | - Reza Malekzadeh
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1411713135, Iran
| | - Vandana Midha
- Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India
| | - Allan Motyer
- Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - David T Okou
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.,Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.,Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.,Centre for Genetics and Genomics Versus Arthritis, Division of Musculosceletal and Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
| | - John Schembri
- Department of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.,Department of Medicine, Christian-Albrechts-University, 24105 Kiel, Germany
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 136-701 Korea
| | - Ajit Sood
- Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India
| | - Atsushi Takahashi
- Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama, 230-0045, Japan
| | - Esther A Torres
- Department of Medicine, University of Puerto Rico Center for IBD, University of Puerto Rico School of Medicine, Rio Piedras, San Juan, PR 00936-5067, USA
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Behrooz Z Alizadeh
- Department of Epidemiology, University Medical Center Groningen, 9713 Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700 AB Groningen, The Netherlands
| | - Sunny H Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - Keiko Yamazaki
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, Riken, Yokohama 351-0198, Japan
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.,Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo, 0372 Oslo, Norway
| | - John D Rioux
- Research Center, Montréal Heart Institute, Université de Montréal and the Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada
| | - Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Medicine, Rutgers Robert Wood Johnson School of Medicine and Department of Genetics, Rutgers University Brunswick and Piscataway, NJ 08903-0019, USA
| | | | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany
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17
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Renal involvement in paediatric inflammatory bowel disease. Pediatr Nephrol 2021; 36:279-285. [PMID: 31820145 PMCID: PMC7815543 DOI: 10.1007/s00467-019-04413-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/16/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease, ulcerative colitis and inflammatory bowel disease unclassified, is a chronic inflammatory disorder that predominantly affects the gastrointestinal (GI) tract and has a rising incidence in both children and adults. Symptoms are caused by inappropriate inflammatory response triggered by interaction between the environment, gut microbiome and host immune system in a genetically susceptible individual. Extranintestinal manifestations of IBD are common and can affect any body system outside the gut; they can precede or run parallel to GI inflammation. Renal involvement in IBD is uncommon and can be part of extraintestinal manifestation or metabolic complications of IBD. Many medications used to treat IBD can cause renal damage. Renal manifestation in children with IBD can range from asymptomatic biochemical abnormalities to variable stages of renal impairment with significant morbidity and even mortality burden.
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18
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Affiliation(s)
- Mary Melissa Roland
- University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, South Carolina, United States of America
| | - Ahmed Dawood Mohammed
- University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, South Carolina, United States of America
| | - Jason Lee Kubinak
- University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, South Carolina, United States of America
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19
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Escudero-Hernández C, Bernardo D, Arranz E, Garrote JA. Is celiac disease really associated with inflammatory bowel disease? REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2019; 112:4-6. [PMID: 31830796 DOI: 10.17235/reed.2019.6779/2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Celiac disease (CeD) and inflammatory bowel disease (IBD) are chronic gastrointestinal disorders of inflammatory origin that develop in response to environmental triggers in genetically predisposed individuals. CeD localizes in the duodenal mucosa, where intolerance develops to dietary gluten from wheat, barley, rye, and some varieties of oats. IBD, in turn, is subdivided primarily into Crohn's disease (CD) and colitis, with ulcerative colitis (UC) being the most thoroughly investigated form.
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Affiliation(s)
| | - David Bernardo
- Unidad Inmunología de las mucosas. IBGM, Universidad de Valladolid
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20
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Abstract
The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This changing landscape of inflammatory bowel disease reflects the new recognition that the youngest children with inflammatory bowel disease are enriched in cases with underlying primary immunodeficiency and monogenic causes. The management of these cases can be quite different, with specific genetic etiologies supporting unique interventions and some requiring hematopoietic cell transplantation for effective treatment.
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Affiliation(s)
- Judith R Kelsen
- Division of Gastroenterology, Hepatology and Nutrition, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Pierre Russo
- Department of Pathology, Division of Allergy Immunology, The Children's Hospital of Philadelphia, ARC 1216-I, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Kathleen E Sullivan
- Division of Allergy Immunology, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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21
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Wang C, Baer HM, Gaya DR, Nibbs RJB, Milling S. Can molecular stratification improve the treatment of inflammatory bowel disease? Pharmacol Res 2019; 148:104442. [PMID: 31491469 PMCID: PMC6902263 DOI: 10.1016/j.phrs.2019.104442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems. IBD is highly heterogeneous; disease severity and outcomes in IBD are highly variable, and patients may experience episodes of relapse and remission. However, treatment often follows a step-up model whereby the patients start with anti-inflammatory agents (corticosteroids or immunosuppressants) and step-up to monoclonal anti-tumour necrosis factor-α (TNFα) antibodies and then other biologics if the initial drugs cannot control disease. Unfortunately, many patients do not respond to the costly biologics, and thus often still require gut-resective surgery, which decreases quality of life. In order to decrease rates of surgery and ineffective treatments, it is important to identify markers that accurately predict disease progression and treatment responses, to inform decisions about the best choice of therapeutics. Here we examine molecular approaches to patient stratification that aim to increase the effectiveness of treatments and potentially reduce healthcare costs. In the future, it may become possible to stratify patients based on their suitability for specific molecular-targeted therapeutic agents, and eventually use molecular stratification for personalised medicine in IBD.
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Affiliation(s)
- Claire Wang
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hannah M Baer
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Simon Milling
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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22
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Ashton JJ, Latham K, Beattie RM, Ennis S. Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 50:885-900. [PMID: 31518029 DOI: 10.1111/apt.15485] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/05/2019] [Accepted: 08/10/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.
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Affiliation(s)
- James J Ashton
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Katy Latham
- Anthony Nolan Research Institute, University College London, London, UK
| | - Robert Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
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23
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Genetic Studies of Inflammatory Bowel Disease-Focusing on Asian Patients. Cells 2019; 8:cells8050404. [PMID: 31052430 PMCID: PMC6563043 DOI: 10.3390/cells8050404] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/19/2019] [Accepted: 04/26/2019] [Indexed: 12/25/2022] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is not well-understood; however, increased and persistent intestinal inflammation, due to inappropriate immune responses that are caused by interactions between genetic factors, gut microbiota, and environmental factors, are thought to lead to IBD. Various studies have identified more than 240 genetic variants related to IBD. These genetic variants are involved in innate and adaptive immunity, autophagy, defective bacterial handing, interleukin-23 and 10 signaling, and so on. According to several epidemiological and clinical studies, the phenotypes and clinical course of IBD differ between Asians and Europeans. Although the risk loci for IBD typically overlap between Asians and Westerners, genetic heterogeneity has been detected in many loci/genes, such as NOD2/CARD15, TNFSF15 and human leukocyte antigen, contributing to the risk of IBD. Thus, although common pathways exist between Westerners and Asians in the development of IBD, their significance may differ for individual pathways. Although genetic studies are not universally applicable in the clinical field, they may be useful for diagnosing and categorizing IBD, predicting therapeutic responses and toxicity to drugs, and assessing prognosis by risk modeling, thereby enabling precision medicine for individual patients.
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24
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Gershony LC, Belanger JM, Short AD, Le M, Hytönen MK, Lohi H, Famula TR, Kennedy LJ, Oberbauer AM. DLA class II risk haplotypes for autoimmune diseases in the bearded collie offer insight to autoimmunity signatures across dog breeds. Canine Genet Epidemiol 2019; 6:2. [PMID: 30783534 PMCID: PMC6376674 DOI: 10.1186/s40575-019-0070-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 01/24/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Primary hypoadrenocorticism (Addison's disease, AD) and symmetrical lupoid onychodystrophy (SLO) are two clinical conditions with an autoimmune etiology that occur in multiple dog breeds. In man, autoimmunity is associated with polymorphisms in immune-related genes that result in a reduced threshold for, or defective regulation of, T cell activation. The major histocompatibility complex (MHC) class II genes encode molecules that participate in these functions, and polymorphisms within these genes have been associated with autoimmune conditions in dogs and humans. Bearded collies have a relatively high prevalence of autoimmune diseases, particularly AD and SLO. Our study assessed the relationship between particular MHC (dog leukocyte antigen, DLA) class II haplotypes and the two autoimmune diseases most common in this breed. Moreover, five unrelated breeds at increased risk for AD were studied for comparative purposes and analyzed in the context of extant literature. RESULTS A single DLA class II three-locus haplotype, determined by sequence-based typing, was associated with increased risk for AD (DLA-DRB1*009:01/DQA1*001:01/DQB1*008:02) in bearded collies. Comparative analysis with the five additional breeds showed limited allele sharing, with DQA1*001:01 and DQB1*002:01 being the only alleles observed in all breeds. A distinct three-locus risk haplotype (DLA-DRB1*001:01/DQA1*001:01/DQB1*002:01) was associated with AD in the West Highland white terrier and Leonberger. Two different risk haplotypes were associated with increased risk for SLO in the bearded collie (DLA-DRB1*018:01/DQA1*001:01/DQB1*002:01 and DLA-DRB1*018:01/DQA1*001:01/ DQB1*008:02). CONCLUSION Two-locus DQ haplotypes composed of DLA-DQA1*001:01 in association with DLA-DQB1*002:01 or DLA-DQB1*008:02 make up the four risk haplotypes identified in the present study and are also found in other risk haplotypes previously associated with diabetes mellitus and hypothyroidism across different dog breeds. Our findings build upon previously published data to suggest that this two-locus (DQ) model serves as a good indicator for susceptibility to multiple organ-specific autoimmune diseases in the canine population. However, it is also clear that additional loci are necessary for actual disease expression. Investigation of affected and unaffected dogs carrying these predisposing DQ haplotype signatures may allow for the identification of those additional genetic components that determine autoimmune disease expression and organ specificity.
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Affiliation(s)
- Liza C. Gershony
- Department of Animal Science, University of California, One Shields Ave, Davis, CA 95616 USA
- Brazilian National Council for Scientific and Technological Development (CNPq) fellow, Brasília, Brazil
| | - Janelle M. Belanger
- Department of Animal Science, University of California, One Shields Ave, Davis, CA 95616 USA
| | - Andrea D. Short
- Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
| | - Myly Le
- Department of Animal Science, University of California, One Shields Ave, Davis, CA 95616 USA
| | - Marjo K. Hytönen
- Research Programs Unit, Molecular Neurology, and Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Hannes Lohi
- Research Programs Unit, Molecular Neurology, and Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Thomas R. Famula
- Department of Animal Science, University of California, One Shields Ave, Davis, CA 95616 USA
| | - Lorna J. Kennedy
- Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
| | - Anita M. Oberbauer
- Department of Animal Science, University of California, One Shields Ave, Davis, CA 95616 USA
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25
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Zhang L, Wu TT. Inflammatory Bowel Disease. SURGICAL PATHOLOGY OF NON-NEOPLASTIC GASTROINTESTINAL DISEASES 2019:373-424. [DOI: 10.1007/978-3-030-15573-5_15] [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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Crowley E, Muise A. Inflammatory Bowel Disease: What Very Early Onset Disease Teaches Us. Gastroenterol Clin North Am 2018; 47:755-772. [PMID: 30337031 DOI: 10.1016/j.gtc.2018.07.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, of which ulcerative colitis and Crohn's disease are the 2 most prevailing entities. Very early onset IBD (VEO-IBD) children diagnosed with IBD under age 6 years. Although the etiology of IBD is mostly unknown, it involves a complex interaction among host genetics, microbiota, environmental factors, and aberrant immune responses. Advances in the understanding of the genetic contribution, which appears to be much more significant in younger children, gives us a useful insight into the pathogenesis and potential future therapeutic targets in IBD.
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Affiliation(s)
- Eileen Crowley
- Cell Biology Program, Division of Gastroenterology, Hepatology and Nutrition, Inflammatory Bowel Disease Center, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; School of Medicine, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; Department of Pediatric Gastroenterology, Hepatology and Nutrition, SickKids, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
| | - Aleixo Muise
- Department of Biochemistry, Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Gastroenterology, Hepatology and Nutrition, Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, SickKids, Inflammatory Bowel Disease Centre, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
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Sharara AI, Al Awadhi S, Alharbi O, Al Dhahab H, Mounir M, Salese L, Singh E, Sunna N, Tarcha N, Mosli M. Epidemiology, disease burden, and treatment challenges of ulcerative colitis in Africa and the Middle East. Expert Rev Gastroenterol Hepatol 2018; 12:883-897. [PMID: 30096985 DOI: 10.1080/17474124.2018.1503052] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis is an idiopathic, chronic, inflammatory bowel disorder characterized by an unpredictable course of alternating cycles of relapse and remission. Traditionally viewed as a disease of Western countries, the prevalence of ulcerative colitis is reported to be increasing in the developing world. In these regions, there is the potential to further explore the etiology of the disease, mainly through genetic studies. With this in mind, we consider available data relating to the epidemiology, clinical manifestations, and disease course of ulcerative colitis in Africa and the Middle East. Current treatment approaches in these countries are also reviewed and discussed in the context of new, small molecule, orally administered therapies. Areas covered: Available data on the epidemiology, clinical manifestations, and risk factors of ulcerative colitis in Africa and the Middle East are reviewed using a PubMed database search. Expert commentary: Epidemiologic studies from African and Middle Eastern countries suggest disease trends similar to the West, and an important health and economic burden. The management of ulcerative colitis within these developing countries is challenging, with the need to improve early diagnosis, access to healthcare, and patient education, along with facilitation of access to treatment options and improvement of medication adherence.
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Affiliation(s)
- Ala I Sharara
- a Division of Gastroenterology , American University of Beirut Medical Center , Beirut , Lebanon
| | | | - Othman Alharbi
- c Gastroenterology Division , King Khalid University Hospital, King Saud University , Riyadh , Kingdom of Saudi Arabia
| | - Hisham Al Dhahab
- d Department of Gastroenterology , Royal Hospital , Muscat , Oman
| | | | - Leonardo Salese
- f Department of Gastroenterology , Inflammation and Immunology Medical Affairs, Pfizer Inc , Collegeville , PA , USA
| | - Ena Singh
- f Department of Gastroenterology , Inflammation and Immunology Medical Affairs, Pfizer Inc , Collegeville , PA , USA
| | - Nancy Sunna
- g Department of Inflammation and Immunology , Pfizer Inc , Amman , Jordan
| | | | - Mahmoud Mosli
- h Department of Medicine , King Abdulaziz University , Jeddah , Kingdom of Saudi Arabia
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Aberrantly Expressed Genes and miRNAs in Slow Transit Constipation Based on RNA-Seq Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2617432. [PMID: 30186855 PMCID: PMC6112260 DOI: 10.1155/2018/2617432] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/26/2018] [Accepted: 07/18/2018] [Indexed: 02/06/2023]
Abstract
Background This study aims to identify the key genes and miRNAs in slow transit constipation (STC). Methods MRNA and miRNA expression profiling were obtained. Differentially expressed genes (DEGs) and miRNAs were identified followed by the regulatory network construction. Functional annotation analysis and protein-protein interaction (PPI) network were conducted. The electronic validation was performed. Results Hsa-miR-2116-3p, hsa-miR-3622a-5p, hsa-miR-424-5p, and hsa-miR-1273-3p covered most DEGs. HLA-DRB1, HLA-DRB5, C3, and ICAM were significantly involved in staphylococcus aureus infection. The PPI network generated several hub proteins including ZBTB16, FBN1, CCNF, and CDK1. Electronic validation of HLA-DRB1, PTGDR, MKI67, BIRC5, CCNF, and CDK1 was consistent with the RNA-sequencing analysis. Conclusion Our study might be helpful in understanding the pathology of STC at the molecular level.
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Furue K, Ito T, Tsuji G, Kadono T, Nakahara T, Furue M. Autoimmunity and autoimmune co-morbidities in psoriasis. Immunology 2018; 154:21-27. [PMID: 29315555 PMCID: PMC5904708 DOI: 10.1111/imm.12891] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/18/2017] [Accepted: 12/29/2017] [Indexed: 12/12/2022] Open
Abstract
Psoriasis is characterized by widespread scaly erythematous plaques that cause significant physical and psychological burdens for the affected individuals. Accelerated inflammation driven by the tumour necrosis factor-α/interleukin-23/interleukin-17 axis is now known to be the major mechanism in the development of psoriasis. In addition, psoriasis has an autoimmune nature that manifests as autoreactive T cells and is co-morbid with other autoimmune diseases, such as autoimmune bullous diseases, vitiligo, alopecia and thyroiditis. In this article, we review the recent topics on autoimmunity and autoimmune co-morbidities in psoriasis.
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Affiliation(s)
| | - Takamichi Ito
- Department of DermatologyKyushu UniversityFukuokaJapan
| | - Gaku Tsuji
- Department of DermatologyKyushu UniversityFukuokaJapan
| | - Takafumi Kadono
- Department of DermatologySt Marianna University School of MedicineKawasakiJapan
| | - Takeshi Nakahara
- Department of DermatologyKyushu UniversityFukuokaJapan
- Division of Skin Surface SensingDepartment of DermatologyKyushu UniversityFukuokaJapan
| | - Masutaka Furue
- Department of DermatologyKyushu UniversityFukuokaJapan
- Division of Skin Surface SensingDepartment of DermatologyKyushu UniversityFukuokaJapan
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30
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Mescheriakova JY, Hintzen RQ. No excess of autoimmune diseases in multiple sclerosis families from the Netherlands. Acta Neurol Scand 2018; 137:531-537. [PMID: 29315461 DOI: 10.1111/ane.12896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2017] [Indexed: 01/20/2023]
Abstract
OBJECTIVES Autoimmune diseases (AIDs) cluster in families; however, to what extent AIDs co-occur in MS multiplex families with two or more affected individuals is still controversial. The study aimed to evaluate coexisting AIDs in this type of families from the Netherlands. MATERIALS AND METHODS A total of 155 MS multiplex families (155 MS probands, 959 first-degree relatives and 212 spouses) were characterized for a history of 11 AIDs by means of a self-administered questionnaire. RESULTS In 43.2% of MS multiplex families, at least one AID was present in the first-degree relatives. Overall, the frequency of AIDs was not significantly different between patients with MS (11%), their first-degree family members (11%) and controls (5.2%). After correction for age at inclusion and gender, the odds ratios (OR) for AIDs were not significant for patients with MS (OR = 1.8 [0.77-4.34], P = .17) and first-degree family members (OR = 2.0 [0.98-4.10], P = .06) when both compared to spouses. The frequency of AIDs in mothers did not differ from that in fathers after correction for sex bias (19% vs 8%, P = .51). A presence of AID was more often reported in maternal than paternal second-degree relatives (23% vs 10%, P = .0020). CONCLUSION Although nearly half of the Dutch MS multiplex families reported an AID, no excess of AIDs was present in patients with MS from multiplex families or their first-degree family members compared to the spouses.
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Affiliation(s)
- J. Y. Mescheriakova
- Department of Neurology; MS Centre ErasMS; Erasmus Medical Centre; Rotterdam The Netherlands
| | - R. Q. Hintzen
- Department of Neurology; MS Centre ErasMS; Erasmus Medical Centre; Rotterdam The Netherlands
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Prinz JC. Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis. Front Immunol 2018; 9:954. [PMID: 29760713 PMCID: PMC5936982 DOI: 10.3389/fimmu.2018.00954] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 04/17/2018] [Indexed: 01/08/2023] Open
Abstract
Psoriasis is a complex immune-mediated inflammatory skin disease characterized by T-cell-driven epidermal hyperplasia. It occurs on a strong genetic predisposition. The human leukocyte antigen (HLA)-class I allele HLA-C*06:02 on psoriasis susceptibility locus 1 (PSORS1 on 6p21.3) is the main psoriasis risk gene. Other HLA-class I alleles encoding HLA molecules presenting overlapping peptide repertoires show associations with psoriasis as well. Outside the major histocompatibility complex region, genome-wide association studies identified more than 60 psoriasis-associated common gene variants exerting only modest individual effects. They mainly refer to innate immune activation and the interleukin-23/Th/c17 pathway. Given their strong risk association, explaining the role of the HLA-risk alleles is essential for elucidating psoriasis pathogenesis. Psoriasis lesions develop upon epidermal infiltration, activation, and expansion of CD8+ T cells. The unbiased analysis of a paradigmatic Vα3S1/Vβ13S1-T-cell receptor from a pathogenic epidermal CD8+ T-cell clone of an HLA-C*06:02+ psoriasis patient had revealed that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation, and it identified a peptide form ADAMTS-like protein 5 as an HLA-C*06:02-presented melanocyte autoantigen. These data demonstrate that psoriasis is an autoimmune disease, where the predisposing HLA-class I alleles promote organ-specific inflammation through facilitating a T-cell response against a particular skin-specific cell population. This review discusses the role of HLA-class I alleles in the pathogenic psoriatic T-cell immune response. It concludes that as a principle of T-cell driven HLA-associated inflammatory diseases proinflammatory traits promote autoimmunity in the context of certain HLA molecules that present particular autoantigens.
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Affiliation(s)
- Jörg Christoph Prinz
- Department of Dermatology, University Clinics, Ludwig-Maximilian-University of Munich, Munich, Germany
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32
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Bosca-Watts MM, Minguez M, Planelles D, Navarro S, Rodriguez A, Santiago J, Tosca J, Mora F. HLA-DQ: Celiac disease vs inflammatory bowel disease. World J Gastroenterol 2018; 24:96-103. [PMID: 29358886 PMCID: PMC5757130 DOI: 10.3748/wjg.v24.i1.96] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 11/22/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the genetic predisposition to celiac disease (CeD) in inflammatory bowel disease (IBD) patients by quantifying the frequency of CeD-related human leucocyte antigen (HLA) (HLA-CeD: HLA-DQ2 and -DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease.
METHODS We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors.
RESULTS 1034 subjects were analyzed: 457 IBD [207 ulcerative coliti (UC) and 250 Crohn’s disease (CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD (P = 0.0852). HLA-DQ2 was less frequent in UC patients (P = 0.0287), and HLA-DQ8 in CD (P = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls (P = 0.001) and UC patients (etiological fraction = 15%).
CONCLUSION HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.
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Affiliation(s)
- Marta Maia Bosca-Watts
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Miguel Minguez
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Dolores Planelles
- Histocompatibility Department of the Transfusion Center of the Valencian Community, Valencia 46014, Spain
| | - Samuel Navarro
- Pathology Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Alejandro Rodriguez
- Digestive Disease Department of the Hospital Virgen del Castillo of Yecla, Yecla 30510, Spain
| | - Jesus Santiago
- Digestive Disease Department of the Hospital de Manises, Valencia 46940, Spain
| | - Joan Tosca
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Francisco Mora
- Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
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Iwamoto T, Yashima K, Morio K, Ueda N, Ikebuchi Y, Kawaguchi K, Harada K, Isomoto H. Association of Clinical Features with Human Leukocyte Antigen in Japanese Patients with Ulcerative Colitis. Yonago Acta Med 2018. [DOI: 10.33160/yam.2018.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Taku Iwamoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Keiko Morio
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Naoki Ueda
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
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Kridin K, Zelber-Sagi S, Comaneshter D, Cohen AD. Ulcerative colitis associated with pemphigus: a population-based large-scale study. Scand J Gastroenterol 2017; 52:1360-1364. [PMID: 28954561 DOI: 10.1080/00365521.2017.1380839] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The coexistence of pemphigus and ulcerative colitis (UC) has been described, but the association between the two entities was not examined in the past. The primary endpoint of this study was to investigate the association between pemphigus and UC. MATERIALS AND METHODS Patients with pemphigus were compared to age-, sex- and ethnicity-matched control subjects regarding the prevalence of UC in a cross-sectional study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was conducted utilizing the computerized database of Clalit Health Services. RESULTS The study enrolled 1985 pemphigus patients and 9874 controls. The prevalence rate of UC was greater in patients with pemphigus than in controls (0.9% vs. 0.4%, respectively; p = .004). In a multivariate analysis pemphigus was independently associated with UC (odds ratio 1.9, 95% confidence interval 1.1-3.3, p = .034). This association was stronger among younger patients, and persisted after performing a sensitivity-analysis including only patients who were prescribed pemphigus-specific medications. CONCLUSIONS Pemphigus is significantly associated with UC. Thus, physicians treating patients with pemphigus should be aware of this possible association. Further research is warranted to better understand the mechanism underlying this association.
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Affiliation(s)
- Khalaf Kridin
- a Department of Dermatology , Rambam Health Care Campus , Haifa , Israel
| | - Shira Zelber-Sagi
- b School of Public Health, Faculty of Social Welfare and Health Sciences , University of Haifa , Haifa , Israel
| | - Doron Comaneshter
- c Department of Quality Measurements and Research, Chief Physician's Office , Clalit Health Services , Tel Aviv , Israel
| | - Arnon D Cohen
- c Department of Quality Measurements and Research, Chief Physician's Office , Clalit Health Services , Tel Aviv , Israel.,d Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences , Ben-Gurion University of the Negev , Beer-Sheva , Israel
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35
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Lew D, Yoon SM, Yan X, Robbins L, Haritunians T, Liu Z, Li D, McGovern DPB. Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients. World J Gastroenterol 2017; 23:7265-7273. [PMID: 29142473 PMCID: PMC5677193 DOI: 10.3748/wjg.v23.i40.7265] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 08/25/2017] [Accepted: 09/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations.
METHODS This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer’s protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.
RESULTS Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn’s disease, IgA ASCA (P = 0.04) and IgG-ASCA (P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions (P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event.
CONCLUSION Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic , and pathways associations.
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Affiliation(s)
- Daniel Lew
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Soon Man Yoon
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Xiaofei Yan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Lori Robbins
- Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Zhenqiu Liu
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Dalin Li
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Dermot PB McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
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Abstract
Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD.
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Affiliation(s)
- Ming-Hsi Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
| | - Michael F Picco
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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37
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Prinz JC. Autoimmune aspects of psoriasis: Heritability and autoantigens. Autoimmun Rev 2017; 16:970-979. [PMID: 28705779 DOI: 10.1016/j.autrev.2017.07.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 06/10/2017] [Indexed: 12/28/2022]
Abstract
Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.
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Affiliation(s)
- Jörg Christoph Prinz
- Department of Dermatology, University Clinics, Ludwig-Maximilian-University of Munich, Munich, Germany.
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38
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Sifuentes-Dominguez L, Patel AS. Genetics and Therapeutics in Pediatric Ulcerative Colitis: the Past, Present and Future. F1000Res 2016; 5. [PMID: 26973787 PMCID: PMC4776672 DOI: 10.12688/f1000research.7440.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2016] [Indexed: 12/19/2022] Open
Abstract
Ulcerative colitis (UC) is a relapsing and remitting disease with significant phenotypic and genotypic variability. Though more common in adults, UC is being increasingly diagnosed in childhood. The subsequent lifelong course of disease results in challenges for the patient and physician. Currently, there is no medical cure for UC. Even though surgical removal of the colon can be curative, complications including infertility in females make colectomy an option often considered only when the disease presents with life-threatening complications or when medical management fails. One of the greatest challenges the clinician faces in the care of patients with UC is the inability to predict at diagnosis which patient is going to respond to a specific therapy or will eventually require surgery. This therapeutic conundrum frames the discussion to follow, specifically the concept of individualized or personalized treatment strategies based on genetic risk factors. As we move to therapeutics, we will elucidate traditional approaches and discuss known and novel agents. As we look to the future, we can expect increasing integrated approaches using several scientific disciplines to inform how genetic interactions shape and mold the pathogenesis and therapeutics of UC.
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Affiliation(s)
| | - Ashish S Patel
- Children's Health, UT Southwestern Medical Center, Dallas, Texas, USA
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Kevans D, Silverberg MS, Borowski K, Griffiths A, Xu W, Onay V, Paterson AD, Knight J, Croitoru K. IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients. J Crohns Colitis 2016; 10:209-15. [PMID: 26512135 PMCID: PMC5007582 DOI: 10.1093/ecco-jcc/jjv197] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 10/15/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
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Affiliation(s)
- David Kevans
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mark S. Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Krzysztof Borowski
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada
| | - Anne Griffiths
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada
| | - Wei Xu
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Venus Onay
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada
| | - Andrew D. Paterson
- The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
| | - Jo Knight
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada,Institute of Medical Science, University of Toronto, Toronto, ON, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Ken Croitoru
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, and racial and ethnic differences in disease prevalence. Recently, several new genes have been identified to be involved in the genetic susceptibility to IBD. The characterization of novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD. The development of genetic markers associated with clinical outcomes in patients with IBD will be very important in the future. The progress of molecular biology tools (microarrays, proteomics, and epigenetics) have progressed the field of the genetic markers discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize, and analyze large amounts of data generated by the technological advances. The techniques available for markers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics, and gene expression analyses) and proteomics. This could be a potential great benefit in predicting the course of disease in individual patients and in guiding appropriate medical therapy.
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Abstract
There have been significant advances in our understanding of human autoimmunity that have led to improvements in classification and diagnosis and, most importantly, research advances in new therapies. The importance of autoimmunity and the mechanisms that lead to clinical disease were first recognized about 50 years ago following the pioneering studies of Macfarlane Burnett and his Nobel Prize-winning hypothesis of the 'forbidden clone'. Such pioneering efforts led to a better understanding not only of autoimmunity, but also of lymphoid cell development, thymic education, apoptosis and deletion of autoreactive cells. Contemporary theories suggest that the development of an autoimmune disease requires a genetic predisposition and environmental factors that trigger the immune pathways that lead, ultimately, to tissue destruction. Despite extensive research, there are no genetic tools that can be used clinically to predict the risk of autoimmune disease. Indeed, the concordance of autoimmune disease in identical twins is 12-67%, highlighting not only a role for environmental factors, but also the potential importance of stochastic or epigenetic phenomena. On the other hand, the identification of cytokines and chemokines, and their cognate receptors, has led to novel therapies that block pathological inflammatory responses within the target organ and have greatly improved the therapeutic effect in patients with autoimmune disease, particularly rheumatoid arthritis. Further advances involving the use of multiplex platforms for diagnosis and identification of new therapeutic agents should lead to major breakthroughs within the next decade.
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Affiliation(s)
- Lifeng Wang
- Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Fu-Sheng Wang
- Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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Tseng CC, Yen JH, Tsai WC, Ou TT, Wu CC, Sung WY, Hsieh MC, Chang SJ. Reduced incidence of Crohn's disease in systemic sclerosis: a nationwide population study. BMC Musculoskelet Disord 2015; 16:251. [PMID: 26370572 PMCID: PMC4570507 DOI: 10.1186/s12891-015-0693-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 08/21/2015] [Indexed: 12/28/2022] Open
Abstract
Background To date, there has been no studies to evaluate the incidence of Crohn’s disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn’s disease and its relationship with sex and age in patients with systemic sclerosis. Methods We enrolled patients with systemic sclerosis and controls from Taiwan’s Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn’s disease in systemic sclerosis patients, and 95 % confidence interval (95 % CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). Results The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn’s disease (SIR: 0.18, 95 % CI = 0.05–0.62; SIR: 0.10, 95 % CI = 0.05–0.21, respectively). The risk of incident Crohn’s disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn’s disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95 % CI = 0.06–0.21, p < 0.001). Conclusions Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.
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Affiliation(s)
- Chia-Chun Tseng
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Jeng-Hsien Yen
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Wen-Chan Tsai
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Tsan-Teng Ou
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Cheng-Chin Wu
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Wan-Yu Sung
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Ming-Chia Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan. .,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
| | - Shun-Jen Chang
- Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung, Taiwan.
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Mahdi BM. Role of HLA typing on Crohn's disease pathogenesis. Ann Med Surg (Lond) 2015; 4:248-53. [PMID: 26288728 PMCID: PMC4537883 DOI: 10.1016/j.amsu.2015.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/10/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) is the main type of chronic inflammatory bowel disease of unknown etiology. Evidence from family and twin studies suggests that genetics plays a significant role in predisposing an individual to develop Crohn's disease. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators which is expressed in hematopoietic compartment cells and intestinal epithelial cells as well as in paneth cells, where NOD2 may play an important role in the pathogenesis of Crohn disease in the gastrointestinal system. This leads to alteration the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has two functions, first an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. Thus, NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in intestinal epithelial cells as well as in paneth cells. Further confirmation of a genetic predisposition comes from studies of the association between the human leukocyte antigen (HLA) system and CD. The immunogenetic predisposition may be considered an important requirement for the development of CD, as several alleles of human major histocompatibility complex had an association with CD. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility in a population, studies of HLA allele sharing within families suggest that this region contributes between 10% and 33% of the total genetic risk of Crohn's disease.
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Moran CJ, Klein C, Muise AM, Snapper SB. Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 2015; 21:1166-75. [PMID: 25895007 PMCID: PMC6165626 DOI: 10.1097/mib.0000000000000329] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.
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Affiliation(s)
- Christopher J. Moran
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Christoph Klein
- Dr von Hauner Children’s Hospital, Ludwig Maximilians University, Munich, Germany
| | - Aleixo M. Muise
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
| | - Scott B. Snapper
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts
- Division of Gastroenterology and Hepatology, Brigham & Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
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Central role of gimap5 in maintaining peripheral tolerance and T cell homeostasis in the gut. Mediators Inflamm 2015; 2015:436017. [PMID: 25944983 PMCID: PMC4405212 DOI: 10.1155/2015/436017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 09/15/2014] [Indexed: 01/01/2023] Open
Abstract
Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)—including whole exome or genome sequencing—have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of “IBD-prone” animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans, GIMAP5 has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4+ T cell-mediated early-onset colitis.
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Weizman AV, Huang B, Targan S, Dubinsky M, Fleshner P, Kaur M, Ippoliti A, Panikkath D, Vasiliauskas E, Shih D, McGovern DPB, Melmed GY. Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study. J Cutan Med Surg 2015; 19:125-31. [PMID: 25775631 DOI: 10.2310/7750.2014.14053] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). OBJECTIVE To better characterize PG features and management among an IBD cohort. METHODS Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. RESULTS Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. CONCLUSIONS We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients.
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Affiliation(s)
- Adam V Weizman
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Brian Huang
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Stephan Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Marla Dubinsky
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Phillip Fleshner
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Manreet Kaur
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Andrew Ippoliti
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Deepa Panikkath
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Eric Vasiliauskas
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - David Shih
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
| | - Gil Y Melmed
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CAWomen's College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ONDepartment of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CAMedical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA
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Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DPB, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 2015; 47:172-9. [PMID: 25559196 PMCID: PMC4310771 DOI: 10.1038/ng.3176] [Citation(s) in RCA: 236] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 12/04/2014] [Indexed: 02/08/2023]
Abstract
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
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Affiliation(s)
- Philippe Goyette
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
| | | | - Dermot Mallon
- 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
| | - Eva Ellinghaus
- Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany
| | - Luke Jostins
- 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. [2] Christ Church, University of Oxford, St Aldates, UK
| | - Hailiang Huang
- 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Stephan Ripke
- 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Elena S Gusareva
- 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium
| | - Vito Annese
- 1] Unit of Gastroenterology, IRCCS-CSS (Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza) Hospital, San Giovanni Rotondo, Italy. [2] Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy
| | - Stephen L Hauser
- Department of Neurology, University of California, San Francisco, San Francisco, California, USA
| | - Jorge R Oksenberg
- Department of Neurology, University of California, San Francisco, San Francisco, California, USA
| | - Ingo Thomsen
- Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany
| | - Stephen Leslie
- 1] Murdoch Children's Research Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia
| | - Mark J Daly
- 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Kristel Van Steen
- 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium
| | - Richard H Duerr
- 1] Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. [2] Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | | | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA
| | - James A Traherne
- 1] Cambridge Institute for Medical Research, Cambridge, UK. [2] Department of Pathology, University of Cambridge, Cambridge, UK
| | - Mary N Carrington
- 1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [2] Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA
| | - Vasilis Kosmoliaptsis
- 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK
| | - Tom H Karlsen
- 1] Research Institute of Internal Medicine, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [2] Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [3] K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany
| | - John D Rioux
- 1] Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada
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Muro M, López-Hernández R, Mrowiec A. Immunogenetic biomarkers in inflammatory bowel diseases: Role of the IBD3 region. World J Gastroenterol 2014; 20:15037-15048. [PMID: 25386052 PMCID: PMC4223237 DOI: 10.3748/wjg.v20.i41.15037] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/19/2013] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8+ cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4+ T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.
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Associations of HLA class I alleles in Japanese patients with Crohn's disease. Genes Immun 2014; 16:54-6. [PMID: 25373727 DOI: 10.1038/gene.2014.61] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 08/29/2014] [Accepted: 09/12/2014] [Indexed: 12/19/2022]
Abstract
Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.
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