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Lu H, Suo Z, Lin J, Cong Y, Liu Z. Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease. Biomark Res 2024; 12:76. [PMID: 39095853 PMCID: PMC11295551 DOI: 10.1186/s40364-024-00612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive. MAIN BODY In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD. CONCLUSION In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.
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Affiliation(s)
- Huiying Lu
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Zhimin Suo
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
| | - Jian Lin
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Yingzi Cong
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China.
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2
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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3
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Hu Y, Hu Q, Li Y, Lu L, Xiang Z, Yin Z, Kabelitz D, Wu Y. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther 2023; 8:434. [PMID: 37989744 PMCID: PMC10663641 DOI: 10.1038/s41392-023-01653-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/23/2023] Open
Abstract
The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell immunology and its role in diseases. Initially, we elucidate functional differences between γδ T cells and their αβ T cell counterparts. We also provide an overview of major milestones in γδ T cell research since their discovery in 1984. Furthermore, we delve into the intricate biological processes governing their origin, development, fate decisions, and T cell receptor (TCR) rearrangement within the thymus. By examining the mechanisms underlying the anti-tumor functions of distinct γδ T cell subtypes based on γδTCR structure or cytokine release, we emphasize the importance of accurate subtyping in understanding γδ T cell function. We also explore the microenvironment-dependent functions of γδ T cell subsets, particularly in infectious diseases, autoimmune conditions, hematological malignancies, and solid tumors. Finally, we propose future strategies for utilizing allogeneic γδ T cells in tumor immunotherapy. Through this comprehensive review, we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers of γδ T cells, ultimately contributing to further advancements in harnessing the therapeutic potential of γδ T cells.
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Affiliation(s)
- Yi Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Qinglin Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Zheng Xiang
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Zhinan Yin
- Biomedical Translational Research Institute, Jinan University, Guangzhou, Guangdong, 510632, China.
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China.
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4
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Dow CT, Lin NW, Chan ED. Sarcoidosis, Mycobacterium paratuberculosis and Noncaseating Granulomas: Who Moved My Cheese. Microorganisms 2023; 11:microorganisms11040829. [PMID: 37110254 PMCID: PMC10143120 DOI: 10.3390/microorganisms11040829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 04/29/2023] Open
Abstract
Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago, "anonymous mycobacteria" were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement, though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma-while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium subsp. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn's disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the "non-cheesy" granuloma of sarcoidosis actually contains the difficult-to-detect "cheese", MAP; MAP did not move, it was there all along.
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Affiliation(s)
- Coad Thomas Dow
- McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA
| | - Nancy W Lin
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO 80206, USA
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Edward D Chan
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Academic Affairs, National Jewish Health, Denver, CO 80206, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Department of Medicine, Aurora, CO 80045, USA
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5
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Jans D, Cleynen I. The genetics of non-monogenic IBD. Hum Genet 2023; 142:669-682. [PMID: 36720734 DOI: 10.1007/s00439-023-02521-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/10/2023] [Indexed: 02/02/2023]
Abstract
Inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as main subtypes, is a prototypical multifactorial disease with both genetic and environmental factors involved. Genetically, IBD covers a wide spectrum from monogenic to polygenic forms. In polygenic disease, many genetic variants each contribute a small amount to disease risk. With the advent of genome-wide association studies (GWAS), it became possible to find these variants and corresponding genes, leading so far to the discovery of ca 240 loci associated with IBD. Together, these however explain only 20-25% of the heritability of IBD, leaving a large portion unaccounted for. This missing heritability might be hidden in common variants with even lower effect than the ones currently found through GWAS, but also in rare variants which can be found through large-scale sequencing studies or potentially in multiplex families. In this review, we will give an overview of the current knowledge about the genetics of non-monogenic IBD and how it differs from the monogenic form(s), and future perspectives. The history of IBD genetic studies from twin studies over linkage studies to GWAS, and finally large-scale sequencing studies and the revisiting of multiplex families will be discussed.
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Affiliation(s)
- Deborah Jans
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium
| | - Isabelle Cleynen
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium.
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6
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Goren I, Sharar Fischler T, Yanai H, Pal P, Adigopula B, Pendyala S, Ganesh G, Vishnubhotla R, Rabinowitz KM, Shaham Barda E, Yadamreddy D, Godny L, Peleg N, Banerjee R, Dotan I. Newly Diagnosed Crohn's Disease Patients in India and Israel Display Distinct Presentations and Serological Markers: Insights from Prospective Cohorts. J Clin Med 2022; 11:jcm11236899. [PMID: 36498474 PMCID: PMC9737641 DOI: 10.3390/jcm11236899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/12/2022] [Accepted: 11/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Crohn’s disease (CD) incidence is rising in India. However, features of newly diagnosed patients with CD in this population are largely unknown. The Indo-Israeli IBD GastroEnterology paRtnership (TiiiGER) aimed to investigate differences in presentation among patients with newly diagnosed CD in India and Israel, and to explore phenotype−serotype correlations. Methods: A prospective observational cohort study of consecutive adults (>18 years) conducted in two large referral centers in India and Israel (2014−2018). Clinical data, an antiglycan serological panel, and 20 CD-associated genetic variants were analyzed. Outcomes: complicated phenotype at diagnosis and early complicated course (hospitalizations/surgeries) within 2 years of diagnosis. Results: We included 260 patients (104, Indian (65.4%, male; age, 37.8); 156 Israeli (49.4%, male; 31.8, age)). Median lag time from symptoms onset to diagnosis was 10.5 (IQR 3−38) vs. 3 (IQR 1−8) months in Indian vs. Israeli patients (p < 0.001). Complicated phenotype at diagnosis was observed in 48% of Indian and 30% of Israeli patients (p = 0.003). Complicated phenotype was associated with higher anti-Saccharomyces cerevisiae antibody (ASCA) seropositivity rate among Israeli patients (p < 0.001), but not among Indian patients. Antiglycan serology did not correlate with the tested genetic variants. Early complicated course occurred in 28 (18%) Israeli and 13 (12.5%) Indian patients. The time from diagnosis to complication was comparable (log rank p = 0.152). Antiglycan serology did not correlate with a complicated early course in either cohort. Conclusions: There are significant differences in patients presenting with newly diagnosed CD in India and Israel, including phenotype and distinct biomarkers at diagnosis. These differences suggest different genetic and environmental disease modifiers.
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Affiliation(s)
- Idan Goren
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
| | - Tali Sharar Fischler
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Henit Yanai
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Partha Pal
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Bhargavi Adigopula
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Sushmitha Pendyala
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Girish Ganesh
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Ravikanth Vishnubhotla
- Department of Genomics and Molecular Biology, Institute of Translational Research, Asian Institute of Gastroenterology and AIG Hospitals, Hyderabad 500032, India
| | - Keren Masha Rabinowitz
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Hospital Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49414, Israel
| | - Efrat Shaham Barda
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Hospital Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49414, Israel
| | - Durga Yadamreddy
- Department of Genomics and Molecular Biology, Institute of Translational Research, Asian Institute of Gastroenterology and AIG Hospitals, Hyderabad 500032, India
| | - Lihi Godny
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Noam Peleg
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Rupa Banerjee
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Iris Dotan
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
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7
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Sterling KG, Dodd GK, Alhamdi S, Asimenios PG, Dagda RK, De Meirleir KL, Hudig D, Lombardi VC. Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease. Int J Mol Sci 2022; 23:13328. [PMID: 36362150 PMCID: PMC9655506 DOI: 10.3390/ijms232113328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
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Affiliation(s)
| | - Griffin Kutler Dodd
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Shatha Alhamdi
- Clinical Immunology and Allergy Division, Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia
| | | | - Ruben K. Dagda
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | | | - Dorothy Hudig
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Vincent C. Lombardi
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
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8
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Genetic Variants of DMBT1 and SFTPD and Disease Severity in Paediatric Inflammatory Bowel Disease—A Polish Population-Based Study. CHILDREN 2021; 8:children8110946. [PMID: 34828659 PMCID: PMC8618964 DOI: 10.3390/children8110946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 11/16/2022]
Abstract
Deleted in malignant brain tumours 1 protein (DMBT1) and surfactant protein D (SFTPD) are antimicrobial peptides previously linked to inflammatory bowel disease (IBD) susceptibility. This study attempts to link the most potential IBD-associated polymorphisms in DMBT1 and SFTPD with the disease severity in children. A total of 406 IBD patients (Crohn’s disease (CD) n = 214 and ulcerative colitis (UC) n = 192) were genotyped using hydrolysis probe assay. Clinical expression was described by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification), systemic steroid, immunosuppressive, biological, and surgical treatment, number of exacerbation-caused hospitalisations, relapses and nutritional status. IBD patients with the risk genotype (AA) in DMBT1 rs2981804 had more frequent biological treatment (AA: vs. AG/GG; p = 0.012), concomitant diseases (AA vs. AG vs. GG; p = 0.015) and cutaneous manifestations (AA vs. AG/GG, p = 0.008). In UC, rs2981804 genotypes might be linked with albumin concentrations at diagnosis (AA vs. AG vs. GG; p = 0.009). In CD, DMBT1 rs2981745 was significantly associated with the number of severe relapses per year of disease (p = 0.020) and time-to-immunosuppression (p = 0.045). SFTPD was seemingly found to be associated with age at first immunosuppression in IBD (CC vs. CT vs. TT; p = 0.048). In conclusion, selected polymorphisms of DMBT1 and SFTPD might be associated with some disease severity measures in children with IBD. However, the magnitude of associations and their clinical relevance might be minor.
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9
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Petryszyn P, Dudkowiak R, Gruca A, Jaźwińska-Tarnawska E, Ekk-Cierniakowski P, Poniewierka E, Wiela-Hojeńska A, Głowacka K. C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case-Control and Meta-Analysis Study. Genes (Basel) 2021; 12:genes12091419. [PMID: 34573401 PMCID: PMC8465101 DOI: 10.3390/genes12091419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/30/2022] Open
Abstract
P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn's disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour.
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Affiliation(s)
- Paweł Petryszyn
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
- Correspondence: ; Tel.: +48-717840601
| | - Robert Dudkowiak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Agnieszka Gruca
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Ewa Jaźwińska-Tarnawska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | | | - Elżbieta Poniewierka
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (R.D.); (E.P.)
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
| | - Krystyna Głowacka
- Department of Clinical Pharmacology, Wroclaw Medical University, 50-571 Wroclaw, Poland; (A.G.); (E.J.-T.); (A.W.-H.); (K.G.)
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10
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Atreya R, Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease. Nat Rev Gastroenterol Hepatol 2021; 18:544-558. [PMID: 33712743 DOI: 10.1038/s41575-021-00424-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 01/31/2023]
Abstract
Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
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Affiliation(s)
- Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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11
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Immunologic Complications and Graft Survival in Crohn's Disease and NOD2 Mutant Non-Crohn's Disease Adult Recipients Following Intestine Transplantation. Transplant Direct 2020; 6:e556. [PMID: 32607422 PMCID: PMC7266359 DOI: 10.1097/txd.0000000000001006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 11/26/2022] Open
Abstract
Despite improved outcomes in the modern era of targeted immunotherapy, intestinal failure and chronic parenteral nutrition remains a significant burden for patients with Crohn’s disease (CD) worldwide. Transplantation is a key component of management when a patient with CD suffers from life-threatening complications of parenteral nutrition. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is a risk factor for both development of CD and intestinal allograft rejection.
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12
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Mizuno N, Kume K, Nagatani Y, Matsuda S, Iwata T, Ouhara K, Kajiya M, Takeda K, Matsuda Y, Tada Y, Ohsawa R, Morino H, Mihara K, Fujita T, Kawaguchi H, Shiba H, Kawakami H, Kurihara H. Aggressive periodontitis and NOD2 variants. J Hum Genet 2020; 65:841-846. [PMID: 32424308 DOI: 10.1038/s10038-020-0777-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/01/2020] [Accepted: 05/04/2020] [Indexed: 12/30/2022]
Abstract
Aggressive periodontitis (AgP) occurs at an early age and causes rapid periodontal tissue destruction. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) encodes a protein with two caspase recruitment domains and eleven leucine-rich repeats. This protein is expressed mainly in peripheral blood leukocytes and is involved in immune response. NOD2 variants have been associated with increased susceptibility to Crohn's disease, and recently, NOD2 was reported as a causative gene in AgP. The present study aimed to identify potential NOD2 variants in an AgP cohort (a total of 101 patiens: 37 patients with positive family histories and 64 sporadic patients). In the familial group, six patients from two families had a reported heterozygous missense variant (c.C931T, p.R311W). Four patients in the sporadic group had a heterozygous missense variant (c.C1411T, p.R471C), with no reported association to the disease. Overall, two NOD2 variants, were identified in 10% of our AgP cohort. These variants were different from the major variants reported in Crohn's disease. More cases need to be investigated to elucidate the role of NOD2 variants in AgP pathology.
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Affiliation(s)
- Noriyoshi Mizuno
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Kodai Kume
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yukiko Nagatani
- Department of Dental Hygiene, University of Shizuoka, Junior College, Shizuoka, Japan
| | - Shinji Matsuda
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Iwata
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhisa Ouhara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Katsuhiro Takeda
- Department of Biological Endodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukiko Matsuda
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yui Tada
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Ryosuke Ohsawa
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Morino
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Keichiro Mihara
- International Regenerative Medical Center, Fujita Health University, Aichi, Japan
| | - Tsuyoshi Fujita
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Kawaguchi
- Department of General Dentistry, Hiroshima University Hospital, Hiroshima, Japan
| | - Hideki Shiba
- Department of Biological Endodontics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideshi Kawakami
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Hidemi Kurihara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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13
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Changes in the Intestinal Microbiota Are Seen Following Treatment with Infliximab in Children with Crohn's Disease. J Clin Med 2020; 9:jcm9030687. [PMID: 32143438 PMCID: PMC7141282 DOI: 10.3390/jcm9030687] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 02/08/2023] Open
Abstract
The aim of the study was to determine the impact of biological treatment with tumor necrosis factor α antibodies (anti-TNF-α) on the intestinal microbiome of children with severe Crohn's disease (CD) and to evaluate the differences in the intestinal microbiome between patients treated with biological therapy and healthy children. Microbiota composition was analyzed by 16S next-generation sequencing (NGS) and microbial profiles were compared between studied groups. Fifty-four samples (from 18 patients before and after anti-TNF-α induction therapy and 18 healthy children) were used in the sequencing analysis. Shannon's diversity index (p = 0.003, adj. p = 0.010) and observed operational taxonomic units (OTUs) (p = 0.007, adj. p = 0.015) were different between controls and patients with prior therapy for CD. Statistically significant dissimilarities between beta diversity metrics, indicating distinct community composition across groups, were observed in patients with CD before and after therapy. We did not observe any differences between controls and patients with CD after therapy. Core microbiome analysis at species level showed that 32 species were present only in patients with CD but not in controls. The results show that biological treatment is associated with changes in the intestinal microbiome of patients with CD: these changes result in an intestinal microbiome pattern similar to that seen in healthy children. Long-term observation is necessary to determine whether treatment can lead to full restoration of a healthy-like microbiome.
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14
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Zhang M, Wang X, Jiang X, Yang X, Wen C, Zhi M, Gao X, Hu P, Liu H. Polymorphisms of the TNF Gene and Three Susceptibility Loci Are Associated with Crohn's Disease and Perianal Fistula Crohn's Disease: A Study among the Han Population from South China. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2019; 25:9637-9650. [PMID: 31844038 PMCID: PMC6929548 DOI: 10.12659/msm.917244] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Background Although 90 susceptibility loci of Crohn’s disease (CD) have been confirmed in the Asian population, susceptibility genes for perianal fistula of CD (pCD) in this population remain unknown. This study explored susceptibility genes for CD and pCD in the Han population from South China. Material/Methods In total, 490 patients diagnosed with CD between July 2012 and June 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University were included and divided into the CD group (n=240) and the pCD group (n=250). The healthy control group was composed of 260 volunteers. Peripheral blood samples were taken, and single nucleotide polymorphism (SNP) locus sequencing was used to screen for susceptibility loci. SNPs were sequenced using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Results Nine SNPs in TNFSF1 on chromosome 9 were associated with CD. Among them, the rs6478106 locus is a risk locus for CD. The distribution frequency of the T allele of the rs6478106 SNP was significantly different between cases and controls (32.49% versus 18.27%, P<0.001). Rs72553867, located in the IRGM gene on chromosome 5, rs4409764, located in the NKX2–3 gene on chromosome 10, and rs3731772, located in the AOX1 gene on chromosome 2, were susceptibility factors for pCD. Nine SNPs located in TNFSF15 on chromosome 9 were related to CD in Han individuals from Southern China. Conclusions The rs6478106 T allele is associated with the risk of CD in the investigated population. SNPs rs72553867 (IRGM gene), rs4409764 (NKX2–3 gene), and rs3731772 (AOX1 gene) increase the risk of pCD.
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Affiliation(s)
- Min Zhang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland)
| | - Xiaoyan Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland).,Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Xiaodong Jiang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland)
| | - Xiangling Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland).,Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Chuangyu Wen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland).,Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
| | - Min Zhi
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland)
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland)
| | - Pinjin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland).,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland)
| | - Huanliang Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China (mainland).,Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (mainland)
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15
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Zhu Y, Jiang H, Chen Z, Lu B, Li J, Shen X. Genetic association between IL23R rs11209026 and rs10889677 polymorphisms and risk of Crohn’s disease and ulcerative colitis: evidence from 41 studies. Inflamm Res 2019; 69:87-103. [DOI: 10.1007/s00011-019-01296-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/11/2019] [Accepted: 10/31/2019] [Indexed: 01/30/2023] Open
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16
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Tricarico PM, Boniotto M, Genovese G, Zouboulis CC, Marzano AV, Crovella S. An Integrated Approach to Unravel Hidradenitis Suppurativa Etiopathogenesis. Front Immunol 2019; 10:892. [PMID: 31105704 PMCID: PMC6494959 DOI: 10.3389/fimmu.2019.00892] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 04/08/2019] [Indexed: 12/21/2022] Open
Abstract
Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory disease involving hair follicles that presents with painful nodules, abscesses, fistulae, and hypertrophic scars, typically occurring in apocrine gland bearing skin. Establishing a diagnosis of HS may take up to 7 years after disease onset. HS severely impairs the quality of life of patients and its high frequency causes significant costs for health care system. HS patients have an increased risk of developing associated diseases, such as inflammatory bowel diseases and spondyloarthropathies, thereby suggesting a common pathophysiological mechanism. Familial cases, which are around 35% of HS patients, have allowed the identification of susceptibility genes. HS is perceived as a complex disease where environmental factors trigger chronic inflammation in the skin of genetically predisposed individuals. Despite the efforts made to understand HS etiopathogenesis, the exact mechanisms at the basis of the disease need to be still unraveled. In this review, we considered all OMICs studies performed on HS and observed that OMICs contribution in the context of HS appeared as not clear enough and/or rich of useful clinical information. Indeed, most studies focused only on one aspect—genome, transcriptome, or proteome—of the disease, enrolling small numbers of patients. This is quite limiting for the genetic studies, from different geographical areas and looking at a few aspects of HS pathogenesis without any integration of the findings obtained or a comparison among different studies. A strong need for an integrated approach using OMICs tools is required to discover novel actors involved in HS etiopathogenesis. Moreover, we suggest the constitution of consortia to enroll a higher number of patients to be analyzed following common and consensus OMICs strategies. Comparison and integration with the findings present in the OMICs repositories are mandatory. In a theoretic pipeline, the Skin-OMICs profile obtained from each HS patient should be compared and integrated with repositories and literature data by using appropriate InterOMICs approach. The final goal is not only to improve the knowledge of HS etiopathogenesis but also to provide novel tools to the clinicians with the eventual aim of offering a tailored treatment for HS patients.
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Affiliation(s)
- Paola M Tricarico
- Department of Advanced Diagnostics, Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy
| | - Michele Boniotto
- University of Paris Est-Créteil and INSERM U955/IMRB-Team 16, Créteil, France
| | - Giovanni Genovese
- UOC Dermatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Dipartimento di Fisiopatologia Medico-Chirurgica e Dei Trapianti, Università degli Studi di Milano, Milan, Italy
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany
| | - Angelo V Marzano
- UOC Dermatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Dipartimento di Fisiopatologia Medico-Chirurgica e Dei Trapianti, Università degli Studi di Milano, Milan, Italy
| | - Sergio Crovella
- Department of Advanced Diagnostics, Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy
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Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life 2019; 12:113-122. [PMID: 31406511 PMCID: PMC6685307 DOI: 10.25122/jml-2018-0075] [Citation(s) in RCA: 367] [Impact Index Per Article: 61.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/27/2019] [Indexed: 12/11/2022] Open
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are classified as chronic inflammatory bowel diseases (IBD) which have similar symptoms and lead to digestive disorders and inflammation in the digestive system. The reason why they occur is still a mystery. A number of factors can be attributed to the prevalence of CD and UC, some of which include geographical location, inappropriate diet, genetics, and inappropriate immune response. Both diseases are more often diagnosed in urban areas compared to rural areas and both have their own challenges and side effects, but the patients can still have a good quality of life. Given the fact that the prevalence of this disease is higher at younger ages and that it disrupts half the life of the patient, it will, most likely, become a major health problem in the near future, even in developing countries. By reviewing valid scientific resources and evaluating new methods of addressing this disease, the present study aims to provide researchers and patients with new insights into this field and facilitate access to new treatments.
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Affiliation(s)
- Seyed Saeid Seyedian
- Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Forogh Nokhostin
- Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrdad Dargahi Malamir
- Faculty of Medicine, Medical doctor of Internal Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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18
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Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease. Stem Cells Int 2019; 2019:8010645. [PMID: 31015842 PMCID: PMC6444246 DOI: 10.1155/2019/8010645] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) include colitis ulcerosa and Crohn's disease, besides the rare microscopic colitis. Both diseases show a long-lasting, relapsing-remitting, or even chronic active course with tremendous impact on quality of life. IBDs frequently cause disability, surgical interventions, and high costs; as in other autoimmune diseases, their prevalent occurrence at an early phase of life raises the burden on health care systems. Unfortunately, our understanding of the pathogenesis is still incomplete and treatment therefore largely focuses on suppressing the resulting excessive inflammation. One obstacle for deciphering the causative processes is the scarcity of models that parallel the development of the disease, since intestinal inflammation is mostly induced artificially; moreover, the intestinal epithelium, which strongly contributes to IBD pathogenesis, is difficult to assess. Recently, the development of intestinal epithelial organoids has overcome many of those problems. Here, we give an overview on the current understanding of the pathogenesis of IBDs with reference to the limitations of previous well-established experimental models. We highlight the advantages and detriments of recent organoid-based experimental setups within the IBD field and suggest possible future applications.
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Cheluvappa R. Identification of New Potential Therapies for Colitis Amelioration Using an Appendicitis-Appendectomy Model. Inflamm Bowel Dis 2019; 25:436-444. [PMID: 30329049 DOI: 10.1093/ibd/izy332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Indexed: 12/18/2022]
Abstract
The appendix contains copious lymphoid tissue and is constantly exposed to gut flora. Appendicitis followed by appendectomy (AA), when done at a young age, prevents or significantly ameliorates inflammatory bowel diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our unique murine AA model is the only existing experimental model of AA. Herein, the appendiceal pathology closely resembles the pathological features of human appendicitis. Our AA model protects against experimental colitis in an age-, bacteria- and antigen-dependent manner. Appendicitis-appendectomy performed in the most proximal colon curbs T helper 17 (Th17) cell activity, diminishes autophagy, modulates interferon activity-associated molecules, and suppresses endothelin vasoactivity-mediated immunopathology in the most distal colon. These changes induced by AA contribute to limiting colitis pathology. Manipulating and modulating various aspects of these pathways, pathophysiology, and molecular interactions will assist the development of novel therapeutic options to manage IBD. Competitive inhibition of the Th17 cell recruitment factor CCL20 or the chemokine CCL17 with antibodies, combinatorial peptides, or small molecules may limit colitic pathology. The chemokines CCL5 and CXCL11 could be investigated as potential therapies. Inhibition of the autophagy-associated molecules VPS15, LAMP2, LC3A, XBP1, or ULK1 may decrease colitic pathology. Curtailing endothelin-activity may decrease colitic impact. The antiproliferative, immunomodulatory molecules IFIT1, IFIT2, IFIT3, and IFI44 may have direct therapeutic value in ameliorating colitis. The molecules IRF4, IRF8, IRF2BP1, IFRD1, and IFRD2 are potentially good target molecules to competitively inhibit towards curbing colitis.
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Affiliation(s)
- Rajkumar Cheluvappa
- Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, NSW, Australia
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20
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Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
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Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
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21
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Alexoudi A, Alexoudi I, Gatzonis S. Parkinson's disease pathogenesis, evolution and alternative pathways: A review. Rev Neurol (Paris) 2018; 174:699-704. [PMID: 30131173 DOI: 10.1016/j.neurol.2017.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 11/25/2017] [Accepted: 12/11/2017] [Indexed: 12/21/2022]
Abstract
Sporadic Parkinson's disease (PD) is one of the most common neurodegenerative diseases of the elderly. In the scientific literature, surveys aiming to investigate the potential diagnostic biomarkers for PD have focused on skin and intestinal tissue biopsies, whereas more recent studies have reported an association between PD and skin disorders, such as seborrheic dermatitis and rosacea. In addition, a connection between PD and Crohn's disease has been established. These data suggest the hypothesis of a possible link between the gastrointestinal tract and skin and the development of PD. In fact, the nervous system, gastrointestinal tract and skin are analogous in their embryological development and, therefore, have molecular networks and pathogenic pathways in common. Based on these data, it may be assumed that the gastrointestinal tract and skin might be implicated in the pathogenesis of PD. The evolutionary hypothesis might also be a useful tool for further investigations into the overlap across neurological, gastrointestinal and skin disorders.
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Affiliation(s)
- A Alexoudi
- Department of Neurosurgery, University of Athens, School of Medicine, Evangelismos Hospital, Ipsilantou 45-47, 10676 Athens, Greece.
| | - I Alexoudi
- Department of Dermatology, University Dermatology Royal Free Hospital, London, UK
| | - S Gatzonis
- Department of Neurosurgery, University of Athens, School of Medicine, Evangelismos Hospital, Ipsilantou 45-47, 10676 Athens, Greece
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Abstract
The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene.
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Affiliation(s)
- Anna Negroni
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy
| | - Maria Pierdomenico
- Department of Pediatrics and Infantile Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Department of Pediatrics and Infantile Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Laura Stronati
- Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy
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23
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Tamzaourte M, Errabih I, Krami H, Maha F, Maria L, Benzzoubeir N, Ouazzani L, Sefiani A, Ouazzani H. [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease]. Pan Afr Med J 2017; 27:116. [PMID: 28819537 PMCID: PMC5554695 DOI: 10.11604/pamj.2017.27.116.9187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/29/2017] [Indexed: 12/16/2022] Open
Abstract
L'objectif était de déterminer la prévalence des mutations du gène NOD2/CARD15 dans un groupe de patients Marocains atteint de Maladie de Crohn et étudier sa corrélation génotype-expression phénotypique. Etude transversale cas témoin menée sur une durée de 16 mois. Ont été inclus 101 patients atteints de la maladie de Crohn, entre Janvier 2012 et Avril 2013 ainsi qu'un groupe contrôle de 107 patients. L'analyse génétique a consisté à rechercher 3 variants du gène NOD2: p.Arg702Trp, p.Gly908Arg et p.Leu1007fsins. Puis une étude de corrélation génotype-expression phénotypique a été menée. L'analyse génétique des patients atteint de maladie de crohn a mis en évidence la présence de la mutation NOD2 chez 14 patients (13,77%) contre 7 patients (6,53%) du groupe témoin. L'étude de la fréquence des différents allèles a retrouvé la mutation de p.Gly908Arg dans 6,43%, p.Leu1007fsins dans 0,99% et p.Arg702Trp dans 0,49% contre respectivement 2,80%, 0% et 0,46% dans le groupe témoin. L'étude de la corrélation génotype, expression phénotypique a démontré que la mutation CARD15 est corrélée à une localisation iléo-caecale de la maladie, à une présentation fistulisante et sténosante ainsi qu'à une évolution sévère avec recours fréquent à la chirurgie et aux immunosuppresseurs. La prévalence de la mutation NOD2/ CARD15 dans notre série est faible. Cette mutation est corrélée à une forme grave de la maladie.
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Affiliation(s)
- Mouna Tamzaourte
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ikram Errabih
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Hayat Krami
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Fadlouallah Maha
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Lahmiri Maria
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Nadia Benzzoubeir
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Laaziza Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ahmed Sefiani
- Service de Génétique Médicale, Centre Nationale d'Hygiène, Rabat, Maroc
| | - Houria Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
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Cugno M, Borghi A, Marzano AV. PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment. Am J Clin Dermatol 2017; 18:555-562. [PMID: 28236224 DOI: 10.1007/s40257-017-0265-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis usually manifesting as skin ulcers with undermined erythematous-violaceous borders. It may be isolated, associated with systemic conditions or occurring in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). From a physiopathological point of view, all these conditions share common mechanisms consisting of over-activation of the innate immune system leading to increased production of the interleukin (IL)-1 family and 'sterile' neutrophil-rich cutaneous inflammation. From a genetic point of view, a number of mutations affecting the proteins of the inflammasome complex (the molecular platform responsible for triggering autoinflammation) or the proteins that regulate inflammasome function have been described in these disorders. As these debilitating entities are all associated with the over-expression of IL-1 and tumour necrosis factor (TNF)-α, biological drugs specifically targeting these cytokines are currently the most effective treatments but, given the emerging role of IL-17 in the pathogenesis of these syndromes, IL-17 antagonists may represent the future management of these conditions.
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Affiliation(s)
- Massimo Cugno
- Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Via Pace, 9, 20122, Milan, Italy.
| | - Alessandro Borghi
- Dipartimento di Scienze Mediche, Sezione di Dermatologia e Malattie Infettive, Università degli Studi di Ferrara, Ferrara, Italy
| | - Angelo V Marzano
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Unità Operativa di Dermatologia, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
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NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients. Sci Rep 2017; 7:7026. [PMID: 28765628 PMCID: PMC5539147 DOI: 10.1038/s41598-017-06268-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 06/08/2017] [Indexed: 12/27/2022] Open
Abstract
Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn's disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.
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Schnerch J, Prasse A, Vlachakis D, Schuchardt KL, Pechkovsky DV, Goldmann T, Gaede KI, Müller-Quernheim J, Zissel G. Functional Toll-Like Receptor 9 Expression and CXCR3 Ligand Release in Pulmonary Sarcoidosis. Am J Respir Cell Mol Biol 2017; 55:749-757. [PMID: 27390897 DOI: 10.1165/rcmb.2015-0278oc] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Sarcoidosis is a granulomatous disease characterized by a T-helper type 1 (Th1) cell-dominated alveolitis. As a role of bacteria in the pathogenesis of sarcoidosis has been discussed, Toll-like receptors (TLRs) may be involved in the initiation of a first immune reaction. We analyzed expression and functional relevance of several TLRs in bronchoalveolar lavage (BAL) cells from patients with pulmonary sarcoidosis. In parallel, we determined the release of C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 by BAL cells from patients with pulmonary sarcoidosis. Nucleotide-binding oligomerization domain-containing protein (NOD) 1 and 2, TLR2, TLR6, and TLR9 expression by BAL cells was analyzed by real-time RT-PCR and cell surface expression by flow cytometry. Chemokine release was measured in BAL cell culture supernatants by ELISA. We found increased TLR9 mRNA expression in patients with sarcoidosis with chest X-ray type I and II and TLR9 protein expression in BAL cells from patients with chest X-ray type II and III. Stimulation with CpG nucleotides increased CXCL10 release by BAL cells from patients with sarcoidosis type II significantly compared with control subjects or other patients with sarcoidosis. In contrast, no increase in TNF, IL-12p40, or CXCL8 was detected. Spontaneous release of CXCL10, but not CXCL9 or CXCL11, by cultured BAL cells was also highest in cells from patients with chest X-ray type II. We found a significant association between TLR9 expression and CD4+ lymphocytes in BAL. Our data demonstrate that TLR9 ligands may contribute to the immunopathogenesis of sarcoidosis via induction of CXCL10 release in the alveolar macrophages.
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Affiliation(s)
- Jasmin Schnerch
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
| | - Antje Prasse
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
| | - Dimitrios Vlachakis
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
| | - Kathrin L Schuchardt
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
| | - Dmitri V Pechkovsky
- 2 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Torsten Goldmann
- 3 Clinical and Experimental Pathology, Division of Clinical Medicine, Research Centre Borstel, Borstel, Germany.,4 Airway Research Center North (ARCN), Member of the German Center for Lung Research, Borstel, Germany; and
| | - Karoline I Gaede
- 4 Airway Research Center North (ARCN), Member of the German Center for Lung Research, Borstel, Germany; and.,5 BioMaterialBank North, Division of Clinical Medicine, Research Centre Borstel, Borstel, Germany
| | - Joachim Müller-Quernheim
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
| | - Gernot Zissel
- 1 Department of Pneumology, Centre for Medicine, Medical Centre-University of Freiburg, Freiburg, Germany
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Dwiyanti R, Hatta M, Natzir R, Pratiwi S, Sabir M, Yasir Y, Noviyanthi RA, Junita AR, Tandirogan N, Amir M, Fias M, Saning J, Bahar B. Association of Typhoid Fever Severity with Polymorphisms NOD2, VDR and NRAMP1 Genes in Endemic Area, Indonesia. JOURNAL OF MEDICAL SCIENCES 2017. [DOI: 10.3923/jms.2017.133.139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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28
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Chirieleison SM, Marsh RA, Kumar P, Rathkey JK, Dubyak GR, Abbott DW. Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease. J Biol Chem 2017; 292:9666-9679. [PMID: 28404814 DOI: 10.1074/jbc.m117.781500] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/03/2017] [Indexed: 12/22/2022] Open
Abstract
The X-linked inhibitor of apoptosis (XIAP) protein has been identified as a key genetic driver of two distinct inflammatory disorders, X-linked lymphoproliferative syndrome 2 (XLP-2) and very-early-onset inflammatory bowel disease (VEO-IBD). Molecularly, the role of XIAP mutations in the pathogenesis of these disorders is unclear. Recent work has consistently shown XIAP to be critical for signaling downstream of the Crohn's disease susceptibility protein nucleotide-binding oligomerization domain-containing 2 (NOD2); however, the reported effects of XLP-2 and VEO-IBD XIAP mutations on cell death have been inconsistent. In this manuscript, we describe a CRISPR-mediated genetic system for cells of the myeloid lineage in which XIAP alleles can be replaced with disease-associated XIAP variants expressed at endogenous levels to simultaneously study inflammation-related cell death and NOD2 signaling. We show that, consistent with previous studies, NOD2 signaling is critically dependent on the BIR2 domain of XIAP. We further used this system to reconcile the aforementioned inconsistent XIAP cell death data to show that XLP-2 and VEO-IBD XIAP mutations that exhibit a loss-of-function NOD2 phenotype also lower the threshold for inflammatory cell death. Last, we identified and studied three novel patient XIAP mutations and used this system to characterize NOD2 and cell death phenotypes driven by XIAP. The results of this work support the role of XIAP in mediating NOD2 signaling while reconciling the role of XLP-2 and VEO-IBD XIAP mutations in inflammatory cell death and provide a set of tools and framework to rapidly test newly discovered XIAP variants.
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Affiliation(s)
| | - Rebecca A Marsh
- the Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio 45229
| | | | | | - George R Dubyak
- Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and
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Gabbani T, Deiana S, Marocchi M, Annese V. Genetic risk variants as therapeutic targets for Crohn's disease. Expert Opin Ther Targets 2017; 21:381-390. [PMID: 28281904 DOI: 10.1080/14728222.2017.1296431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.
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Affiliation(s)
- Tommaso Gabbani
- a Gastroenterology UO , Azienda Unita Sanitaria Locale della Romagna , Forlì , Italy
| | - Simona Deiana
- b Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Margherita Marocchi
- c Division of Gastroenterology , AOU Modena University Hospital , Modena , Italy
| | - Vito Annese
- d Department of Gastroenterology , Valiant Clinic , Dubai , UAE
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30
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Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol Hepatol 2017; 2:224-234. [PMID: 28404137 DOI: 10.1016/s2468-1253(16)30111-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/02/2016] [Accepted: 09/02/2016] [Indexed: 01/11/2023]
Abstract
The study of the genetic underpinnings of inflammatory bowel disease has made great progress since the identification of NOD2 as a major susceptibility gene. Novel genotyping and sequencing technologies have led to the discovery of 242 common susceptibility loci, 45 of which have been fine-mapped to statistically conclusive causal variants; 50 genes associated with very-early-onset inflammatory disease have been identified. The evolving genetic architecture of inflammatory bowel disease has deepened our understanding of its pathogenesis through identification of major disease associated pathways-knowledge that has the potential to indicate novel drug targets or markers for personalised medicine. However, many causal variants have yet to be identified, and a large proportion of missing heritability still needs to be accounted for. In addition, the medical and scientific communities are probably not yet fully harnessing the power of these genetic discoveries.
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31
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Mortaz E, Adcock IM, Abedini A, Kiani A, Kazempour-Dizaji M, Movassaghi M, Garssen J. The role of pattern recognition receptors in lung sarcoidosis. Eur J Pharmacol 2017; 808:44-48. [PMID: 28108375 DOI: 10.1016/j.ejphar.2017.01.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 01/15/2017] [Accepted: 01/16/2017] [Indexed: 12/21/2022]
Abstract
Sarcoidosis is a granulomatous disorder of unknown etiology. Infection, genetic factors, autoimmunity and an aberrant innate immune system have been explored as potential causes of sarcoidosis. The etiology of sarcoidosis remains unknown, and it is thought that it might be caused by an infectious agent in a genetically predisposed, susceptible host. Inflammation results from recognition of evolutionarily conserved structures of pathogens (Pathogen-associated molecular patterns, PAMPs) and/or from reaction to tissue damage associated patterns (DAMPs) through recognition by a limited number of germ line-encoded pattern recognition receptors (PRRs). Due to the similar clinical and histopathological picture of sarcoidosis and tuberculosis, Mycobacterium tuberculosis antigens such early secreted antigen (ESAT-6), heat shock proteins (Mtb-HSP), catalase-peroxidase (katG) enzyme and superoxide dismutase A peptide (sodA) have been often considered as factors in the etiopathogenesis of sarcoidosis. Potential non-TB-associated PAMPs include lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria, peptidoglycan, lipoteichoic acid, bacterial DNA, viral DNA/RNA, chitin, flagellin, leucine-rich repeats (LRR), mannans in the yeast cell wall, and microbial HSPs. Furthermore, exogenous non-organic antigens such as metals, silica, pigments with/without aluminum in tattoos, pesticides, and pollen have been evoked as potential causes of sarcoidosis. Exposure of the airways to diverse infectious and non-infectious agents may be important in the pathogenesis of sarcoidosis. The current review provides and update on the role of PPRs and DAMPs in the pathogenesis of sarcoidsis.
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Affiliation(s)
- Esmaeil Mortaz
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ian M Adcock
- Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK
| | - Atefhe Abedini
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arda Kiani
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehdi Kazempour-Dizaji
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Movassaghi
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), USA
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands; Nutricia Research Centre for Specialized Nutrition, Utrecht, The Netherlands
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Gabbani T, Deiana S, Annese AL, Lunardi S, Annese V. The genetic burden of inflammatory bowel diseases: implications for the clinic? Expert Rev Gastroenterol Hepatol 2016; 10:1109-1117. [PMID: 27258545 DOI: 10.1080/17474124.2016.1196131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation. Their etiology is multifactorial, with complex interactions between genetic and environmental factors, which are still largely unclear. Areas covered: The influence of genetics is clearly demonstrated by important epidemiological data, including familial aggregation and concordance in twins. In 2001, the first genetic susceptibility gene for IBD, the NOD2 gene, was identified. Currently, thanks to genetic wide association studies, over 200 susceptibility genetic markers are know. Expert commentary: However, clinically highly relevant gene associations are still very limited and the usefulness of these information in the current clinical strategies for treatment and surveillance of IBD is weak. Nevertheless, the recent identification of some genetic risk variants has clarified some newbiological pathways of these diseases thus paving the way for the discoveries in the near future of new targeted therapies.
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Affiliation(s)
- Tommaso Gabbani
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Simona Deiana
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Antonio Luca Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Sarah Lunardi
- b Division of Internal Medicine 4 , AOU Careggi University Hospital , Florence , Italy
| | - Vito Annese
- a Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
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33
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Ye BD, McGovern DP. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 2016; 12:1091-107. [PMID: 27156530 PMCID: PMC5083126 DOI: 10.1080/1744666x.2016.1184972] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.
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Affiliation(s)
- Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Marzano AV, Borghi A, Meroni PL, Cugno M. Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation. Br J Dermatol 2016; 175:882-891. [PMID: 27106250 DOI: 10.1111/bjd.14691] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2015] [Indexed: 12/13/2022]
Abstract
Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on the lower extremities. It may occur in the context of classic syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), as well as in a recently described entity named PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Pyoderma gangrenosum has recently been included within the spectrum of autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. In PAPA syndrome, different mutations involving the PSTPIP1 gene, via an increased binding affinity to pyrin, induce the assembly of inflammasomes. These are molecular platforms involved in the activation of caspase 1, a protease that cleaves inactive prointerleukin (pro-IL)-1β to its active isoform IL-1β. The overproduction of IL-1β triggers the release of a number of proinflammatory cytokines and chemokines, which are responsible for the recruitment and activation of neutrophils, leading to neutrophil-mediated inflammation. In SAPHO syndrome, the activation of the PSTPIP2 inflammasome has been suggested to play a role in inducing the dysfunction of the innate immune system. Patients with PASH have recently been reported to present alterations of genes involved in well-known autoinflammatory diseases, such as PSTPIP1, MEFV, NOD2 and NLRP3. Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation.
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Affiliation(s)
- A V Marzano
- Unità Operativa di Dermatologia, IRCCS Fondazione Cá Granda, Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.
| | - A Borghi
- Dipartimento di Scienze Mediche, Sezione di Dermatologia e Malattie Infettive, Università degli Studi di Ferrara, Ferrara, Italy
| | - P L Meroni
- Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - M Cugno
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Sezione di Medicina Interna, Università degli Studi di Milano, IRCCS Fondazione Cá Granda, Ospedale Maggiore Policlinico, Milan, Italy
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Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn's Disease. Front Med (Lausanne) 2016; 3:24. [PMID: 27303667 PMCID: PMC4885006 DOI: 10.3389/fmed.2016.00024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/13/2016] [Indexed: 12/11/2022] Open
Abstract
Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we review the genetic factors that have been associated with the development of fibrosis in patients with CD, as well as their potential pathophysiological mechanism(s). We also hypothesize on clinical implications, if any, and future research directions.
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Affiliation(s)
- Bram Verstockt
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven , Leuven , Belgium
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Epistatic interaction between TLR4 and NOD2 in patients with Crohn's Disease: relation with risk and phenotype in a Spanish cohort. Immunobiology 2016; 221:927-33. [PMID: 27290609 DOI: 10.1016/j.imbio.2016.05.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 05/18/2016] [Accepted: 05/27/2016] [Indexed: 01/11/2023]
Abstract
Crohn's Disease is one of the two major forms of the Inflammatory Bowel Diseases and, although the etiology is not completely understood, the confluence of environmental and genetic factors has been demonstrated. The aim of this study was to determine the distribution of TLR4 variants in a Spanish cohort of Crohn's Disease patients and their relation with phenotype and common NOD2 variants. A total of 371 Crohn's Disease (CD) patients and 636 healthy controls (HC) were included. Single Nucleotide Polimorphisms (SNPs) in TLR4 (D299G and T399I) and NOD2 (R702W and G908R) detection was performed by a Taqman(®) Allelic Discrimination Assay. 1007insC NOD2 variant was analyzed using a PCR combined with fluorescent technology and the different alleles were determined depending on the PCR products size. D299G and T399I were related to CD only in patients carrying NOD2 variants (NOD2+/TLR4+ haplotype) (p=0.036; OR=1.924), increasing the risk to develop CD when 1007insC and TLR4 variants were both present (OR=4.886). We also described a strong association between mutant NOD2 and CD risk (p<0.001, OR=3.214). R702W, G908R and 1007insC were associated when they were considered separately (p<0.001; p=0.002; p<0.001, respectively). Moreover, the patients carrying any mutant D299G or T399I polymorphisms were predisposed to develop a stricturing disease (p=0.013; OR=2.391), especially in the presence of NOD2 mutation (p=0.002; OR=4.989). In this study, ileal disease was also associated with the presence of at least one NOD2 susceptibility allele (p=0.001; OR=3.838) and, the risk of ileal CD was increased if TLR4 variants were presents (p<0.050; OR=4.160). TLR4 variants were related to bowel perforation, independently of NOD2.
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Gutiérrez A, Zapater P, Juanola O, Sempere L, García M, Laveda R, Martínez A, Scharl M, González-Navajas JM, Such J, Wiest R, Rogler G, Francés R. Gut Bacterial DNA Translocation is an Independent Risk Factor of Flare at Short Term in Patients With Crohn's Disease. Am J Gastroenterol 2016; 111:529-40. [PMID: 26902226 DOI: 10.1038/ajg.2016.8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 12/03/2015] [Indexed: 02/08/2023]
Abstract
OBJECTIVES We aimed at evaluating bacterial DNA (bactDNA) presence in blood of Crohn's disease (CD) patients in remission as an independent risk factor of flare at 6 months. METHODS This is a prospective, multicenter study on CD patients with Crohn's disease activity index (CDAI)<150. The primary end point was time-to-relapse as evaluated by CDAI>150 in the following 6 months. BactDNA in blood, the nucleotide-binding oligomerization domain containing 2 (NOD2) genotype, and serum cytokine levels were determined at baseline. RESULTS A total of 288 patients were included. BactDNA was detected in 98 patients (34.0%). A variant-NOD2 genotype was identified in 114 patients (39.6%). Forty patients (14%) relapsed during follow-up. Multivariate survival analysis identified bactDNA as an independent risk factor of flare (hazard ratio (HR) 8.75 (4.02-19.06) 95% confidence interval (CI)). Hospitalization, surgery, switch of treatment, initiation and escalation of anti-tumor necrosis factor (TNF) therapy, steroids initiation, and increased fecal calprotectin levels at 6 months were associated with bactDNA at baseline. A logistic regression analysis showed bactDNA as an independent and significant predictive factor of hospitalization (odds ratio (OR) 11.9 (3.4-42.3); P<0.001), steroids startup (OR 8.5 (2.7-27.1); P<0.001), and switch of treatment (OR 3.5 (1.6-7.7); P=0.002) at 6 months. No relationship was observed between bactDNA and mucosal lesions in patients with colonoscopy at admission. Serum pro-inflammatory cytokines were significantly increased in patients with bactDNA or a variant-NOD2 genotype. The combination of both factors induced decreased anti-TNF-α levels and a higher percentage of patients on intensified anti-TNF therapy. CONCLUSIONS BactDNA is an independent risk factor of relapse at 6 months in CD patients. BactDNA is also independently associated with an increased risk of hospitalization, switch of treatment, and steroids initiation.
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Affiliation(s)
- Ana Gutiérrez
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Oriol Juanola
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Sempere
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Marifé García
- Servicio Digestivo, Hospital Universitario de Elche, Alicante, Spain
| | - Raquel Laveda
- Hospital Clínico Universitario de San Juan, Alicante, Spain
| | | | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zìrich, Zìrich, Switzerland
| | | | - José Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Reiner Wiest
- Department of Gastroenterology, University Clinic for Visceral Medicine, Inselspital, Bern, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zìrich, Zìrich, Switzerland
| | - Rubén Francés
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
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Defining Disease Severity in Inflammatory Bowel Diseases: Current and Future Directions. Clin Gastroenterol Hepatol 2016; 14:348-354.e17. [PMID: 26071941 DOI: 10.1016/j.cgh.2015.06.001] [Citation(s) in RCA: 302] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/01/2015] [Accepted: 06/03/2015] [Indexed: 02/07/2023]
Abstract
Although most treatment algorithms in inflammatory bowel disease (IBD) begin with classifying patients according to disease severity, no formal validated or consensus definitions of mild, moderate, or severe IBD currently exist. There are 3 main domains relevant to the evaluation of disease severity in IBD: impact of the disease on the patient, disease burden, and disease course. These measures are not mutually exclusive and the correlations and interactions between them are not necessarily proportionate. A comprehensive literature search was performed regarding current definitions of disease severity in both Crohn's disease and ulcerative colitis, and the ability to categorize disease severity in a particular patient. Although numerous assessment tools for symptoms, quality of life, patient-reported outcomes, fatigue, endoscopy, cross-sectional imaging, and histology (in ulcerative colitis) were identified, few have validated thresholds for categorizing disease activity or severity. Moving forward, we propose a preliminary set of criteria that could be used to classify IBD disease severity. These are grouped by the 3 domains of disease severity: impact of the disease on the patient (clinical symptoms, quality of life, fatigue, and disability); measurable inflammatory burden (C-reactive protein, mucosal lesions, upper gastrointestinal involvement, and disease extent), and disease course (including structural damage, history/extension of intestinal resection, perianal disease, number of flares, and extraintestinal manifestations). We further suggest that a disease severity classification should be developed and validated by an international group to develop a pragmatic means of identifying patients with severe disease. This is increasingly important to guide current therapeutic strategies for IBD and to develop treatment algorithms for clinical practice.
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Donor Nucleotide-Binding Oligomerization–Containing Protein 2 (NOD2) Single Nucleotide Polymorphism 13 Is Associated with Septic Shock after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 2015; 21:1399-404. [DOI: 10.1016/j.bbmt.2015.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 05/13/2015] [Indexed: 01/26/2023]
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Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with Crohn's disease. J Gastroenterol 2015; 50:758-68. [PMID: 25500977 DOI: 10.1007/s00535-014-1020-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 11/20/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Anti-TNF-α therapies interact with the tolerogenic response in patients with Crohn's disease, modulating inflammation. However, drug levels and the genetic background may affect this interaction. METHODS Patients with Crohn's disease in remission on biologic monotherapy were enrolled in this study. FoxP3+ lymphocytes, NOD2 genotype, serum cytokine, anti-TNF-α levels, and anti-drug antibodies were evaluated. Regulatory T cell response to infliximab was evaluated in vitro. RESULTS Fifty-seven patients were included. Thirty-nine patients (68.4%) were receiving non-intensified biologic therapy whereas 18 patients (31.6%) were under an intensified biologic schedule due to loss of response. Eleven intensified patients (61.1%) showed a variant NOD2 genotype vs 9 on non-intensified biologics (23%, p < 0.01). Percentage of FoxP3+ T cells and serum free anti-TNF-α levels were significantly higher in patients with a wild-type vs variant NOD2 genotype, either under non-intensified or intensified schedule. Increasing amounts of infliximab significantly increased the expression of FoxP3+ T cells and anti-TNF-α levels in the supernatant from wild-type NOD2 patients cultured cells whereas the induction of FoxP3+ T cells and anti-TNF-α levels in the supernatant from variant NOD2 patients cultured cells were significantly lower. TNF-α and IL-10 showed a correlation with the FoxP3+ T cell population percentage and serum levels of anti-TNF-α, irrespective of NOD2 genotype. Eight variant NOD2 patients (66.6%) vs 4 wild-type NOD2 patients (8.8%) showed a perianal phenotype (p = 0.01). A significant reduction of the percentage of FoxP3+ T cells and serum levels of anti-TNF-α was observed in patients with the associated perianal disease. CONCLUSION Anti-TNF-α loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with CD.
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Abstract
Scandinavian researchers have contributed to the present understanding of inflammatory bowel disease (IBD). Important epidemiological data and family risk factors have been reported from all the Nordic countries, original twin studies mainly from Denmark and Sweden, and relationships to cancer and surgery mostly from Sweden. In collaboration with the industry, development of medical compounds was for a long time in the front line of international research, and the Scandinavian countries participated in the clinical breakthrough of biologic treatment. At present, many Nordic centers are working in the forefront of IBD research. An increasing number of young investigators have entered the scene along with the extended distribution of University clinics and research laboratories in these countries. This presentation of IBD gives a brief overview in the fields of clinical epidemiology and molecular biology. Many areas are covered by International collaborations with partners from Nordic centers. IBD was a topic focused by the founders of Scandinavian Journal of Gastroenterology. After 50 years one may state that the journal's history reflects important pieces of scientific knowledge within these diseases. The early scope of Johannes Myren for IBD was shown through his work in the original World Association of Gastroenterology (OMG), and after 50 years we can clearly support the view that global perspectives in IBD are increasingly important.
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Affiliation(s)
- Morten H Vatn
- Institute of Clinical Medicine, Campus Ahus, University of Oslo , Oslo , Norway
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Sechi LA, Dow CT. Mycobacterium avium ss. paratuberculosis Zoonosis - The Hundred Year War - Beyond Crohn's Disease. Front Immunol 2015; 6:96. [PMID: 25788897 PMCID: PMC4349160 DOI: 10.3389/fimmu.2015.00096] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/18/2015] [Indexed: 12/15/2022] Open
Abstract
The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn's disease has been debated for more than a century. The controversy is due to the fact that Crohn's disease is so similar to a disease of MAP-infected ruminant animals, Johne's disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn's specimens as well as dedicated specialty labs successful in culturing MAP from Crohn's patients have provided strong argument for MAP's role in Crohn's disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders.
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Affiliation(s)
- Leonardo A Sechi
- Department of Biomedical Sciences, University of Sassari , Sassari , Italy
| | - Coad Thomas Dow
- McPherson Eye Research Institute, University of Wisconsin , Madison, WI , USA ; Chippewa Valley Eye Clinic , Eau Claire, WI , USA
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Marzano AV, Ceccherini I, Gattorno M, Fanoni D, Caroli F, Rusmini M, Grossi A, De Simone C, Borghi OM, Meroni PL, Crosti C, Cugno M. Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases. Medicine (Baltimore) 2014; 93:e187. [PMID: 25501066 PMCID: PMC4602806 DOI: 10.1097/md.0000000000000187] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.
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Affiliation(s)
- Angelo V Marzano
- From the Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti (AVM, DF, CC), Università degli Studi di Milano, Unità Operativa di Dermatologia, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano; UOC Genetica Medica (IC, FC, MR, AG), Istituto Giannina Gaslini; Pediatria II (MG), Istituto Giannina Gaslini, Genova; Dipartimento di Dermatologia (CDS), Università Cattolica del Sacro Cuore, Roma; Dipartimento di Scienze Cliniche e di Comunità (OMB, PLM), Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, Milano; IRCCS Istituto Auxologico Italiano, Milano, Italy (OMB); and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti (MC), Università degli Studi di Milano, Unità Operativa di Medicina Interna, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
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Yang DH, Yang SK, Song K, Hong M, Park SH, Lee HS, Kim JB, Lee HJ, Park SK, Jung KW, Kim KJ, Ye BD, Byeon JS, Myung SJ, Kim JH, Shin US, Yu CS, Lee I. TNFSF15 is an independent predictor for the development of Crohn's disease-related complications in Koreans. J Crohns Colitis 2014; 8:1315-26. [PMID: 24835165 DOI: 10.1016/j.crohns.2014.04.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 03/22/2014] [Accepted: 04/04/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease involving the whole gastrointestinal tract. TNFSF15 has been proved as a susceptibility gene for CD, but there are few reports about the association between TNFSF15 single nucleotide polymorphisms (SNPs) and the clinical course of CD. AIM To investigate the association between TNFSF15 genotypes and the clinical course of CD in Koreans. METHODS A total of 906 CD patients having TNFSF15 genotype data and clinical information were recruited from CD registry database of a tertiary referral center. The association between five TNFSF15 SNPs (rs4574921, rs3810936, rs6478108, rs6478109, and rs7848647) and various clinical parameters including stricture, non-perianal penetrating complications, bowel resection, and reoperation was investigated. RESULTS Among the five SNPs, rs6478108 CC genotype was associated with the development of stricture and non-perianal penetrating complications during follow-up (HR for stricture=1.706, 95% confidence interval 1.178-2.471, P=0.005; HR for non-perianal penetrating complications=1.667, 95% confidence interval 1.127-2.466, P=0.010), and rs4574921 CC genotype was associated with the development of perianal fistula (HR=2.386, 95% confidence interval 1.204-4.727, P=0.013) by multivariate analysis. However, there was no significant association of cumulative operation and reoperation rate with 5 SNPs of TNFSF15. CONCLUSION In Korean patients with CD, non-risk allele homozygotes of TNFSF15 SNPs rs6478108 and rs4574921 are independent genetic predictive factors for the development of strictures/non-perianal penetrating complications and perianal fistula, respectively.
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Affiliation(s)
- Dong-Hoon Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
| | - Myunghee Hong
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ho-Su Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ji-Beom Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Hyo Jeong Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Soo-Kyung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kee Wook Jung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jin-Ho Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ui Sup Shin
- Department of Surgery, Korea Institute of Radiological and Medical Sciences, Korea Cancer Center Hospital, Seoul, South Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Inchul Lee
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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Zhao H, Jia M, Wang Z, Cheng Y, Luo Z, Chen Y, Xu X, Yang S, Tang Y. Association between NOD2 single nucleotide polymorphisms and Grade III-IV acute graft-versus-host disease: A meta-analysis. ACTA ACUST UNITED AC 2014; 20:254-62. [PMID: 25248089 DOI: 10.1179/1607845414y.0000000202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Objectives The effects of NOD2 single nucleotide polymorphisms (SNPs) on Grade III-IV acute graft-versus-host disease (aGVHD) risk are somewhat contradictory in different studies. The aim of the meta-analysis was to clarify the effects of NOD2 SNPs on the incidence of Grade III-IV aGVHD. Methods We searched PubMed, EMBASE, Web of SCIENCE, WanFang and Chinese National Knowledge Infrastructure (CNKI) databases to collect eligible publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between NOD2 polymorphisms and Grade III-IV aGVHD risk. Results A total of nine studies from eight publications met the inclusion criteria and were included in this meta-analysis. Patient NOD2 SNPs were not associated with aGVHD risk. A tendency of higher risk to develop Grade III-IV aGVHD was found in patients with pairs NOD2 SNPs. Subgroup analyses showed that pairs NOD2 SNPs were associated with Grade III-IV aGVHD in the Caucasian population and in identical sibling donors (IS), but not in matched unrelated donors (MUD). In patients who received hematopoietic stem cell transplantation (HSCT) with T-cell depletion and gut decontamination, there was still an association between pairs NOD2 SNPs and Grade III-IV aGVHD risk. Conclusions Our meta-analysis suggests that pairs NOD2 SNPs, not patient NOD2 SNPs, may be associated with Grade III-IV aGVHD risk, especially in the Caucasian population. It is also indicated that in pairs NOD2 polymorphisms group, patients who receive HSCT from IS may experience higher risk of Grade III-IV aGVHD.
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Meddour Y, Chaib S, Bousseloub A, Kaddache N, Kecili L, Gamar L, Nakkemouche M, Djidjik R, Abbadi MC, Charron D, Boucekkine TE, Tamouza R. NOD2/CARD15 and IL23R genetic variability in 204 Algerian Crohn's disease. Clin Res Hepatol Gastroenterol 2014; 38:499-504. [PMID: 24679666 DOI: 10.1016/j.clinre.2014.02.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 01/15/2014] [Accepted: 02/11/2014] [Indexed: 02/04/2023]
Abstract
NOD2/CARD15 and IL23R gene variants play an important role in the susceptibility to Crohn's disease (CD). Studies of genotype-phenotype relationship suggest that these variants are associated with the development of the disease and specific phenotype. Preliminary reports analyzing the association between these variants have never been made on Algerian CD's. In a case-control design, 204 Algerian with CD diagnosed for at least 5years and 201 controls were included were genotyped for single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene R702W (SNP8, rs2066844), G908R (SNP12, rs2066845) and IL23R R381Q (rs11209026) gene variants were determined using the TaqMan SNP genotyping assays. NOD2/CARD15 908R was carried by 3% of the patients and none in control subjects (χ(2)=8.6, Pc=0.003, OR=13.20). NOD2/CARD15 702W was associated to CD outcome (χ(2)=17.2, Pc=0.00003, OR=12.5) and early onset of disease (group A1, χ(2)=19.3, Pc=1.10(-5), OR=14.05, PM-H=2.10(-6)). IL23R 381Q variants was more frequent in CD's patients than controls (χ(2)=8, Pc=0.005, OR=3.48), it was associated to earlier onset (group A1, χ(2)=7.1, Pc=0.007, OR=1.04, PM-H=0.002), extra-intestinal manifestations (EIM) outcome (χ(2)=10.6, Pc=0.001, OR=1.05, PM-H=0.002) and ileocolonic location (χ(2)=6.8, Pc=0.009, OR=1.05, PM-H=0.001). In this Algerian cohort, NOD2/CARD15 and IL23R variants were associated with CD's outcomes and linked to a particular clinical phenotype.
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Affiliation(s)
- Y Meddour
- Immunology Department, Central Hospital of Army, Algiers, Algeria
| | - S Chaib
- Immunology Department, Central Hospital of Army, Algiers, Algeria
| | - A Bousseloub
- Gastroenterology Department, Central Hospital of Army, Algiers, Algeria
| | - N Kaddache
- Gastroenterology Department, Mustapha Bacha Hospital, Algiers, Algeria
| | - L Kecili
- Gastroenterology Department, Mustapha Bacha Hospital, Algiers, Algeria
| | - L Gamar
- Gastroenterology Department, Mustapha Bacha Hospital, Algiers, Algeria
| | - M Nakkemouche
- Gastroenterology Department, Nafissa Hamoud Hospital, Algiers, Algeria
| | - R Djidjik
- Biology Department, Béni-Messous Hospital, Algiers, Algeria; Immunogenetics and Immunopathology Research Laboratory, Algiers, Algeria.
| | - M C Abbadi
- Immunology Department, Pasteur Institute, Algiers, Algeria; Immunogenetics and Immunopathology Research Laboratory, Algiers, Algeria
| | - D Charron
- Immunology and Histocompatibility Department, CIB-HOB, AP-HP, IUH and INSERM UMRS940, Saint-Louis Hospital, Paris, France
| | - T E Boucekkine
- Gastroenterology Department, Mustapha Bacha Hospital, Algiers, Algeria
| | - R Tamouza
- Immunology and Histocompatibility Department, CIB-HOB, AP-HP, IUH and INSERM UMRS940, Saint-Louis Hospital, Paris, France
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Fowler SA, Ananthakrishnan AN, Gardet A, Stevens CR, Korzenik JR, Sands BE, Daly MJ, Xavier RJ, Yajnik V. SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease. J Crohns Colitis 2014; 8:845-51. [PMID: 24461721 PMCID: PMC4237062 DOI: 10.1016/j.crohns.2014.01.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 12/12/2013] [Accepted: 01/03/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. RESULTS 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p=0.022) and penetrating behavior (HR 3.97, p=0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p=0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p=0.001). NOD2 was not associated with increased risk of surgical recurrence. CONCLUSION Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence.
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Affiliation(s)
- Sharyle A Fowler
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - Agnes Gardet
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | | | - Joshua R Korzenik
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Bruce E Sands
- Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY
| | - Mark J Daly
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | - Ramnik J Xavier
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA,Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA
| | - Vijay Yajnik
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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Festen EAM, Weersma RK. How will insights from genetics translate to clinical practice in inflammatory bowel disease? Best Pract Res Clin Gastroenterol 2014; 28:387-97. [PMID: 24913379 DOI: 10.1016/j.bpg.2014.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/05/2014] [Accepted: 04/13/2014] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies.
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Affiliation(s)
- E A M Festen
- University of Groningen, University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Department of Genetics, The Netherlands
| | - R K Weersma
- University of Groningen, University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands.
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Freire P, Cardoso R, Figueiredo P, Donato MM, Ferreira M, Mendes S, Ferreira AM, Vasconcelos H, Portela F, Sofia C. NOD2 gene mutations in ulcerative colitis: useless or misunderstood? Int J Colorectal Dis 2014; 29:653-61. [PMID: 24651958 DOI: 10.1007/s00384-014-1850-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/09/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE NOD2 mutations have been linked to an increased risk of Crohn's disease and to some of its phenotypes. The association between NOD2 mutations and susceptibility to ulcerative colitis (UC) remains somewhat controversial and potential correlations between these mutations and UC phenotype have not been studied. AIM To assess whether NOD2 mutations are a risk factor for UC in Portugal and if there are any genotype-phenotype correlations in these patients. METHODS The three main NOD2 mutations were searched in 200 patients with UC and in 202 healthy controls. RESULTS NOD2 mutations were present in 28 patients with UC (14.0 %) and in 27 controls (13.4 %) (p = 0.853). Mutation carriers were more likely to receive steroids during the first year of disease than non-carriers (54.2 % vs. 29.6 %, p = 0.018) and among these patients the need for intravenous administration was more frequent in those with the R702W polymorphism (90.0 % vs. 45.5 %, p = 0.014). In patients with severe colitis admitted for intravenous steroids, a greater proportion of mutation carriers was considered intravenous-steroid refractory and required salvage therapy (90.0 % vs. 38.1 %, p = 0.004). Patients with NOD2 mutation were submitted to colectomy more frequently than non-carriers (17.9 % vs. 4.1 %. p = 0.015). No correlation with the need for immunosuppressants/immunomodulators was found. CONCLUSIONS In the Portuguese population, NOD2 mutations do not increase the risk of UC but are associated with a more aggressive course including greater need of steroids in the first year, increased incidence of intravenous-steroid refractoriness and a higher colectomy rate.
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Affiliation(s)
- Paulo Freire
- Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Avenida Bissaya Barreto, 3000, Coimbra, Portugal,
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Bhullar M, Macrae F, Brown G, Smith M, Sharpe K. Prediction of Crohn’s disease aggression through NOD2/ CARD15 gene sequencing in an Australian cohort. World J Gastroenterol 2014; 20:5008-5016. [PMID: 24803813 PMCID: PMC4009534 DOI: 10.3748/wjg.v20.i17.5008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/04/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.
RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.
CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.
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