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1
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Erectile Dysfunction and Treatment: An Analysis of Associated Chronic Health Conditions. Urology 2021; 157:148-154. [PMID: 34428539 DOI: 10.1016/j.urology.2021.08.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/17/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To estimate the association between an erectile dysfunction (ED) diagnosis and other chronic health conditions, as well as, the association between receiving ED treatment and these conditions. METHODS Data was reviewed from the IBM MarketScan Claims and Encounters database between 2008-2017 for men ≥18 years. Of this cohort, common chronic health conditions were identified and the associations of receiving ED treatment and having a chronic health condition was then analyzed. RESULTS We identified 954 512 (38.3%) of the 2 489 069 men ≥18 years with at least one recorded diagnosis of ED, who also had at least one chronic health condition. Eighteen conditions were observed to be positively associated with ED, while eleven conditions were negatively associated. Depression (OR 2.875: 95% CI 2.866, 2.884; P<.001) had the strongest association, while ischemic heart disease (IHD) had the weakest (OR 0.76: 95% CI 0.755, 0.773; P<.001). CONCLUSION Our study found that a diagnosis of ED was strongly associated with concomitant diagnoses of depression, hypertension, diabetes and several autoimmune diseases. Receiving treatment for ED varied between chronic health conditions.
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2
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Eldakhakhny BM, Al Sadoun H, Choudhry H, Mobashir M. In-Silico Study of Immune System Associated Genes in Case of Type-2 Diabetes With Insulin Action and Resistance, and/or Obesity. Front Endocrinol (Lausanne) 2021; 12:641888. [PMID: 33927693 PMCID: PMC8078136 DOI: 10.3389/fendo.2021.641888] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/08/2021] [Indexed: 12/11/2022] Open
Abstract
Type-2 diabetes and obesity are among the leading human diseases and highly complex in terms of diagnostic and therapeutic approaches and are among the most frequent and highly complex and heterogeneous in nature. Based on epidemiological evidence, it is known that the patients suffering from obesity are considered to be at a significantly higher risk of type-2 diabetes. There are several pieces of evidence that support the hypothesis that these diseases interlinked and obesity may aggravate the risk(s) of type-2 diabetes. Multi-level unwanted alterations such as (epi-) genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major sources that promote several complex diseases, and such a heterogeneous level of complexity is considered as a major barrier in the development of therapeutics. With so many known challenges, it is critical to understand the relationships and the shared causes between type-2 diabetes and obesity, and these are difficult to unravel and understand. For this purpose, we have selected publicly available datasets of gene expression for obesity and type-2 diabetes, have unraveled the genes and the pathways associated with the immune system, and have also focused on the T-cell signaling pathway and its components. We have applied a simplified computational approach to understanding differential gene expression and patterns and the enriched pathways for obesity and type-2 diabetes. Furthermore, we have also analyzed genes by using network-level understanding. In the analysis, we observe that there are fewer genes that are commonly differentially expressed while a comparatively higher number of pathways are shared between them. There are only 4 pathways that are associated with the immune system in case of obesity and 10 immune-associated pathways in case of type-2 diabetes, and, among them, only 2 pathways are commonly altered. Furthermore, we have presented SPNS1, PTPN6, CD247, FOS, and PIK3R5 as the overexpressed genes, which are the direct components of TCR signaling.
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Affiliation(s)
- Basmah Medhat Eldakhakhny
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hadeel Al Sadoun
- Stem Cell Unit, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- Cancer and Mutagenesis Unit, Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Mobashir
- SciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
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3
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Akhoon N. Precision Medicine: A New Paradigm in Therapeutics. Int J Prev Med 2021; 12:12. [PMID: 34084309 PMCID: PMC8106271 DOI: 10.4103/ijpvm.ijpvm_375_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 02/04/2020] [Indexed: 11/26/2022] Open
Abstract
A key goal of clinical care is to treat patients as individuals and to approach therapeutics in such a way that it has optimal efficacy and minimal toxicity. With swift technological advances, such as genomic sequencing and molecular targeted drug exploitation, the concept of precision medicine has been robustly promoted in recent years. Precision medicine endeavors to demarcate diseases using multiple data sources from genomics to digital health metrics in order to facilitate an individualized yet "evidence-based" decision regarding diagnostic and therapeutic approaches. In this way, therapeutics can be centered toward patients based on their molecular presentation rather than grouping them into broad categories with a "one size fits all" approach. This review article is aimed to provide a broad overview of the advent and emergence of precision medicine in view of its current implications.
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Affiliation(s)
- Neha Akhoon
- Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India
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4
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Freeley M. Current postgraduate training programs and online courses in precision medicine. Expert Rev Mol Diagn 2020; 20:569-574. [PMID: 31875486 DOI: 10.1080/14737159.2020.1709826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Michael Freeley
- School of Biotechnology (Office X225), Dublin City University , Glasnevin, Ireland
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5
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Actis GC, Pellicano R, Fagoonee S, Ribaldone DG. History of Inflammatory Bowel Diseases. J Clin Med 2019; 8:1970. [PMID: 31739460 PMCID: PMC6912289 DOI: 10.3390/jcm8111970] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 11/02/2019] [Accepted: 11/12/2019] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy.
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Affiliation(s)
| | | | - Sharmila Fagoonee
- Institute of Biostructures and Bioimaging (CNR) c/o Molecular Biotechnology Center, 10126 Turin, Italy;
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6
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Tavakolpour S, Darvishi M, Ghasemiadl M. Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases. Clin Genet 2019; 93:481-497. [PMID: 29194620 DOI: 10.1111/cge.13186] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 11/24/2017] [Accepted: 11/24/2017] [Indexed: 12/12/2022]
Abstract
For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.
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Affiliation(s)
- S Tavakolpour
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - M Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - M Ghasemiadl
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
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7
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Moore L. The IBD Management Puzzle: Do We Have All the Pieces? EUROPEAN MEDICAL JOURNAL 2019. [DOI: 10.33590/emj/10314245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The management of inflammatory bowel disease (IBD) has entered an exciting era, with the optimisation of existing therapies, new strategies being explored that have the potential to further improve patient outcomes, and a growing recognition of the value of a personalised approach to treatment. This symposium explored optimal approaches to using biologic therapy, and the use of therapeutic drug monitoring (TDM) and biomarkers in treatment management.
IBD shows a progressive immunopathogenesis, and a ‘window of opportunity’ exists whereby early intervention may alter the disease course. There is a convincing body of evidence supporting early intervention with anti-TNF-α therapies to improve patient outcomes. Cost is the major barrier to initiating and continuing treatment with biologic therapy. Biosimilars have the potential to reduce costs and increase patient access to biologic therapies, enabling more patients to receive biologic treatment earlier. The use of TDM in the treatment of IBD is increasing and offers benefits over standardised approaches to dosing, and it is likely that emerging dose optimisation tools will enable a personalised approach to treatment in the future.
Many patients experience loss of response to anti-TNF-α therapy. Biomarkers currently used to monitor treatment response include C reactive protein (CRP), faecal calprotectin, and anti-drug antibodies (ADA). Although biomarker identification is still at an early stage for IBD, several genetic, serological, and microbiome markers have also shown promise in predicting response to anti-TNF-α therapy, while other biomarkers are also under investigation for use in diagnosis, predicting response to therapy, and treatment monitoring.
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8
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Manzo A, Bugatti S, Rossi S. Clinical Applications of Synovial Biopsy. Front Med (Lausanne) 2019; 6:102. [PMID: 31134204 PMCID: PMC6524205 DOI: 10.3389/fmed.2019.00102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/25/2019] [Indexed: 11/13/2022] Open
Abstract
The synovial tissue is a primary target of multiple diseases characterized by different pathogenic mechanisms, including infective, deposition, neoplastic, and chronic immune-inflammatory pathologies. Synovial biopsy can have a relevant role in differential diagnosis of specific conditions in clinical practice, although its exploitation remains relatively limited. In particular, no validated synovial-tissue-derived biomarkers are currently available in the clinic to aid in the diagnosis and management in most frequent forms of chronic inflammatory arthropathies, namely rheumatoid arthritis (RA) and the spondyloarthritides (SpA). In this brief review, we will discuss the current spectrum of clinical applications of synovial biopsy in routine rheumatologic care and will provide an analysis of the perspectives for its potential exploitation in patients with chronic inflammatory arthritides.
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Affiliation(s)
- Antonio Manzo
- Rheumatology and Translational Immunology Research Laboratories, Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Serena Bugatti
- Rheumatology and Translational Immunology Research Laboratories, Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Silvia Rossi
- Rheumatology and Translational Immunology Research Laboratories, Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
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9
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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10
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Orabona C, Mondanelli G, Puccetti P, Grohmann U. Immune Checkpoint Molecules, Personalized Immunotherapy, and Autoimmune Diabetes. Trends Mol Med 2018; 24:931-941. [PMID: 30236470 DOI: 10.1016/j.molmed.2018.08.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/29/2018] [Accepted: 08/30/2018] [Indexed: 12/27/2022]
Abstract
Although significant progress has been made in understanding autoimmunity, no immunotherapy to effectively halt immune-mediated destruction of β cells in type 1 diabetes (T1D) is currently available. For successful immunotherapy it will be necessary to identify novel drug targets as well as robust immunologic biomarkers to predict disease heterogeneity and patient responsiveness. Inhibition of immune checkpoint mechanisms represents a novel and effective strategy in tumor immunotherapy. Because they are fundamental to rewiring immune circuits, the underlying mechanisms could be therapeutically enhanced and used as biomarkers in T1D. We examine here current knowledge of immune checkpoint molecules in T1D. One specific immune checkpoint mechanism, namely tryptophan metabolism, may meet the need for a valid drug target and robust biomarker in the quest for effective and personalized immunotherapy in T1D.
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Affiliation(s)
- Ciriana Orabona
- University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy
| | | | - Paolo Puccetti
- University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy
| | - Ursula Grohmann
- University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
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11
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Lemarquis AL, Einarsdottir HK, Kristjansdottir RN, Jonsdottir I, Ludviksson BR. Transitional B Cells and TLR9 Responses Are Defective in Selective IgA Deficiency. Front Immunol 2018; 9:909. [PMID: 29755476 PMCID: PMC5934527 DOI: 10.3389/fimmu.2018.00909] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 04/11/2018] [Indexed: 12/28/2022] Open
Abstract
Selective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naïve and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class-switched memory B cells (CD20+CD27+IgD−) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production.
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Affiliation(s)
- Andri L Lemarquis
- Department of Immunology, Landspítali-University Hospital, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | | | - Rakel N Kristjansdottir
- Department of Immunology, Landspítali-University Hospital, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Ingileif Jonsdottir
- Department of Immunology, Landspítali-University Hospital, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Division of Infectious and Inflammatory Diseases, deCODE Genetics, Reykjavík, Iceland
| | - Bjorn R Ludviksson
- Department of Immunology, Landspítali-University Hospital, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
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12
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Fiocchi C. Inflammatory Bowel Disease: Complexity and Variability Need Integration. Front Med (Lausanne) 2018; 5:75. [PMID: 29619371 PMCID: PMC5873363 DOI: 10.3389/fmed.2018.00075] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 03/07/2018] [Indexed: 12/16/2022] Open
Affiliation(s)
- Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Cleveland, OH, United States.,Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
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13
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Peck RW. Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient. Annu Rev Pharmacol Toxicol 2018; 58:105-122. [DOI: 10.1146/annurev-pharmtox-010617-052446] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Richard W. Peck
- Pharma Research and Exploratory Development, Roche Innovation Center Basel, 4070 Basel, Switzerland
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14
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de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2017; 14:739-749. [PMID: 28831186 DOI: 10.1038/nrgastro.2017.110] [Citation(s) in RCA: 303] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Crohn's disease and ulcerative colitis are prototypical complex diseases characterized by chronic and heterogeneous manifestations, induced by interacting environmental, genomic, microbial and immunological factors. These interactions result in an overwhelming complexity that cannot be tackled by studying the totality of each pathological component (an '-ome') in isolation without consideration of the interaction among all relevant -omes that yield an overall 'network effect'. The outcome of this effect is the 'IBD interactome', defined as a disease network in which dysregulation of individual -omes causes intestinal inflammation mediated by dysfunctional molecular modules. To define the IBD interactome, new concepts and tools are needed to implement a systems approach; an unbiased data-driven integration strategy that reveals key players of the system, pinpoints the central drivers of inflammation and enables development of targeted therapies. Powerful bioinformatics tools able to query and integrate multiple -omes are available, enabling the integration of genomic, epigenomic, transcriptomic, proteomic, metabolomic and microbiome information to build a comprehensive molecular map of IBD. This approach will enable identification of IBD molecular subtypes, correlations with clinical phenotypes and elucidation of the central hubs of the IBD interactome that will aid discovery of compounds that can specifically target the hubs that control the disease.
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Affiliation(s)
- Heitor S P de Souza
- Department of Gastroenterology & Multidisciplinary Research Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA
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15
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Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci 2017; 20:156-166. [PMID: 28092663 DOI: 10.1038/nn.4477] [Citation(s) in RCA: 349] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/12/2016] [Indexed: 12/14/2022]
Abstract
Studies bridging neuroscience and immunology have identified neural pathways that regulate immunity and inflammation. Recent research using methodological advances in molecular genetics has improved our understanding of the neural control of immunity. Here we outline mechanistic insights, focusing on translational relevance and conceptual developments. We also summarize findings from recent clinical studies of bioelectronic neuromodulation in inflammatory and autoimmune diseases.
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16
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Te Velde AA, Bezema T, van Kampen AHC, Kraneveld AD, 't Hart BA, van Middendorp H, Hack EC, van Montfrans JM, Belzer C, Jans-Beken L, Pieters RH, Knipping K, Huber M, Boots AMH, Garssen J, Radstake TR, Evers AWM, Prakken BJ, Joosten I. Embracing Complexity beyond Systems Medicine: A New Approach to Chronic Immune Disorders. Front Immunol 2016; 7:587. [PMID: 28018353 PMCID: PMC5149516 DOI: 10.3389/fimmu.2016.00587] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/28/2016] [Indexed: 12/21/2022] Open
Abstract
In order to combat chronic immune disorders (CIDs), it is an absolute necessity to understand the bigger picture, one that goes beyond insights at a one-disease, molecular, cellular, and static level. To unravel this bigger picture we advocate an integral, cross-disciplinary approach capable of embracing the complexity of the field. This paper discusses the current knowledge on common pathways in CIDs including general psychosocial and lifestyle factors associated with immune functioning. We demonstrate the lack of more in-depth psychosocial and lifestyle factors in current research cohorts and most importantly the need for an all-encompassing analysis of these factors. The second part of the paper discusses the challenges of understanding immune system dynamics and effectively integrating all key perspectives on immune functioning, including the patient’s perspective itself. This paper suggests the use of techniques from complex systems science in describing and simulating healthy or deviating behavior of the immune system in its biopsychosocial surroundings. The patient’s perspective data are suggested to be generated by using specific narrative techniques. We conclude that to gain more insight into the behavior of the whole system and to acquire new ways of combatting CIDs, we need to construct and apply new techniques in the field of computational and complexity science, to an even wider variety of dynamic data than used in today’s systems medicine.
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Affiliation(s)
- Anje A Te Velde
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center , Amsterdam , Netherlands
| | | | - Antoine H C van Kampen
- Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics (KEBB), Academic Medical Center, Amsterdam, Netherlands; Biosystems Data Analysis, Swammerdam Institute for Life Sciences (SILS), University of Amsterdam, Amsterdam, Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands; Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Bert A 't Hart
- Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, Netherlands; Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Neuroscience, University Medical Center, University of Groningen, Groningen, Netherlands
| | - Henriët van Middendorp
- Institute of Psychology, Health, Medical, and Neuropsychology Unit, Faculty of Social and Behavioural Sciences, Leiden University , Leiden , Netherlands
| | - Erik C Hack
- Laboratory of Translational Immunology, University Medical Center Utrecht , Utrecht , Netherlands
| | - Joris M van Montfrans
- Division of Pediatrics, Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht , Utrecht , Netherlands
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University , Wageningen , Netherlands
| | - Lilian Jans-Beken
- Department of Psychology and Educational Sciences, Open University , Heerlen , Netherlands
| | - Raymond H Pieters
- Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; Institute for Life Sciences and Chemistry, HU University of Applied Sciences Utrecht, Utrecht, Netherlands
| | - Karen Knipping
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands; Immunology Platform, Nutricia Research, Utrecht, Netherlands
| | - Machteld Huber
- Institute for Positive Health , Amersfoort , Netherlands
| | - Annemieke M H Boots
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands; Immunology Platform, Nutricia Research, Utrecht, Netherlands
| | - Tim R Radstake
- Laboratory of Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht , Utrecht , Netherlands
| | - Andrea W M Evers
- Institute of Psychology, Health, Medical, and Neuropsychology Unit, Faculty of Social and Behavioural Sciences, Leiden University , Leiden , Netherlands
| | - Berent J Prakken
- Laboratory of Translational Immunology, Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht , Utrecht , Netherlands
| | - Irma Joosten
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre , Nijmegen , Netherlands
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Abstract
In recent decades, innovative strategies to treat patients with inflammatory, immunologically based diseases have advanced in concert with our increased understanding of molecular immunology. Recognition of the spectrum and pathophysiology of autoimmune and autoinflammatory disorders has allowed for the development of cutting-edge therapies for such patients. In this review, key immunotherapeutic approaches for treating inflammatory autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as genetic autoinflammatory diseases, such as cryopyrin associated periodic syndromes, are addressed. Indications, risks and additional considerations in the use of these agents are reviewed.
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Affiliation(s)
- Barbara E Ostrov
- a Department of Pediatrics , Pediatric Rheumatology and Rheumatology, Pediatrician-in-Chief of Penn State Hershey Children's Hospital , Hershey , PA , USA
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18
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Reardon C. Neuro-immune interactions in the cholinergic anti-inflammatory reflex. Immunol Lett 2016; 178:92-6. [PMID: 27542331 DOI: 10.1016/j.imlet.2016.08.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/12/2016] [Accepted: 08/15/2016] [Indexed: 10/21/2022]
Abstract
Communication between the nervous and immune systems can significantly alter immune cell function in a number of inflammatory diseases. Elegant studies have defined a basic functional circuit in a "cholinergic anti-inflammatory pathway" that highlights a unique role for the vagus nerve, and has brought about a resurgence in the field of neuro-immunology. This research has further identified that in addition to tonic signals that can restrain immune cell activation; the anti-inflammatory reflex arc is amiable to targeted stimulation as a therapeutic modality. The success of vagal electrical neural stimulation in a plethora of pre-clinical inflammation models has spurred the development of "electroceuticals" or neurostimulatory devices in the treatment of chronic inflammation. This development has begun despite addressing of fundamental questions such as the functional neural circuitry being crudely mapped and unresolved mechanisms of action of acetylcholine on target immune cells. Perhaps fortuitously, rapid advances in neuroscience techniques may allow us to begin to answer some of these longstanding questions and clarify recent controversies.
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Affiliation(s)
- Colin Reardon
- University of California Davis, School of Veterinary Medicine, Department of Anatomy, Physiology, and Cell Biology, 1089 Veterinary Medicine Drive, VM3B, Room 2007, Davis, CA 95616, United States.
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19
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Danese S, Fiocchi C, Panés J. Drug development in IBD: from novel target identification to early clinical trials. Gut 2016; 65:1233-9. [PMID: 27196598 DOI: 10.1136/gutjnl-2016-311717] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/19/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Humanitas University, Milan, Italy
| | - Claudio Fiocchi
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Julián Panés
- Gastroenterology Department, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
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20
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Townsend MJ, Arron JR. Reducing the risk of failure: biomarker-guided trial design. Nat Rev Drug Discov 2016; 15:517-8. [DOI: 10.1038/nrd.2016.124] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Bingley PJ, Boulware DC, Krischer JP. The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes. Diabetologia 2016; 59:542-9. [PMID: 26676824 PMCID: PMC4742489 DOI: 10.1007/s00125-015-3830-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 11/03/2015] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention. METHODS The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies. RESULTS Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry. CONCLUSIONS/INTERPRETATION Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention.
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Affiliation(s)
- Polly J Bingley
- School of Clinical Sciences, University of Bristol, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
| | - David C Boulware
- Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jeffrey P Krischer
- Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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22
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Rodgers DT, McGrath MA, Pineda MA, Al-Riyami L, Rzepecka J, Lumb F, Harnett W, Harnett MM. The parasitic worm product ES-62 targets myeloid differentiation factor 88-dependent effector mechanisms to suppress antinuclear antibody production and proteinuria in MRL/lpr mice. Arthritis Rheumatol 2015; 67:1023-35. [PMID: 25546822 PMCID: PMC4409857 DOI: 10.1002/art.39004] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 12/16/2014] [Indexed: 12/30/2022]
Abstract
Objective The hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. The aim of this study was to investigate whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage in an MRL/lpr mouse model of systemic lupus erythematosus (SLE). Methods MRL/lpr mice progressively produce high levels of autoantibodies, and the resultant deposition of immune complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria, assessment of kidney histology, determination of antinuclear antibody (ANA) production and cytokine levels, and flow cytometric analysis of relevant cellular populations. Results ES-62 restored the disrupted balance between effector and regulatory B cells in MRL/lpr mice by inhibiting plasmablast differentiation, with a consequent reduction in ANA production and deposition of immune complexes and C3a in the kidneys. Moreover, by reducing interleukin-22 production, ES-62 may desensitize downstream effector mechanisms in the pathogenesis of kidney disease. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62–treated MRL/lpr mice mimicked the protection afforded by the helminth product. Mechanistically, this reflects down-regulation of myeloid differentiation factor 88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic cross-talk among Toll-like receptor–, C3a-, and immune complex–mediated effector mechanisms. Conclusion This study provides the first demonstration of protection against kidney pathology by a parasitic worm–derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on the mechanism of action of ES-62.
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Smilek DE, St. Clair EW. Solving the puzzle of autoimmunity: critical questions. F1000PRIME REPORTS 2015; 7:17. [PMID: 25750735 PMCID: PMC4335798 DOI: 10.12703/p7-17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite recent advances in delineating the pathogenic mechanisms of autoimmune disease, the puzzle that reveals the true picture of these diverse immunological disorders is yet to be solved. We know that the human leukocyte antigen (HLA) loci as well as many different genetic susceptibility loci with relatively small effect sizes predispose to various autoimmune diseases and that environmental factors are involved in triggering disease. Models for mechanisms of disease become increasingly complex as relationships between components of both the adaptive and innate immune systems are untangled at the molecular level. In this article, we pose some of the important questions about autoimmunity where the answers will advance our understanding of disease pathogenesis and improve the rational design of novel therapies. How is autoimmunity triggered, and what components of the immune response drive the clinical manifestations of disease? What determines whether a genetically predisposed individual will develop an autoimmune disease? Is restoring immune tolerance the secret to finding cures for autoimmune disease? Current research efforts seek answers to these big questions.
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Affiliation(s)
- Dawn E. Smilek
- Immune Tolerance Network185 Berry Street #3515, San Francisco, CA 94107USA
| | - E. William St. Clair
- Immune Tolerance Network185 Berry Street #3515, San Francisco, CA 94107USA
- Department of Medicine, Division of Rheumatology and Immunology, School of Medicine, Duke UniversityDurham, NC 27710USA
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Smilek DE, Ehlers MR, Nepom GT. Restoring the balance: immunotherapeutic combinations for autoimmune disease. Dis Model Mech 2014; 7:503-13. [PMID: 24795433 PMCID: PMC4007402 DOI: 10.1242/dmm.015099] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Autoimmunity occurs when T cells, B cells or both are inappropriately activated, resulting in damage to one or more organ systems. Normally, high-affinity self-reactive T and B cells are eliminated in the thymus and bone marrow through a process known as central immune tolerance. However, low-affinity self-reactive T and B cells escape central tolerance and enter the blood and tissues, where they are kept in check by complex and non-redundant peripheral tolerance mechanisms. Dysfunction or imbalance of the immune system can lead to autoimmunity, and thus elucidation of normal tolerance mechanisms has led to identification of therapeutic targets for treating autoimmune disease. In the past 15 years, a number of disease-modifying monoclonal antibodies and genetically engineered biologic agents targeting the immune system have been approved, notably for the treatment of rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although these agents represent a major advance, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require intervention aimed at multiple components of the immune system. To this end, approaches that manipulate cells ex vivo and harness their complex behaviors are being tested in preclinical and clinical settings. In addition, approved biologic agents are being examined in combination with one another and with cell-based therapies. Substantial development and regulatory hurdles must be overcome in order to successfully combine immunotherapeutic biologic agents. Nevertheless, such combinations might ultimately be necessary to control autoimmune disease manifestations and restore the tolerant state.
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Affiliation(s)
- Dawn E Smilek
- The Immune Tolerance Network, 185 Berry Street #3515, San Francisco, CA 94107, USA
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Abstract
The complexity of IBD is well recognized as are the putative four major components of its pathogenesis, i.e. environment, genetic makeup, gut microbiota and mucosal immune response. Each of these components is extremely complex on its own, and at present should be more appropriately defined by the terms 'exposome', 'genome', 'microbiome' and 'immunome', respectively, based on the 'ome' suffix that refers to a totality of some sort. None of these 'omes' is apparently capable of causing IBD by itself; it is instead the intricate and reciprocal interaction among them, through the so-called 'IBD interactome', that results in the emergence of IBD, or more appropriately the 'IBD integrome'. To deal with and understand such overwhelming biological complexity, new approaches and tools are needed, and these are represented by 'omics', defined as the study of related sets of biological molecules in a comprehensive fashion, such as genomics, transcriptomics, proteomics, metabolomics, and so on. Numerous bioinformatics-based tools are available to explore and take advantage of the massive amount of information that can be generated by the analysis of the various omes and their interactions, aiming at identifying the molecular interactome underlying any particular status of health and disease. These novel approaches are fully applicable to IBD and allow us to achieve the ultimate goal of developing and applying personalized medicine and far more effective therapies to individual patients with Crohn's disease and ulcerative colitis. For the practicing gastroenterologist, an omics-based delivery of healthcare may be intimidating, but it must be accepted and implemented if he or she is to provide the best possible care to IBD patients.
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Affiliation(s)
- Claudio Fiocchi
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, and Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
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26
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Arif S, Leete P, Nguyen V, Marks K, Nor NM, Estorninho M, Kronenberg-Versteeg D, Bingley PJ, Todd JA, Guy C, Dunger DB, Powrie J, Willcox A, Foulis AK, Richardson SJ, de Rinaldis E, Morgan NG, Lorenc A, Peakman M. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 2014; 63:3835-45. [PMID: 24939426 PMCID: PMC4207393 DOI: 10.2337/db14-0365] [Citation(s) in RCA: 180] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/12/2014] [Indexed: 12/16/2022]
Abstract
Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.
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Affiliation(s)
- Sefina Arif
- Department of Immunobiology, King's College London School of Medicine, London, U.K
| | - Pia Leete
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K
| | - Vy Nguyen
- Department of Immunobiology, King's College London School of Medicine, London, U.K
| | - Katherine Marks
- Department of Immunobiology, King's College London School of Medicine, London, U.K
| | | | - Megan Estorninho
- Department of Immunobiology, King's College London School of Medicine, London, U.K
| | | | - Polly J Bingley
- School of Clinical Sciences, University of Bristol, Bristol, U.K
| | - John A Todd
- JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K
| | - Catherine Guy
- University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, U.K
| | - David B Dunger
- University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, U.K
| | - Jake Powrie
- Department of Diabetes and Endocrinology, Guy's & St Thomas' Hospital NHS Foundation Trust, London, U.K
| | - Abby Willcox
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K
| | - Alan K Foulis
- Greater Glasgow and Clyde Pathology Department, Southern General Hospital, Glasgow, U.K
| | - Sarah J Richardson
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K
| | - Emanuele de Rinaldis
- National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospital Foundation Trust and King's College London, London, U.K
| | - Noel G Morgan
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K
| | - Anna Lorenc
- National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospital Foundation Trust and King's College London, London, U.K
| | - Mark Peakman
- Department of Immunobiology, King's College London School of Medicine, London, U.K.
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Goel G, Conway KL, Jaeger M, Netea MG, Xavier RJ. Multivariate inference of pathway activity in host immunity and response to therapeutics. Nucleic Acids Res 2014; 42:10288-306. [PMID: 25147207 PMCID: PMC4176341 DOI: 10.1093/nar/gku722] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene–gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene–environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNFα therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method.
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Affiliation(s)
- Gautam Goel
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Kara L Conway
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Martin Jaeger
- Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands
| | - Ramnik J Xavier
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
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Vogl T, Eisenblätter M, Völler T, Zenker S, Hermann S, van Lent P, Faust A, Geyer C, Petersen B, Roebrock K, Schäfers M, Bremer C, Roth J. Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity. Nat Commun 2014; 5:4593. [PMID: 25098555 PMCID: PMC4143994 DOI: 10.1038/ncomms5593] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/03/2014] [Indexed: 12/19/2022] Open
Abstract
Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical molecular imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clinical disease activity in inflammatory and immunological processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in experimental leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive molecular target for novel imaging approaches to monitor clinically relevant inflammatory disorders on a molecular level.
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Affiliation(s)
- Thomas Vogl
- Institute of Immunology, University of Münster, 48149 Münster, Germany
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
- These authors contributed equally to this work
| | - Michel Eisenblätter
- Division of Imaging Sciences and Biomedical Engineering, King’s College London, London SE1 7EH, UK
- Department of Clinical Radiology, University of Münster, 48149 Münster, Germany
- These authors contributed equally to this work
| | - Tom Völler
- Institute of Immunology, University of Münster, 48149 Münster, Germany
| | - Stefanie Zenker
- Institute of Immunology, University of Münster, 48149 Münster, Germany
| | - Sven Hermann
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
- European Institute for Molecular Imaging, University of Münster, 48149 Münster, Germany
| | - Peter van Lent
- Department of Rheumatology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
| | - Andreas Faust
- European Institute for Molecular Imaging, University of Münster, 48149 Münster, Germany
| | - Christiane Geyer
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
- Department of Clinical Radiology, University of Münster, 48149 Münster, Germany
| | - Beatrix Petersen
- Institute of Immunology, University of Münster, 48149 Münster, Germany
| | - Kirsten Roebrock
- Institute of Immunology, University of Münster, 48149 Münster, Germany
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
| | - Michael Schäfers
- European Institute for Molecular Imaging, University of Münster, 48149 Münster, Germany
- Cluster of Excellence EXC 1003 ‘Cells in Motion - CiM’, University of Münster, 48149 Münster, Germany
| | - Christoph Bremer
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
- Department of Radiology, St Franziskus Hospital Münster, 48145 Münster, Germany
| | - Johannes Roth
- Institute of Immunology, University of Münster, 48149 Münster, Germany
- Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany
- Cluster of Excellence EXC 1003 ‘Cells in Motion - CiM’, University of Münster, 48149 Münster, Germany
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29
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Dennis G, Holweg CTJ, Kummerfeld SK, Choy DF, Setiadi AF, Hackney JA, Haverty PM, Gilbert H, Lin WY, Diehl L, Fischer S, Song A, Musselman D, Klearman M, Gabay C, Kavanaugh A, Endres J, Fox DA, Martin F, Townsend MJ. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res Ther 2014; 16:R90. [PMID: 25167216 PMCID: PMC4060385 DOI: 10.1186/ar4555] [Citation(s) in RCA: 268] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 02/25/2014] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood. METHODS We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy. RESULTS We documented evidence for four major phenotypes of RA synovium - lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004). CONCLUSIONS These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases. TRIAL REGISTRATION ClinicalTrials.gov NCT01119859
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