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Park JM, Kim J, Lee YJ, Bae SU, Lee HW. Inflammatory bowel disease-associated intestinal fibrosis. J Pathol Transl Med 2023; 57:60-66. [PMID: 36623814 PMCID: PMC9846010 DOI: 10.4132/jptm.2022.11.02] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 01/11/2023] Open
Abstract
Fibrosis is characterized by a proliferation of fibroblasts and excessive extracellular matrix following chronic inflammation, and this replacement of organ tissue with fibrotic tissue causes a loss of function. Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract, and intestinal fibrosis is common in IBD patients, resulting in several complications that require surgery, such as a stricture or penetration. This review describes the pathogenesis and various factors involved in intestinal fibrosis in IBD, including cytokines, growth factors, epithelial-mesenchymal and endothelial-mesenchymal transitions, and gut microbiota. Furthermore, histopathologic findings and scoring systems used for stenosis in IBD are discussed, and differences in the fibrosis patterns of ulcerative colitis and Crohn's disease are compared. Biomarkers and therapeutic agents targeting intestinal fibrosis are briefly mentioned at the end.
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Affiliation(s)
- Ji Min Park
- Department of Pathology, Keimyung University School of Medicine, Daegu,
Korea
| | - Jeongseok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu,
Korea
| | - Yoo Jin Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu,
Korea
| | - Sung Uk Bae
- Division of Colorectal Surgery, Department of Surgery, Keimyung University School of Medicine, Daegu,
Korea
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Daegu,
Korea
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Saez A, Gomez-Bris R, Herrero-Fernandez B, Mingorance C, Rius C, Gonzalez-Granado JM. Innate Lymphoid Cells in Intestinal Homeostasis and Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:ijms22147618. [PMID: 34299236 PMCID: PMC8307624 DOI: 10.3390/ijms22147618] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn’s disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Claudia Mingorance
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
| | - Cristina Rius
- Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid (UEM), Villaviciosa de Odón, 28670 Madrid, Spain;
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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Abstract
Innate lymphoid cells (ILCs) are a large family of cells of the immune system that performs various functions in immune defense, inflammation, and tissue remodeling. As a part of the innate immune system, ILCs are a distinct form of lymphocytes different from T and B cells. ILCs can provide host defense against the source of infection and initiate the repair and remodeling processes to restore and maintain host body homeostasis. The number of patients with Crohn’s disease (CD) worldwide has continued to increase in recent years and this disease has brought sickness and death to many families. Numerous studies have found that ILCs also undergo a series of alternations during the development of CD and contribute to this disease. Despite this, the pathogenesis of CD is still not fully explained. So, we keep researching and exploring. In this review, we have closely linked the latest progress on ILCs and CD, and introduced, in detail, the specific roles of four different types of ILCs in CD. We also describe new progress in the pathogenesis of CD, with particular emphasis on the plasticity of ILC3s in this disease. These new studies and findings may provide new insights and breakthrough points for the treatment of CD.
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Affiliation(s)
- Ying Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
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Li H, Lai L, Shen J. Development of a susceptibility gene based novel predictive model for the diagnosis of ulcerative colitis using random forest and artificial neural network. Aging (Albany NY) 2020; 12:20471-20482. [PMID: 33099536 PMCID: PMC7655162 DOI: 10.18632/aging.103861] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis is a type of inflammatory bowel disease characterized by chronic and recurrent nonspecific inflammation of the intestinal tract. To find susceptibility genes and develop a novel predictive model of ulcerative colitis, two sets of cases and a control group containing the ulcerative colitis gene expression profile (training set GSE109142 and validation set GSE92415) were downloaded and used to identify differentially expressed genes. A total of 781 upregulated and 127 downregulated differentially expressed genes were identified in GSE109142. The random forest algorithm was introduced to determine 1 downregulated and 29 upregulated differentially expressed genes contributing highest to ulcerative colitis occurrence. Expression data of these 30 genes were transformed into gene expression scores, and an artificial neural network model was developed to calculate differentially expressed genes weights to ulcerative colitis. We established a universal molecular prognostic score (mPS) based on the expression data of the 30 genes and verified the mPS system with GSE92415. Prediction results agreed with that of an independent data set (ROC-AUC=0.9506/PR-AUC=0.9747). Our research creates a reliable predictive model for the diagnosis of ulcerative colitis, and provides an alternative marker panel for further research in disease early screening
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Affiliation(s)
- Hanyang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
| | - Lijie Lai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China.,Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Shanghai Institute of Digestive Disease, Shanghai 200127, China
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Zhang S, Cao L, Li Z, Qu D. Metabolic reprogramming links chronic intestinal inflammation and the oncogenic transformation in colorectal tumorigenesis. Cancer Lett 2019; 450:123-131. [DOI: 10.1016/j.canlet.2019.02.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/18/2019] [Accepted: 02/28/2019] [Indexed: 02/07/2023]
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Mayers MD, Moon C, Stupp GS, Su AI, Wolan DW. Quantitative Metaproteomics and Activity-Based Probe Enrichment Reveals Significant Alterations in Protein Expression from a Mouse Model of Inflammatory Bowel Disease. J Proteome Res 2017; 16:1014-1026. [PMID: 28052195 DOI: 10.1021/acs.jproteome.6b00938] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Tandem mass spectrometry based shotgun proteomics of distal gut microbiomes is exceedingly difficult due to the inherent complexity and taxonomic diversity of the samples. We introduce two new methodologies to improve metaproteomic studies of microbiome samples. These methods include the stable isotope labeling in mammals to permit protein quantitation across two mouse cohorts as well as the application of activity-based probes to enrich and analyze both host and microbial proteins with specific functionalities. We used these technologies to study the microbiota from the adoptive T cell transfer mouse model of inflammatory bowel disease (IBD) and compare these samples to an isogenic control, thereby limiting genetic and environmental variables that influence microbiome composition. The data generated highlight quantitative alterations in both host and microbial proteins due to intestinal inflammation and corroborates the observed phylogenetic changes in bacteria that accompany IBD in humans and mouse models. The combination of isotope labeling with shotgun proteomics resulted in the total identification of 4434 protein clusters expressed in the microbial proteomic environment, 276 of which demonstrated differential abundance between control and IBD mice. Notably, application of a novel cysteine-reactive probe uncovered several microbial proteases and hydrolases overrepresented in the IBD mice. Implementation of these methods demonstrated that substantial insights into the identity and dysregulation of host and microbial proteins altered in IBD can be accomplished and can be used in the interrogation of other microbiome-related diseases.
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Affiliation(s)
- Michael D Mayers
- Department of Molecular and Experimental Medicine, ‡Department of Integrative Structural and Computational Biology, and §Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Clara Moon
- Department of Molecular and Experimental Medicine, ‡Department of Integrative Structural and Computational Biology, and §Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Gregory S Stupp
- Department of Molecular and Experimental Medicine, ‡Department of Integrative Structural and Computational Biology, and §Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Andrew I Su
- Department of Molecular and Experimental Medicine, ‡Department of Integrative Structural and Computational Biology, and §Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Dennis W Wolan
- Department of Molecular and Experimental Medicine, ‡Department of Integrative Structural and Computational Biology, and §Department of Chemical Physiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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Peng LL, Wang Y, Zhu FL, Xu WD, Ji XL, Ni J. IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis. Oncotarget 2017; 8:4849-4863. [PMID: 27902482 PMCID: PMC5354875 DOI: 10.18632/oncotarget.13607] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 11/12/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Since a genome-wide association study revealed that Interleukin-23 receptor (IL-23R) gene is a candidate gene for Ulcerative Colitis (UC), many studies have investigated the association between the IL-23R polymorphisms and UC. However, the results were controversial. The aim of the study was to determine whether the IL-23R polymorphisms confer susceptibility to UC. METHODS A systematic literature search was carried out to identify all potentially relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. RESULTS A total of 33 studies in 32 articles, including 10,527 UC cases and 15,142 healthy controls, were finally involved in the meta-analysis. Overall, a significant association was found between all UC cases and the rs11209026A allele (OR = 0.665, 95% CI = 0.604~0.733, P < 0.001). Similarly, meta-analyses of the rs7517847, rs1004819, rs10889677, rs2201841, rs11209032, rs1495965, rs1343151 and rs11465804 polymorphisms also indicated significant association with all UC (all P < 0.05). Stratification by ethnicity revealed that the rs11209026, rs7517847, rs10889677, rs2201841 andrs11465804 polymorphisms were associated with UC in the Caucasian group, but not in Asians, while the rs1004819 and rs11209032 polymorphisms were found to be related to UC for both Caucasian and Asian groups. However, subgroup analysis failed to unveil any association between the rs1495965 and rs1343151 polymorphisms and UC in Caucasians or Asians. CONCLUSIONS The meta-analysis suggests significant association between IL-23R polymorphisms and UC, especially in Caucasians.
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Affiliation(s)
- Ling-Long Peng
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Ying Wang
- Department of Environmental Health, Suzhou Municipal Center for Disease Prevention and Control, Suzhou, Jiangsu 215004, China
| | - Feng-Ling Zhu
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Wang-Dong Xu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xue-Lei Ji
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Jing Ni
- The Teaching Centre for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
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8
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Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections. PLoS One 2016; 11:e0146585. [PMID: 26751573 PMCID: PMC4713433 DOI: 10.1371/journal.pone.0146585] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 12/18/2015] [Indexed: 02/08/2023] Open
Abstract
Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects.
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Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug-drug interactions. THE PHARMACOGENOMICS JOURNAL 2015; 15:473-87. [PMID: 26526073 DOI: 10.1038/tpj.2015.78] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 08/20/2015] [Accepted: 09/08/2015] [Indexed: 02/08/2023]
Abstract
The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration-time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.
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Juyal G, Negi S, Sood A, Gupta A, Prasad P, Senapati S, Zaneveld J, Singh S, Midha V, van Sommeren S, Weersma RK, Ott J, Jain S, Juyal RC, Thelma BK. Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis. Gut 2015; 64:571-9. [PMID: 24837172 DOI: 10.1136/gutjnl-2013-306625] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Over 100 ulcerative colitis (UC) loci have been identified by genome-wide association studies (GWASs) primarily in Caucasians (CEUs). Many of them have weak effects on disease susceptibility, and the bulk of the heritability cannot be ascribed to these loci. Very little is known about the genetic background of UC in non-CEU groups. Here we report the first GWAS on UC in a genetically distinct north Indian (NI) population. DESIGN A genome-wide scan was performed on 700 cases and 761 controls. 18 single-nucleotide polymorphisms (SNPs) (p<5×10(-5)) were genotyped in an independent cohort of 733 cases and 1148 controls. A linear mixed model was used for case-control association tests. RESULTS Seven novel human leucocyte antigen (HLA)-independent SNPs from chromosome 6, located in 3.8-1, BAT2, MSH5, HSPA1L, SLC44A4, CFB and NOTCH4, exceeded p<5×10(-8) in the combined analysis. To assess the independent biological contribution of such genes from the extended HLA region, we determined the percentage alternative pathway activity of complement factor B (CFB), the top novel hit. The activity was significantly different (p=0.01) between the different genotypes at rs12614 in UC cases. Transethnic comparisons revealed a shared contribution of a fraction of UC risk genes between NI and CEU populations, in addition to genetic heterogeneity. CONCLUSIONS This study shows varying contribution of the HLA region to UC in different populations. Different environmental exposures and the characteristic genetic structure of the HLA locus across ethnic groups collectively make it amenable to the discovery of causative alleles by transethnic resequencing. This may lead to an improved understanding of the molecular mechanisms underlying UC.
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Affiliation(s)
- Garima Juyal
- Department of Genetics, University of Delhi South Campus, New Delhi, India
| | - Sapna Negi
- National Institute of Immunology, New Delhi, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Aditi Gupta
- Department of Genetics, University of Delhi South Campus, New Delhi, India
| | - Pushplata Prasad
- Department of Genetics, University of Delhi South Campus, New Delhi, India
| | | | - Jacques Zaneveld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Shalini Singh
- Department of Genetics, University of Delhi South Campus, New Delhi, India
| | - Vandana Midha
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Suzanne van Sommeren
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Jurg Ott
- Key Laboratory of Mental Health Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Sanjay Jain
- Departments of Physics and Astrophysics, University of Delhi, Delhi, India
| | | | - B K Thelma
- Department of Genetics, University of Delhi South Campus, New Delhi, India
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11
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Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PPD, Seibold P, Fasching PA, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, García-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann MW, Knight JA, Glendon G, Tchatchou S, Alnæs GIG, Borresen-Dale AL, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer HU, Rüdiger T, Jager A, van Deurzen CHM, Tilanus-Linthorst MMA, Muranen TA, Aittomäki K, Blomqvist C, Margolin S, Kosma VM, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips KA, kConFab Investigators, Linn S, Cornelissen S, van den Broek SAJ, Kang D, Choi JY, Park SK, Yoo KY, Hsiung CN, Wu PE, Hou MF, Shen CY, Teo SH, Taib NAM, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy. Breast Cancer Res 2015; 17:18. [PMID: 25849327 PMCID: PMC4374346 DOI: 10.1186/s13058-015-0522-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 01/23/2015] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). METHODS We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. RESULTS Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻⁴) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻⁴), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻⁴). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity. CONCLUSIONS TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
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Affiliation(s)
- Jieping Lei
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
| | - Anja Rudolph
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
| | - Kirsten B Moysich
- />Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 USA
| | - Sajjad Rafiq
- />Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, SO16 6YD UK
| | - Sabine Behrens
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
| | - Ellen L Goode
- />Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - Paul PD Pharoah
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
- />Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN UK
| | - Petra Seibold
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
| | - Peter A Fasching
- />University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen–Nuremberg, Universitätsstrasse 21-23, 91054 Erlangen, Germany
- />Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095 USA
| | - Irene L Andrulis
- />Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada
- />Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8 Canada
| | - Vessela N Kristensen
- />Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway
- />K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
- />Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Sykehusveien 25, 1478 Lørenskog, Norway
| | - Fergus J Couch
- />Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA
| | - Ute Hamann
- />Division of Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
| | - Maartje J Hooning
- />Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075EA Rotterdam, The Netherlands
| | - Heli Nevanlinna
- />Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029 Helsinki, Finland
| | - Ursula Eilber
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
| | - Manjeet K Bolla
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
| | - Joe Dennis
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
| | - Qin Wang
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
| | - Annika Lindblom
- />Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-17177 Sweden
| | - Arto Mannermaa
- />School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
- />Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland
- />Cancer Center, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
| | - Diether Lambrechts
- />Vesalius Research Center (VRC), VIB, Herestraat 49, 3000 Leuven, Belgium
- />Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Montserrat García-Closas
- />Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850 USA
- />Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, SM2 5NG UK
- />Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, SW3 6JB UK
| | - Per Hall
- />Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden
| | - Georgia Chenevix-Trench
- />QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, Queensland 4006 Australia
| | - Mitul Shah
- />Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN UK
| | - Robert Luben
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
| | - Lothar Haeberle
- />University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen–Nuremberg, Universitätsstrasse 21-23, 91054 Erlangen, Germany
| | - Arif B Ekici
- />Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Schlossplatz 4, 91054 Erlangen, Germany
| | - Matthias W Beckmann
- />University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen–Nuremberg, Universitätsstrasse 21-23, 91054 Erlangen, Germany
| | - Julia A Knight
- />Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X 5 Canada
- />Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, Ontario M5T 3M7 Canada
| | - Gord Glendon
- />Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada
| | - Sandrine Tchatchou
- />Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada
| | - Grethe I Grenaker Alnæs
- />Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway
- />K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
| | - Anne-Lise Borresen-Dale
- />Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway
- />K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
| | - Silje Nord
- />Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway
- />K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
| | - Janet E Olson
- />Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - Emily Hallberg
- />Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - Celine Vachon
- />Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - Diana Torres
- />Division of Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- />Institute of Human Genetics, Pontificia Universidad Javeriana, Carrera 7, Bogotá, 11001000 Colombia
| | - Hans-Ulrich Ulmer
- />Frauenklinik der Stadtklinik Baden-Baden, D-7570 Baden-Baden, Germany
| | - Thomas Rüdiger
- />Institute of Pathology, Städtisches Klinikum Karlsruhe, Moltkestrasse 90, 76133 Karlsruhe, Germany
| | - Agnes Jager
- />Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075EA Rotterdam, The Netherlands
| | - Carolien HM van Deurzen
- />Department of Pathology, Erasmus University Medical Center, 3075EA Rotterdam, The Netherlands
| | | | - Taru A Muranen
- />Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029 Helsinki, Finland
| | - Kristiina Aittomäki
- />Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029 Helsinki, Finland
| | - Carl Blomqvist
- />Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00029 HUS Helsinki, Finland
| | - Sara Margolin
- />Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SE-17177 Sweden
| | - Veli-Matti Kosma
- />School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
- />Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland
- />Cancer Center, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
| | - Jaana M Hartikainen
- />School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
- />Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland
- />Cancer Center, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
| | - Vesa Kataja
- />School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
- />Cancer Center, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
- />Jyväskylä Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland
| | - Sigrid Hatse
- />Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- />Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Hans Wildiers
- />Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Ann Smeets
- />Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Jonine Figueroa
- />Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850 USA
| | - Stephen J Chanock
- />Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850 USA
| | - Jolanta Lissowska
- />Department of Cancer Epidemiology and Prevention, Cancer Center and M Sklodowska-Curie Institute of Oncology, 02-781 Warsaw, Poland
| | - Jingmei Li
- />Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden
- />Human Genetics, Genome Institute of Singapore, 60 Biopolis Street 02-01, Singapore, 138672 Singapore
- />Saw Swee Hock School of Public Health, National University of Singapore, MD3, 16 Medical Drive, Singapore, 117597 Singapore
| | - Keith Humphreys
- />Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden
| | - Kelly-Anne Phillips
- />Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Level 1, 723 Swanston Street, Melbourne, Victoria 3010 Australia
- />Sir Peter MacCallum Department of Oncology, University of Melbourne, St Andrews Place East, East Melbourne, Victoria 3002 Australia
| | - kConFab Investigators
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
- />Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 USA
- />Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, SO16 6YD UK
- />Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
- />Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN UK
- />University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen–Nuremberg, Universitätsstrasse 21-23, 91054 Erlangen, Germany
- />Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095 USA
- />Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada
- />Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8 Canada
- />Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway
- />K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
- />Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Sykehusveien 25, 1478 Lørenskog, Norway
- />Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 USA
- />Division of Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- />Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075EA Rotterdam, The Netherlands
- />Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029 Helsinki, Finland
- />Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-17177 Sweden
- />School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
- />Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland
- />Cancer Center, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland
- />Vesalius Research Center (VRC), VIB, Herestraat 49, 3000 Leuven, Belgium
- />Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
- />Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850 USA
- />Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, SM2 5NG UK
- />Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, SW3 6JB UK
- />Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden
- />QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, Queensland 4006 Australia
- />Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Schlossplatz 4, 91054 Erlangen, Germany
- />Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X 5 Canada
- />Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, Ontario M5T 3M7 Canada
- />Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada
- />Institute of Human Genetics, Pontificia Universidad Javeriana, Carrera 7, Bogotá, 11001000 Colombia
- />Frauenklinik der Stadtklinik Baden-Baden, D-7570 Baden-Baden, Germany
- />Institute of Pathology, Städtisches Klinikum Karlsruhe, Moltkestrasse 90, 76133 Karlsruhe, Germany
- />Department of Pathology, Erasmus University Medical Center, 3075EA Rotterdam, The Netherlands
- />Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075EA Rotterdam, The Netherlands
- />Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029 Helsinki, Finland
- />Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00029 HUS Helsinki, Finland
- />Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SE-17177 Sweden
- />Jyväskylä Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland
- />Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- />Department of Cancer Epidemiology and Prevention, Cancer Center and M Sklodowska-Curie Institute of Oncology, 02-781 Warsaw, Poland
- />Human Genetics, Genome Institute of Singapore, 60 Biopolis Street 02-01, Singapore, 138672 Singapore
- />Saw Swee Hock School of Public Health, National University of Singapore, MD3, 16 Medical Drive, Singapore, 117597 Singapore
- />Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Level 1, 723 Swanston Street, Melbourne, Victoria 3010 Australia
- />Sir Peter MacCallum Department of Oncology, University of Melbourne, St Andrews Place East, East Melbourne, Victoria 3002 Australia
- />Division of Molecular Pathology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
- />Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 Korea
- />Department of Biomedical Sciences, Seoul National University Graduate School, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742 Korea
- />Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 Korea
- />Institute of Biomedical Sciences, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
- />Taiwan Biobank, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
- />Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, No.100 , Tzyou 1st Road, Kaohsiung, 807 Taiwan
- />College of Public Health, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402 Taiwan
- />Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS 12/1A, Subang Jaya, 47500 Selangor Malaysia
- />Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
- />Department of Oncology, Faculty of Medicine, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
- />Department of Preventive Medicine, Faculty of Medical SciencesLembah Pantai, Kyushu University, Fukuoka, 812-8582 Japan
- />Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681 Aichi Japan
- />Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681 Aichi Japan
- />Epidemiology Center for Disease Control and Prevention, Mie University Hospital, 1577 Kurimamachiya-cho, Tsu City, Mie Prefecture 514-8507 Japan
- />Human Genotyping Unit-Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- />Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
- />Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
| | - Sabine Linn
- />Division of Molecular Pathology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
| | - Sten Cornelissen
- />Division of Molecular Pathology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
| | | | - Daehee Kang
- />Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 Korea
- />Department of Biomedical Sciences, Seoul National University Graduate School, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742 Korea
| | - Ji-Yeob Choi
- />Department of Biomedical Sciences, Seoul National University Graduate School, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742 Korea
| | - Sue K Park
- />Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 Korea
- />Department of Biomedical Sciences, Seoul National University Graduate School, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742 Korea
| | - Keun-Young Yoo
- />Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 Korea
| | - Chia-Ni Hsiung
- />Institute of Biomedical Sciences, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
| | - Pei-Ei Wu
- />Institute of Biomedical Sciences, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
- />Taiwan Biobank, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
| | - Ming-Feng Hou
- />Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, No.100 , Tzyou 1st Road, Kaohsiung, 807 Taiwan
| | - Chen-Yang Shen
- />Institute of Biomedical Sciences, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
- />Taiwan Biobank, Academia Sinica, Academia Road Nankang, Taipei, 115 Taiwan
- />College of Public Health, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402 Taiwan
| | - Soo Hwang Teo
- />Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS 12/1A, Subang Jaya, 47500 Selangor Malaysia
- />Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
| | - Nur Aishah Mohd Taib
- />Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
| | - Cheng Har Yip
- />Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
| | - Gwo Fuang Ho
- />Department of Oncology, Faculty of Medicine, University Malaya, Lembah Pantai, 59100 Kuala Lumpur, Malaysia
| | - Keitaro Matsuo
- />Department of Preventive Medicine, Faculty of Medical SciencesLembah Pantai, Kyushu University, Fukuoka, 812-8582 Japan
| | - Hidemi Ito
- />Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681 Aichi Japan
| | - Hiroji Iwata
- />Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681 Aichi Japan
| | - Kazuo Tajima
- />Epidemiology Center for Disease Control and Prevention, Mie University Hospital, 1577 Kurimamachiya-cho, Tsu City, Mie Prefecture 514-8507 Japan
| | - Alison M Dunning
- />Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN UK
| | - Javier Benitez
- />Human Genotyping Unit-Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- />Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Kamila Czene
- />Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 171 77 Stockholm, Sweden
| | - Lara E Sucheston
- />Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263 USA
| | - Tom Maishman
- />Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, SO16 6YD UK
| | - William J Tapper
- />Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, SO16 6YD UK
| | - Diana Eccles
- />Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, SO16 6YD UK
| | - Douglas F Easton
- />Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
- />Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN UK
| | - Marjanka K Schmidt
- />Division of Molecular Pathology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
- />Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, The Netherlands
| | - Jenny Chang-Claude
- />Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
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Zemljic M, Pejkovic B, Krajnc I, Lipovsek S. Biological pathways involved in the development of inflammatory bowel disease. Wien Klin Wochenschr 2014; 126:626-33. [PMID: 25256178 DOI: 10.1007/s00508-014-0592-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 08/09/2014] [Indexed: 02/07/2023]
Abstract
Apoptosis, autophagy and necrosis are three distinct functional types of the mammalian cell death network. All of them are characterized by a number of cell's morphological changes. The inappropriate induction of cell death is involved in the pathogenesis of a number of diseases.Pathogenesis of inflammatory bowel diseases (ulcerative colitis, Crohn's disease) includes an abnormal immunological response to disturbed intestinal microflora. One of the most important reason in pathogenesis of chronic inflammatory disease and subsequent multiple organ pathology is a barrier function of the gut, regulating cellular viability. Recent findings have begun to explain the mechanisms by which intestinal epithelial cells are able to survive in such an environment and how loss of normal regulatory processes may lead to inflammatory bowel disease (IBD).This review focuses on the regulation of biological pathways in development and homeostasis in IBD. Better understanding of the physiological functions of biological pathways and their influence on inflammation, immunity, and barrier function will simplify our expertice of homeostasis in the gastrointestinal tract and in upgrading diagnosis and treatment.
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Affiliation(s)
- Mateja Zemljic
- Institute of Anatomy, Histology and Embryology, Faculty of Medicine, University of Maribor, Ljubljanska 5, 2000, Maribor, Slovenia,
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13
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Lee YJ, Park KS. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J Gastroenterol 2014; 20:2456-2469. [PMID: 24627583 PMCID: PMC3949256 DOI: 10.3748/wjg.v20.i10.2456] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/01/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.
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14
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NOD2 mutations affect muramyl dipeptide stimulation of human B lymphocytes and interact with other IBD-associated genes. Dig Dis Sci 2013; 58:2599-607. [PMID: 23709157 DOI: 10.1007/s10620-013-2696-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 04/18/2013] [Indexed: 12/29/2022]
Abstract
BACKGROUND Genetic and functional studies have associated variants in the NOD2/CARD15 gene with Crohn's disease. AIMS This study aims to replicate the association of three common NOD2 mutations with Crohn's disease, study its effect on NOD2 expression in B cells and its interaction with other IBD-associated genes. METHODS A total of 294 IBD patients (179 familial IBD, 115 sporadic IBD) and 298 unrelated healthy controls were from central Pennsylvania. NOD2 mutations were analyzed by primer-specific amplification, PCR based-RFLP, and validated with the ABI SNPlexM genotyping system. Gene-gene interaction was studied using a statistical model for epistasis analysis. RESULTS Three common NOD2 mutations are associated with Crohn's disease (p=5.08×10(-7), 1.67×10(-6), and 1.87×10(-2) for 1007fs, R720W, and G908R, respectively), but not with ulcerative colitis (p=0.1046, 0.1269, and 0.8929, respectively). For IBD overall, 1007finsC (p=4.4×10(-5)) and R720W (p=9.24×10(-5)) were associated with IBD, but not G908R (p=0.1198). We revealed significant interactions of NOD2 with other IBD susceptibility genes IL23R, DLG5, and OCTN1. We discovered that NOD2 was expressed in both normal human peripheral blood B cells and in EBV-transformed B cell lines. Moreover, we further demonstrated that muramyl dipeptide (MDP) stimulation of B lymphocytes up-regulated expression of NF-κB-p50 mRNA. CONCLUSION NOD2 is expressed in peripheral B cells, and the up-regulation of NOD2 expression by MDP was significantly impaired by NOD2 mutations. The finding suggests a possible role of NOD2 in the immunological response in IBD pathogenesis.
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García-Domenech R, Gálvez-Llompart M, Zanni R, Recio MC, Gálvez J. QSAR methods for the discovery of new inflammatory bowel disease drugs. Expert Opin Drug Discov 2013; 8:933-49. [PMID: 23668227 DOI: 10.1517/17460441.2013.800043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) represents an important class of chronic gastrointestinal tract disease. And although there are already several useful treatments to reduce and control the symptoms, there is still no cure. One drug discovery technique used is the computer-aided (in silico) discovery approach which has largely demonstrated efficacy. Computational techniques, when used in combination with traditional drug discovery methodology, greatly increase the chance of drug discovery in a sustainable and economical fashion. AREAS COVERED This review aims to provide the most recent and important advances of in silico IBD drug discovery. While this review is mainly focused on QSAR methods, especially those based on molecular topology (MT), additional topics, such as docking or comparative field analysis are also addressed. EXPERT OPINION IBD is a worldwide growing health concern that can only be currently treated in symptomatic and palliative way; thus, the search for new drugs is imperative. Computer-aided methods, which focus on the drug-receptor interaction, are essential tool in this regard. It is noted, however that a major problem is that although there are many known receptors associated with IBD, none of these have yet been found essential. The use of other approaches, including QSAR methodology, is certainly a complementary and attractive alternative; especially QSAR methods based on MT, which has proven successful in other drug discovery.
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Affiliation(s)
- Ramón García-Domenech
- University of Valencia, Faculty of Pharmacy, Department of Physical Chemistry, Molecular Connectivity and Drug Design Research Unit, Avda. V.A. Estellés, s/n, 46100 Burjassot, Valencia, Spain.
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Correale C, Genua M, Vetrano S, Mazzini E, Martinoli C, Spinelli A, Arena V, Peyrin-Biroulet L, Caprioli F, Passini N, Panina-Bordignon P, Repici A, Malesci A, Rutella S, Rescigno M, Danese S. Bacterial sensor triggering receptor expressed on myeloid cells-2 regulates the mucosal inflammatory response. Gastroenterology 2013; 144:346-356.e3. [PMID: 23108068 DOI: 10.1053/j.gastro.2012.10.040] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 10/19/2012] [Accepted: 10/24/2012] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIMS Triggering receptor expressed on myeloid cells (TREM)-2 is a surface receptor detected on macrophages, dendritic cells, and microglia that binds repeated anionic motifs on yeast and Gram-positive and Gram-negative bacteria. Little is known about TREM-2 expression and function in the intestine or its role in inflammatory bowel disease (IBD). We investigated the expression of TREM-2 in the intestinal lamina propria and its role in the development of colonic inflammation. METHODS We measured levels of TREM-2 in lamina propria mononuclear cells from surgical specimens collected from patients with IBD or cancer (controls). We analyzed the development of colitis in TREM-2 knockout and wild-type mice. Colon samples were isolated from mice and analyzed for cytokine expression, phagocytosis of bacteria, proliferation in colonic crypts, lamina propria mononuclear cell function, and T-cell activation by ovalbumin. RESULTS TREM-2 was virtually absent from colon samples of control patients, but levels were significantly higher in within the inflamed mucosa of patients with IBD; it was mainly expressed by CD11c(+) cells. Levels of TREM-2 increased as acute or chronic colitis was induced in mice. TREM-2 knockout mice developed less severe colitis than wild-type mice; the knockout mice lost less body weight, had a lower disease activity index, and had smaller mucosal lesions in endoscopic analysis. Colon dendritic cells from TREM-2 knockout mice produced lower levels of inflammatory cytokines and had reduced levels of bacterial killing and T-cell activation than cells from wild-type mice. CONCLUSIONS TREM-2 contributes to mucosal inflammation during development of colitis in mice. Levels of TREM-2 are increased within the inflamed mucosa of patients with IBD, indicating its potential as a therapeutic target.
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Affiliation(s)
- Carmen Correale
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Marco Genua
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Stefania Vetrano
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Elisa Mazzini
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Chiara Martinoli
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Antonino Spinelli
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Vincenzo Arena
- Department of Pathology, Catholic University Medical School, Rome, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U954, University Hospital of Nancy, Henri Poincaré University, Vandœuvre-lès-Nancy, France
| | - Flavio Caprioli
- U.O. Gastroenterologia 2, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy
| | | | | | - Alessandro Repici
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Alberto Malesci
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Sergio Rutella
- Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Maria Rescigno
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Silvio Danese
- Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
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Clark PM, Dawany N, Dampier W, Byers SW, Pestell RG, Tozeren A. Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases. Inflamm Bowel Dis 2012; 18:2315-33. [PMID: 22488912 DOI: 10.1002/ibd.22958] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 02/27/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a complex disorder involving pathogen infection, host immune response, and altered enterocyte physiology. Incidences of IBD are increasing at an alarming rate in developed countries, warranting a detailed molecular portrait of IBD. METHODS We used large-scale data, bioinformatics tools, and high-throughput computations to obtain gene and microRNA signatures for Crohn's disease (CD) and ulcerative colitis (UC). These signatures were then integrated with systemic literature review to draw a comprehensive portrait of IBD in relation to autoimmune diseases. RESULTS The top upregulated genes in IBD are associated with diabetogenesis (REG1A, REG1B), bacterial signals (TLRs, NLRs), innate immunity (DEFA6, IDO1, EXOSC1), inflammation (CXCLs), and matrix degradation (MMPs). The downregulated genes coded tight junction proteins (CLDN8), solute transporters (SLCs), and adhesion proteins. Genes highly expressed in UC compared to CD included antiinflammatory ANXA1, transporter ABCA12, T-cell activator HSH2D, and immunoglobulin IGHV4-34. Compromised metabolisms for processing of drugs, nitrogen, androgen and estrogen, and lipids in IBD correlated with an increase in specific microRNA. Highly expressed IBD genes constituted targets of drugs used in gastrointestinal cancers, viral infections, and autoimmunity disorders such as rheumatoid arthritis and asthma. CONCLUSIONS This study presents a clinically relevant gene-level portrait of IBD subtypes and their connectivity to autoimmune diseases. The study identified candidates for repositioning of existing drugs to manage IBD. Integration of mice and human data point to an altered B-cell response as a cause for upregulation of genes in IBD involved in other aspects of immune defense such as interferon-inducible responses.
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Affiliation(s)
- Peter M Clark
- Center for Integrated Bioinformatics, Drexel University, Philadelphia, Pennsylvania 19104, USA
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Attinkara R, Mwinyi J, Truninger K, Regula J, Gaj P, Rogler G, Kullak-Ublick GA, Eloranta JJ. Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res Notes 2012; 5:461. [PMID: 22929053 PMCID: PMC3517390 DOI: 10.1186/1756-0500-5-461] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 08/01/2012] [Indexed: 12/15/2022] Open
Abstract
Background Pathogenesis of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), involves interaction between environmental factors and inappropriate immune responses in the intestine of genetically predisposed individuals. Bile acids and their nuclear receptor, FXR, regulate inflammatory responses and barrier function in the intestinal tract. Methods We studied the association of five variants (rs3863377, rs7138843, rs56163822, rs35724, rs10860603) of the NR1H4 gene encoding FXR with IBD. 1138 individuals (591 non-IBD, 203 UC, 344 CD) were genotyped for five NR1H4 genetic variants with TaqMan SNP Genotyping Assays. Results We observed that the NR1H4 SNP rs3863377 is significantly less frequent in IBD cases than in non-IBD controls (allele frequencies: P = 0.004; wild-type vs. SNP carrier genotype frequencies: P = 0.008), whereas the variant rs56163822 is less prevalent in non-IBD controls (allele frequencies: P = 0.027; wild-type vs. SNP carrier genotype frequencies: P = 0.035). The global haplotype distribution between IBD and control patients was significantly different (P = 0.003). This also held true for the comparison between non-IBD and UC groups (P = 0.004), but not for the comparison between non-IBD and CD groups (P = 0.079). Conclusions We show that genetic variation in FXR is associated with IBD, further emphasizing the link between bile acid signaling and intestinal inflammation.
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Affiliation(s)
- Ragam Attinkara
- Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland
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Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18:3635-61. [PMID: 22851857 PMCID: PMC3406417 DOI: 10.3748/wjg.v18.i28.3635] [Citation(s) in RCA: 193] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
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Camilleri M, Katzka DA. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1075-84. [PMID: 22403795 PMCID: PMC3362100 DOI: 10.1152/ajpgi.00537.2011] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/05/2012] [Indexed: 01/31/2023]
Abstract
The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, α(2)-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNFα, GNβ3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT(3) genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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Chiodini RJ, Chamberlin WM, Sarosiek J, McCallum RW. Crohn's disease and the mycobacterioses: a quarter century later. Causation or simple association? Crit Rev Microbiol 2012; 38:52-93. [PMID: 22242906 DOI: 10.3109/1040841x.2011.638273] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It has been more than 25 years since Mycobacterium paratuberculosis was first proposed as an etiologic agent in Crohn's disease based on the isolation of this organism from several patients. Since that time, a great deal of information has been accumulated that clearly establishes an association between M. paratuberculosis and Crohn's disease. However, data are conflicting and difficult to interpret and the field has become divided into committed advocates and confirmed skeptics. This review is an attempt to provide a thorough and objective summary of current knowledge from both basic and clinical research from the views and interpretations of both the antagonists and proponents. The reader is left to draw his or her own conclusions related to the validity of the issues and claims made by the opposing views and data interpretations. Whether M. paratuberculosis is a causative agent in some cases or simply represents an incidental association remains a controversial topic, but current evidence suggests that the notion should not be so readily dismissed. Remaining questions that need to be addressed in defining the role of M. paratuberculosis in Crohn's disease and future implications are discussed.
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Affiliation(s)
- Rodrick J Chiodini
- Divisions of Infectious Diseases, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA.
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Fitch PM, Henderson P, Schwarze J. Respiratory and gastrointestinal epithelial modulation of the immune response during viral infection. Innate Immun 2012; 18:179-189. [PMID: 21239454 DOI: 10.1177/1753425910391826] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Respiratory and enteric viral infections cause significant morbidity and mortality world-wide and represent a major socio-economic burden. Many of these viruses have received unprecedented public and media interest in recent years. A popular public misconception is that viruses are a threat to which the human body has only limited defences. However, the majority of primary and secondary exposures to virus are asymptomatic or induce only minor symptoms. The mucosal epithelial surfaces are the main portal of entry for viral pathogens and are centrally involved in the initiation, maintenance and polarisation of the innate and adaptive immune response to infection. This review describes the defences employed by the epithelium of the respiratory and gastrointestinal tracts during viral infections with focus on epithelial modulation of the immune response at the innate/adaptive interface.
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Affiliation(s)
- Paul M Fitch
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, UK.
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Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease. Pharmacogenet Genomics 2011; 21:559-64. [PMID: 21832969 DOI: 10.1097/fpc.0b013e328348f70c] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Inflammatory bowel diseases (IBDs), Crohn's disease, and ulcerative colitis (UC), are multifactorial disorders, characterized by chronic inflammation of the intestine. A number of genetic components have been proposed to contribute to IBD pathogenesis. In this case-control study, we investigated the association between two common vitamin D-binding protein (DBP) genetic variants and IBD susceptibility. These two single nucleotide polymorphisms (SNPs) in exon 11 of the DBP gene, at codons 416 (GAT>GAG; Asp>Glu) and 420 (ACG>AAG; Thr>Lys), have been previously suggested to play roles in the etiology of other autoimmune diseases. METHODS Using TaqMan SNP technology, we have genotyped 884 individuals (636 IBD cases and 248 non-IBD controls) for the two DBP variants. RESULTS On statistical analysis, we observed that the DBP 420 variant Lys is less frequent in IBD cases than in non-IBD controls (allele frequencies, P=0.034; homozygous carrier genotype frequencies, P=0.006). This inverse association between the DBP 420 Lys and the disease remained significant, when non-IBD participants were compared with UC (homozygous carrier genotype frequencies, P=0.022) or Crohn's disease (homozygous carrier genotype frequencies, P=0.016) patients separately. Although the DBP position 416 alone was not found to be significantly associated with IBD, the haplotype DBP_2, consisting of 416 Asp and 420 Lys, was more frequent in the non-IBD population, particularly notably when compared with the UC group (Odds ratio, 4.390). CONCLUSION Our study adds DBP to the list of potential genes that contribute to the complex genetic etiology of IBD, and further emphasizes the association between vitamin D homeostasis and intestinal inflammation.
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Repnik K, Potočnik U. Haplotype in the IBD5 region is associated with refractory Crohn's disease in Slovenian patients and modulates expression of the SLC22A5 gene. J Gastroenterol 2011; 46:1081-91. [PMID: 21695374 DOI: 10.1007/s00535-011-0426-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2011] [Accepted: 05/27/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown. METHODS We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients. RESULTS We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270-3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307-0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130-2.100) with refractory Crohn's disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs. CONCLUSIONS Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn's disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.
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Affiliation(s)
- Katja Repnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Slomškov Trg 15, 2000 Maribor, Slovenia
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Pedroso I, Breen G. Gene set analysis and network analysis for genome-wide association studies. Cold Spring Harb Protoc 2011; 2011:2011/9/pdb.top065581. [PMID: 21880815 DOI: 10.1101/pdb.top065581] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
The application of high-throughput genotyping in humans has yielded numerous insights into the genetic basis of human phenotypes and an unprecedented amount of genetic data. Genome-wide association studies (GWAS) have increased in number in recent years, but the variants that have been found have generally explained only a tiny proportion of the estimated genetic contribution to phenotypic variation. This article summarizes the progress made in the development of gene set analysis (GSA) and network analysis for GWAS was a way to identify the underlying molecular processes of human phenotypes. It also highlights some promising findings and indicates future directions that may greatly enhance the analysis and interpretation of GWAS.
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Abstract
PURPOSE OF REVIEW Hidradenitis suppurativa is a chronic or relapsing inflammatory cutaneous disorder manifested by recurrent formation of abscesses, fistulating sinus and scarring in the apocrine-gland-bearing skin. This review discusses the different aetiological theories and management opportunities. RECENT FINDINGS Current understanding of the pathogenesis suggests that hyperkeratosis of the infundibulum, leading to follicular occlusion of the pilosebaceous unit plays a role. Bacterial infection with staphylococci, Escherichia coli and streptococcus is considered as a secondary event in the pathogenesis. Smoking and obesity are both known as risk factors and are associated with more severe disease course. Recently, more attention has been put into the understanding of the immunopathology of the skin and the results indicate that hidradenitis suppurativa may be considered as an inflammatory disease of unknown cause based on a defect in the hair follicle immunity. The treatments are most appropriately chosen on the basis of disease severity and the existence of any associated risk factors or comorbidities. There are three levels in the management of hidradenitis suppurativa: topical options, systemic options and surgical methods including laser therapy. At each level several treatment principles have shown themselves to be efficient, and may therefore be used either alone or in combination. Therapies are generally effective against microorganisms, inflammation or infundibular hyperkeratosis. Where an antimicrobial therapy is used, the drugs used often have significant additional immunomodulatory effects. SUMMARY The recent studies give us a better insight into the pathogenesis of hidradenitis suppurativa and should translate into improved therapies.
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Palffy R, Gardlik R, Behuliak M, Jani P, Balakova D, Kadasi L, Turna J, Celec P. Salmonella-mediated gene therapy in experimental colitis in mice. Exp Biol Med (Maywood) 2011; 236:177-83. [PMID: 21321314 DOI: 10.1258/ebm.2010.010277] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Bacterial gene therapy - bactofection is a simple and effective method to deliver plasmid DNA into target tissue. We hypothesize that oral in vivo bactofection can be an interesting approach to influence the course of inflammatory bowel diseases. The aim of this study was to prove the effects of antioxidative and anti-inflammatory bactofection in dextran sulfate sodium (DSS)-treated mice. Attenuated bacteria Salmonella Typhimurium SL7207 carrying plasmids with genes encoding Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 were prepared. Male Balb/c mice had ad libitum access to 1% DSS solution in drinking water during 10 days (mild model of colitis). The animals were daily fed with 200 Mio bacteria via gastric gavage during the experiment. Fecal consistency, clinical status, food and water intake were monitored. After 10 days samples were taken and markers of oxidative stress and inflammatory cytokine levels were measured. Colonic tissue was scored histologically by a blinded investigator. DSS treatment significantly increased the levels of inflammatory cytokines and malondialdehyde as a marker of lipoperoxidation in the colon. Anti-inflammatory gene therapy improved the total antioxidative capacity. In comparison with the untreated group, bacterial gene therapy lowered the histological colitis score. Salmonella-mediated antioxidative and anti-inflammatory gene therapy alleviated colitis in mice. The effect seems to be mediated by increased antioxidative status. Further studies will show whether recombinant probiotics expressing therapeutic gene might be used for the therapy of inflammatory bowel diseases.
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Affiliation(s)
- Roland Palffy
- Insitute of Molecular Biomedicine, Comenius University, Bratislava, Slovak Republic
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28
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Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, International Inflammatory Bowel Disease Genetics Constortium, Cotsapas C, Daly MJ. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet 2011; 7:e1001273. [PMID: 21249183 PMCID: PMC3020935 DOI: 10.1371/journal.pgen.1001273] [Citation(s) in RCA: 407] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Accepted: 12/09/2010] [Indexed: 12/14/2022] Open
Abstract
Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.
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Affiliation(s)
- Elizabeth J. Rossin
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
- Health Science and Technology MD Program, Harvard University and Massachusetts Institute of Technology, Boston, Massachusetts, United States of America
- Harvard Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts, United States of America
| | - Kasper Lage
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark
| | - Soumya Raychaudhuri
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - Ramnik J. Xavier
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Diana Tatar
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Yair Benita
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | | | - Chris Cotsapas
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
| | - Mark J. Daly
- Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
- Health Science and Technology MD Program, Harvard University and Massachusetts Institute of Technology, Boston, Massachusetts, United States of America
- Harvard Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts, United States of America
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Latella G, Fiocchi C, Caprili R. News from the "5th International Meeting on Inflammatory Bowel Diseases" CAPRI 2010. J Crohns Colitis 2010; 4:690-702. [PMID: 21122584 DOI: 10.1016/j.crohns.2010.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2010] [Accepted: 08/22/2010] [Indexed: 02/06/2023]
Abstract
At the "5th International Meeting on Inflammatory Bowel Diseases selected topics of inflammatory bowel disease (IBD), including the environment, genetics, the gut flora, the cell response and immunomodulation were discussed in order to better understand specific clinical and therapeutic aspects. The incidence of IBD continues to rise, both in low and in high-incidence areas. It is believed that factors associated with 'Westernization' may be conditioning the expression of these disorders. The increased incidence of IBD among migrants from low-incidence to high-incidence areas within the same generation suggests a strong environmental influence. The development of genome-wide association scanning (GWAS) technologies has lead to the discovery of more than 100 IBD loci. Some, as the Th 17 pathway genes, are shared between Crohn's disease (CD) and ulcerative colitis (UC), while other are IBD subtype-specific (autophagy genes, epithelial barrier genes). Disease-specific therapies targeting these pathways should be developed. Epigenetic regulation of the inflammatory response also appears to play an important role in the pathogenesis of IBD. The importance of gut flora in intestinal homeostasis and inflammation was reinforced, the concepts of eubiosis and dysbiosis were introduced, and some strategies for reverting dysbiosis to a homeostatic state of eubiosis were proposed. The current status of studies on the human gut microbiota metagenome, metaprotome, and metabolome was also presented. The cell response in inflammation, including endoplasmic reticulum (ER) stress responses, autophagy and inflammasome-dependent events were related to IBD pathogenesis. It was suggested that inflammation-associated ER stress responses may be a common trait in the pathogenesis of various chronic immune and metabolic diseases. How innate and adaptive immunity signaling events can perpetuate chronic inflammation was discussed extensively. Signal transduction pathways provide intracellular mechanisms by which cells respond and adapt to multiple environmental stresses. The identification of these signals has led to a greater mechanistic understanding of IBD pathogenesis and pointed to potentially new therapeutic targets. A critical analysis of clinical trials and of risk-benefit of biological therapy was presented. The problem of Epstein-Barr virus (EBV) and lymphoma in IBD was extensively discussed. Lymphomas can develop in intestinal segments affected by IBD and are in most cases associated with EBV. The reasons of treatment failure were also analyzed both from basic and clinical points of view. Two very interesting presentations on the integration of research and clinical care in the near future closed the meeting. These presentations were focused on macrotrends affecting healthcare delivery and research, and the need to innovate traditional infrastructures to deal with these changing trends as well as new opportunities to accelerate scientific knowledge.
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Affiliation(s)
- Giovanni Latella
- Department of Internal Medicine, GI Unit, University of L'Aquila, L'Aquila, Italy.
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The role of CDX2 in intestinal homeostasis and inflammation. Biochim Biophys Acta Mol Basis Dis 2010; 1812:283-9. [PMID: 21126581 DOI: 10.1016/j.bbadis.2010.11.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 11/19/2010] [Accepted: 11/22/2010] [Indexed: 12/17/2022]
Abstract
Many transcription factors are known to control transcription at several promoters, while others are only active at a few places. However, due to their importance in controlling cellular functions, aberrant transcription factor function and inappropriate gene regulation have been shown to play a causal role in a large number of diseases and developmental disorders. Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa caused by dysregulation of the intestinal immune homeostasis. The aetiology of IBD is thought to be a combination of genetic and environmental factors, including luminal bacteria. The Caudal-related homeobox transcription factor 2 (CDX2) is critical in early intestinal differentiation and has been implicated as a master regulator of the intestinal homeostasis and permeability in adults. When expressed, CDX2 modulates a diverse set of processes including cell proliferation, differentiation, cell adhesion, migration, and tumorigenesis. In addition to these critical cellular processes, there is increasing evidence for linking CDX2 to intestinal inflammation. The aim of the present paper was to review the current knowledge of CDX2 in regulation of the intestinal homeostasis and further to reveal its potential role in inflammation.
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Abstract
The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.
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Repnik K, Potocnik U. CTLA4 CT60 single-nucleotide polymorphism is associated with Slovenian inflammatory bowel disease patients and regulates expression of CTLA4 isoforms. DNA Cell Biol 2010; 29:603-10. [PMID: 20491567 DOI: 10.1089/dna.2010.1021] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
We have evaluated functional polymorphism (rs3087243; in literature known also as CTLA4 CT60) in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene, previously associated with several autoimmune diseases, for potential association with inflammatory bowel diseases (IBD). In addition, we investigated correlations between CTLA4 CT60 polymorphism and CTLA4 gene expression in peripheral blood lymphocytes and colon biopsies from IBD patients. We genotyped CTLA4 CT60 polymorphism in 266 healthy control subjects and 481 IBD patients and found statistically lower frequency of CTLA4 CT60 AA genotype in IBD patients (13.72%) compared to control subjects (23.31%; p = 0.001, odds ratio [OR] = 0.504) as well as lower allele frequency of minor A allele in IBD patients (0.346) compared to control subjects (0.461, p < 0.001, OR = 0.623). The association was confirmed with both major forms of IBD, Crohn's disease, and ulcerative colitis (UC), but was slightly stronger in UC patients, particularly when we compared allele frequency of A allele in UC patients (0.299) and control subjects (0.461, p < 0.001, OR = 0.500). We found lower expression of the CTLA4 gene in blood lymphocytes from IBD patients compared to control subjects (p < 0.001) and higher CTLA4 expression in biopsies taken from inflamed part of the colon compared to noninflamed part of the colon (p = 0.021). We found lower expression of soluble CTLA4 isoform than membrane-bound full-length isoform in peripheral blood lymphocytes from IBD patients compared to control subjects (p = 0.010) and in lymphocytes from IBD patients with CTLA4 CT60 GG genotype compared to IBD patients with AA genotype (p = 0.034). Our genotype and gene expression data suggest that CTLA4 plays a role in IBD pathogenesis. Polymorphism CTLA4 CT60 contributes to genetic susceptibility to IBD in Slovenian population and regulates expression of CTLA4 isoforms.
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Affiliation(s)
- Katja Repnik
- Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Maribor, Slovenia
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Lapis K. [Barrier- and autophagic functions of the intestinal epithelia: role of disturbances in the pathogenesis of Crohn's disease]. Orv Hetil 2010; 151:1645-55. [PMID: 20860961 DOI: 10.1556/oh.2010.28942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn's disease is a widely known debilitating chronic inflammatory disease, mostly affecting terminal ileum and/or colon. Epidemiological, familial and twin studies suggest that genetic factors play an important role in susceptibility to the disease. Clinical observations suggest that ill-defined environmental factors also play a part. Advances in molecular genotyping technology, statistical methodologies, bioinformatics and the combined use of them in genome wide scanning and association studies resulted in the identification of more than 30 susceptibility genes and loci associated with Crohn's disease and revealed and highlighted a number of new previously unsuspected pathways playing a role in the pathogenesis of Crohn's disease. Close association of the disease with polymorphisms in the genes encoding the pattern recognition receptors particularly the NOD2 protein, the Wnt pathway transcription factor Tcf4 (also known as TCFL2) and the autophagic regulator ATG16L1 have been found. The polymorphisms involved are associated with decreased defensin production (defensin deficiency) which can lead to changes in the composition of the commensal microbial flora, defects in the intestinal barrier functions and bacterial invasion of the mucosa. Other recently recognized consequences of the polymorphisms involving the genes encoding NOD2 and ATG16L1 proteins are that the truncated NOD2 protein is unable to induce autophagy and this protein, just like the ATG16L1 T300A mutant protein, leads to failure adequately to destroy phagocytosed bacteria. The consequence is persisting low level infection, chronic intestinal inflammation, tissue injury and the clinical symptoms of the disease. Thus, Crohn's disease can be seen to be caused by defects in the innate immune defense, in particular defects in bacterial processing and clearance. The accumulated evidence suggests that Crohn's disease is associated with an exaggerated adaptive immune response to the persisting intestinal microbes in genetically susceptible hosts. Intervention in these circumstances should probably be geared to strengthening of the innate immune responses rather than simple attempts to suppress adaptive immunity.
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Affiliation(s)
- Károly Lapis
- Semmelweis Egyetem, Altalános Orvostudományi Kar I. Patológiai és Kísérleti Rákkutató Intézet Budapest.
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Ng SC, Plamondon S, Kamm MA, Hart AL, Al-Hassi HO, Guenther T, Stagg AJ, Knight SC. Immunosuppressive effects via human intestinal dendritic cells of probiotic bacteria and steroids in the treatment of acute ulcerative colitis. Inflamm Bowel Dis 2010; 16:1286-98. [PMID: 20155842 DOI: 10.1002/ibd.21222] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND In ulcerative colitis (UC) gut bacteria drive inflammation. Bacterial recognition and T-cell responses are shaped by intestinal dendritic cells (DCs); therapeutic effects of probiotic bacteria may relate to modulation of intestinal DC. The probiotic mixture, VSL#3, increases interleukin (IL)-10 and downregulates IL-12p40 production by DC in vitro. We evaluated in vivo effects of oral VSL#3 and steroids on colonic DC in patients with acute UC. METHODS Rectal biopsies were obtained from patients with active UC before and after treatment with VSL#3, corticosteroids, or placebo, and from healthy controls. Myeloid colonic DC were studied from freshly isolated lamina propria cells using multicolor flow cytometry. Surface expression of activation markers, CD40, CD86, pattern recognition receptors, Toll-like receptor (TLR)-2 and TLR-4 were assessed. Changed function was measured from ongoing intracellular IL-10, IL-12p40, IL-6, and IL-13 production. RESULTS Acute UC colonic myeloid DC were producing more IL-10 and IL-12p40 than control DC (P = 0.01). In VSL#3-treated patients DC TLR-2 expression decreased (P < 0.05), IL-10 production increased and IL-12p40 production decreased (P < 0.005); 10/14 patients on VSL#3 showed a clinical response. Corticosteroids also resulted in increased IL-10 and reduced IL-12p40 production by DC. Conversely, in patients on placebo, TLR-2 expression and intensity of staining for IL-12p40 and IL-6 increased (all P < 0.05); 5/14 patients on placebo showed a clinical response (P = NS). CONCLUSIONS Despite small numbers of human colonic DC available, we showed that treatment of UC patients with probiotic VSL#3 and corticosteroids induced "favorable" intestinal DC function in vivo, increasing regulatory cytokines and lowering proinflammatory cytokines and TLR expression. These effects may contribute to therapeutic benefit.
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Affiliation(s)
- Siew C Ng
- Antigen Presentation Research Group, Faculty of Medicine, Imperial College London, Northwick Park and St Mark's Campus, Watford Road, Harrow, UK
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Fleming A, Jankowski J, Goldsmith P. In vivo analysis of gut function and disease changes in a zebrafish larvae model of inflammatory bowel disease: a feasibility study. Inflamm Bowel Dis 2010; 16:1162-72. [PMID: 20128011 DOI: 10.1002/ibd.21200] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this study was to develop a model of inflammatory bowel disease (IBD) in zebrafish larvae, together with a method for the rapid assessment of gut morphology and function in vivo thereby enabling medium-throughput compound screening. METHODS Assays were performed using larval zebrafish from 3-8 days postfertilization (d.p.f.) in 96-well plates. Gut morphology and peristalsis were observed in vivo using fluorescent imaging following ingestion of fluorescent dyes. IBD was induced by addition of 2,4,6-trinitrobenzenesulfonic acid (TNBS) to the medium within the well. Pathology was assessed in vivo using fluorescent imaging and postmortem by histology, immunohistochemistry, and electron microscopy. Therapeutic compounds were evaluated by coadministration with TNBS. RESULTS A novel method of investigating gut architecture and peristalsis was devised using fluorescent imaging of live zebrafish larvae. Archetypal changes in gut architecture consistent with colitis were observed throughout the gut. Significant changes in goblet cell number and tumor necrosis factor alpha (TNF-alpha) antibody staining were used to quantify disease severity and rescue. Prednisolone and 5-amino salicylic acid treatment ameliorated the disease changes. Candidate therapeutic compounds (NOS inhibitors, thalidomide, and parthenolide) were assessed and a dissociation was observed between efficacy assessed using a single biochemical measure (TNF-alpha staining) versus an assessment of the entire disease state. CONCLUSIONS Gut physiology and pathology relevant to human disease state can be rapidly modeled in zebrafish larvae. The model is suitable for medium-throughput chemical screens and is amenable to genetic manipulation, hence offers a powerful novel premammalian adjunct to the study of gastrointestinal disease.
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Scharl M, Rogler G. Microbial sensing by the intestinal epithelium in the pathogenesis of inflammatory bowel disease. Int J Inflam 2010; 2010:671258. [PMID: 21188218 PMCID: PMC3003992 DOI: 10.4061/2010/671258] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2010] [Accepted: 05/17/2010] [Indexed: 01/01/2023] Open
Abstract
Recent years have raised evidence that the intestinal microbiota plays a crucial role in the pathogenesis of chronic inflammatory bowels diseases. This evidence comes from several observations. First, animals raised under germ-free conditions do not develop intestinal inflammation in several different model systems. Second, antibiotics are able to modulate the course of experimental colitis. Third, genetic polymorphisms in a variety of genes of the innate immune system have been associated with chronic intestinal inflammatory diseases. Dysfunction of these molecules results in an inappropriate response to bacterial and antigenic stimulation of the innate immune system in the gastrointestinal tract. Variants of pattern recognition receptors such as NOD2 or TLRs by which commensal and pathogenic bacteria can be detected have been shown to be involved in the pathogenesis of IBD. But not only pathways of microbial detection but also intracellular ways of bacterial processing such as autophagosome function are associated with the risk to develop Crohn's disease. Thus, the "environment concept" and the "genetic concept" of inflammatory bowel disease pathophysiology are converging via the intestinal microbiota and the recognition mechanisms for an invasion of members of the microbiota into the mucosa.
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Affiliation(s)
- Michael Scharl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland
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Singh UP, Singh NP, Singh B, Mishra MK, Nagarkatti M, Nagarkatti PS, Singh SR. Stem cells as potential therapeutic targets for inflammatory bowel disease. Front Biosci (Schol Ed) 2010; 2:993-1008. [PMID: 20515838 DOI: 10.2741/s115] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The incidence and prevalence of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), are rising. According to some estimates >1 million new cases of IBD arise in the United States annually. The conventional therapies available for IBD range from anti-inflammatory drugs to immunosuppressive agents, but these therapies generally fail to achieve satisfactory results due to their side effects. Interest in a new therapeutic option, that is, biological therapy, has gained much momentum recently due to its focus on different stages of the inflammatory process. Stem cell (SC) research has become a new direction for IBD therapy due to our recent understanding of cell populations involved in the pathogenic process. To this end, hematopoietic and mesenchymal stem cells are receiving more attention from IBD investigators. The intestinal environment, with its crypts and niches, supports incoming embryonic and hematopoietic stem cells and allows them to engraft and differentiate. The above findings suggest that, in the future, SC-based therapy will be a promising alternative to conventional therapy for IBD. In this review, we discuss SCs as potential therapeutic targets for future treatment of IBD.
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Affiliation(s)
- Udai P Singh
- Pathology and Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
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Nakagome S, Takeyama Y, Mano S, Sakisaka S, Matsui T, Kawamura S, Oota H. Population-specific susceptibility to Crohn's disease and ulcerative colitis; dominant and recessive relative risks in the Japanese population. Ann Hum Genet 2010; 74:126-36. [PMID: 20367632 DOI: 10.1111/j.1469-1809.2010.00567.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Crohn's disease (CD), a type of chronic inflammatory bowel disease (IBD), is commonly found in European and East Asian countries. The calculated heritability of CD appears to be higher than that of ulcerative colitis (UC), another type of IBD. Recent genome-wide association studies (GWAS) have identified more than thirty CD-associated genes/regions in the European population. In the East Asian population, however, a clear association between CD and an associated gene has only been detected with TNFSF15. In order to determine if CD susceptibility differs geographically, nine SNPs from seven of the European CD-associated genomic regions were selected for analysis. The genotype frequencies for these SNPs were compared among the 380 collected Japanese samples, which consisted of 212 IBD cases and 168 controls. We detected a significant association of both CD and UC with only the TNFSF15 gene. Analysis by the modified genotype relative risk test (mGRR) indicated that the risk allele of TNFSF15 is dominant for CD, but is recessive for UC. These results suggest that CD and UC susceptibility differs between the Japanese and European populations. Furthermore, it is also likely that CD and UC share a causative factor which exhibits a different dominant/recessive relative risk in the Japanese population.
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Affiliation(s)
- Shigeki Nakagome
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan
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Smith MA, Marinaki AM, Sanderson JD. Pharmacogenomics in the treatment of inflammatory bowel disease. Pharmacogenomics 2010; 11:421-37. [PMID: 20235796 DOI: 10.2217/pgs.10.4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.
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Affiliation(s)
- Melissa A Smith
- Department of Gastroenterology, 1st Floor, College House, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK
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Abstract
Autophagy is a cellular quality control process by which cytoplasmic constituents including proteins, protein aggregates, organelles, and invading pathogens can be delivered to lysosomes for degradation. Autophagy is activated in response to changes in the internal status of the cell and/or changes in the extracellular environment. It is therefore essential for the maintenance of cellular homeostasis and for an efficient response to cellular stresses. As such autophagy has been implicated either in the pathogenesis, or response to a wide variety of diseases, bacterial, and viral infections, and ageing.
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Cherayil BJ. Cross-talk between iron homeostasis and intestinal inflammation. Gut Microbes 2010; 1:65-69. [PMID: 21327119 PMCID: PMC3035137 DOI: 10.4161/gmic.1.1.10863] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 12/01/2009] [Accepted: 12/07/2009] [Indexed: 02/03/2023] Open
Abstract
Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in November, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions.
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Reiff C, Delday M, Rucklidge G, Reid M, Duncan G, Wohlgemuth S, Hörmannsperger G, Loh G, Blaut M, Collie-Duguid E, Haller D, Kelly D. Balancing inflammatory, lipid, and xenobiotic signaling pathways by VSL#3, a biotherapeutic agent, in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2009; 15:1721-36. [PMID: 19639558 DOI: 10.1002/ibd.20999] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The interleukin 10 knockout mouse (IL10-KO) is a model of human inflammatory bowel disease (IBD) used to study host microbial interactions and the action of potential therapeutics. Using Affymetrix data analysis, important signaling pathways and transcription factors relevant to gut inflammation and antiinflammatory probiotics were identified. METHODS Affymetrix microarray analysis on both wildtype (WT) and IL10-KO mice orally administered with and without the probiotic VSL#3 was performed and the results validated by real-time polymerase chain reaction (PCR), immunocytochemistry, proteomics, and histopathology. Changes in metabolically active bacteria were assessed with denaturing gradient gel electrophoresis (DGGE). RESULTS Inflammation in IL10-KO mice was characterized by differential regulation of inflammatory, nuclear receptor, lipid, and xenobiotic signaling pathways. Probiotic intervention resulted in downregulation of CXCL9 (fold change [FC] = -3.98, false discovery rate [FDR] = 0.019), CXCL10 (FC = -4.83, FDR = 0.0008), CCL5 (FC = -3.47, FDR = 0.017), T-cell activation (Itgal [FC = -4.72, FDR = 0.00009], Itgae [FC = -2.54 FDR = 0.0044]) and the autophagy gene IRGM (FC = -1.94, FDR = 0.01), a recently identified susceptibility gene in human IBD. Consistent with a marked reduction in integrins, probiotic treatment decreased the number of CCL5+ CD3+ double-positive T cells and upregulated galectin2, which triggers apoptosis of activated T cells. Importantly, genes associated with lipid and PPAR signaling (PPARalpha [FC = 2.36, FDR = 0.043], PPARGC1alpha [FC = 2.58, FDR = 0.016], Nr1d2 [FC = 3.11, FDR = 0.0067]) were also upregulated. Altered microbial diversity was noted in probiotic-treated mice. CONCLUSIONS Bioinformatics analysis revealed important immune response, phagocytic and inflammatory pathways dominated by elevation of T-helper cell 1 type (TH1) transcription factors in IL10-KO mice. Probiotic intervention resulted in a site-specific reduction of these pathways but importantly upregulated PPAR, xenobiotic, and lipid signaling genes, potential antagonists of NF-kappaB inflammatory pathways.
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Affiliation(s)
- C Reiff
- Rowett Institute of Nutrition and Health, Aberdeen University, Aberdeen, UK
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Reiff C, Kelly D. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int J Med Microbiol 2009; 300:25-33. [PMID: 19800289 DOI: 10.1016/j.ijmm.2009.08.004] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD) and both diseases lead to high morbidity and health care costs. Complex interactions between the immune system, enteric commensal bacteria and host genotype are thought to underlie the development of IBD although the precise aetiology of this group of diseases is still unknown. The understanding of the composition and complexity of the normal gut microbiota has been greatly aided by the use of molecular methods and is likely to be further increased with the advent of metagenomics and metatranscriptomics approaches, which will allow an increasingly more holistic assessment of the microbiome with respect to both diversity and function of the commensal gut microbiota. Studies thus far have shown that the intestinal microbiota drives the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD. Probiotics which deliver some of the beneficial immunomodulatory effects of the commensal gut microbiota and induce immune homeostasis have been proposed as a suitable treatment for mild to moderate IBD. This review provides an overview over the current understanding of the commensal gut microbiota, its interactions with the mucosal immune system and its capacity to induce both gut homeostasis as well as dysregulation of the immune system. Bacterial-host events, including interactions with pattern recognition receptors (PRRs) expressed on epithelial cells and dendritic cells (DCs) and the resultant impact on immune responses at mucosal surfaces will be discussed.
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Affiliation(s)
- Caroline Reiff
- Department of Gut Immunology, Rowett Institute of Nutrition and Health, Greenburn Road, Bucksburn, AB21 9SB Aberdeen, UK
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Abstract
The inflammatory bowel diseases have undergone an explosion of discovery in the last 10 years. The overwhelming focus of this has been in genetics and immune mechanisms of disease. While the former has provided critical information on predisposing factors, the latter has resulted in a panoply of novel immune-based therapies and technologies. These range from an improved approach to the use of conventional immunomodulators, such as azathioprine and 6-mercaptopurine, to commonplace availability of anti-tumor necrosis factor agents such as infliximab and adalimumab, through to small molecule inhibition of immune mediators. Unusual treatments, such as helminth infestation, stem cell transplantation, and leucocytapheresis, all derive from the burgeoning understanding of pathogenesis. Most important to our successful use of these therapies will be a fundamental understanding of the patient phenotypes and genotypes that will dictate particular treatment approaches in the future.
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Affiliation(s)
- Michael C Grimm
- St George Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
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Abstract
Recent studies have provided important insights into the pathogenesis of inflammatory bowel disease (IBD). The development of new therapeutic agents has been triggered by basic research and studies in mouse models of IBD. It is expected that improved translational research will lead to optimized therapy and new individualized treatment options.
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Affiliation(s)
- Markus F Neurath
- Department of Medicine, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
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Burzynski G, Shepherd IT, Enomoto H. Genetic model system studies of the development of the enteric nervous system, gut motility and Hirschsprung's disease. Neurogastroenterol Motil 2009; 21:113-27. [PMID: 19215589 PMCID: PMC4041618 DOI: 10.1111/j.1365-2982.2008.01256.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The enteric nervous system (ENS) is the largest and most complicated subdivision of the peripheral nervous system. Its action is necessary to regulate many of the functions of the gastrointestinal tract including its motility. Whilst the ENS has been studied extensively by developmental biologists, neuroscientists and physiologists for several decades it has only been since the early 1990s that the molecular and genetic basis of ENS development has begun to emerge. Central to this understanding has been the use of genetic model organisms. In this article, we will discuss recent advances that have been achieved using both mouse and zebrafish model genetic systems that have led to new insights into ENS development and the genetic basis of Hirschsprung's disease.
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Affiliation(s)
- G Burzynski
- Department of Biology, Emory University, Atlanta, GA 30322, USA
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