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Taylor JP, Blum SI, Graffeo HC, Shang Q, Qiu S, Green TJ, Botta D, Lund FE, Tse HM. The Type 1 Diabetes-Associated Single Nucleotide Polymorphism rs1990760 in IFIH1 Is Associated with Increased Basal Type I IFNs and IFN-stimulated Gene Expression. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1415-1428. [PMID: 39373578 DOI: 10.4049/jimmunol.2400344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 09/18/2024] [Indexed: 10/08/2024]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that is caused by a combination of genetic and environmental risk factors. In this study, we sought to determine whether a known genetic risk factor, the rs1990760 single nucleotide polymorphism (SNP) (A946T) in IFIH1, resulted in a gain of function in the MDA5 protein and the effects of this mutation on the regulation of type I IFNs during infection with the diabetogenic virus coxsackievirus B3. We found that in cell lines overexpressing the risk variant IFIH1946T there was an elevated level of basal type I IFN signaling and increased basal IFN-stimulated gene expression. An investigation into the mechanism demonstrated that recombinant MDA5 with the A946T mutation had increased ATPase activity in vitro. We also assessed the effect of this SNP in primary human PBMCs from healthy donors to determine whether this SNP influenced their response to infection with coxsackievirus B3. However, we observed no significant changes in type I IFN expression or downstream induction of IFN-stimulated genes in PBMCs from donors carrying the risk allele IFIH1946T. These findings demonstrate the need for a deeper understanding of how mutations in T1D-associated genes contribute to disease onset in specific cellular contexts.
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Affiliation(s)
- Jared P Taylor
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Samuel I Blum
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Hollis C Graffeo
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Qiao Shang
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Shihong Qiu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Todd J Green
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Davide Botta
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
- Heersink School of Medicine, Immunology Institute, University of Alabama at Birmingham, Birmingham, AL
| | - Frances E Lund
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
- Heersink School of Medicine, Immunology Institute, University of Alabama at Birmingham, Birmingham, AL
| | - Hubert M Tse
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
- Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, KS
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2
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Nhau PT, Gamede M, Sibiya N. COVID-19-Induced Diabetes Mellitus: Comprehensive Cellular and Molecular Mechanistic Insights. PATHOPHYSIOLOGY 2024; 31:197-209. [PMID: 38651404 PMCID: PMC11036300 DOI: 10.3390/pathophysiology31020016] [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: 02/12/2024] [Revised: 04/06/2024] [Accepted: 04/07/2024] [Indexed: 04/25/2024] Open
Abstract
Despite evidence demonstrating the risks of developing diabetes mellitus because of SARS-CoV-2, there is, however, insufficient scientific data available to elucidate the relationship between diabetes mellitus and COVID-19. Research indicates that SARS-CoV-2 infection is associated with persistent damage to organ systems due to the systemic inflammatory response. Since COVID-19 is known to induce these conditions, further investigation is necessary to fully understand its long-term effects on human health. Consequently, it is essential to consider the effect of the COVID-19 pandemic when predicting the prevalence of diabetes mellitus in the future, especially since the incidence of diabetes mellitus was already on the rise before the pandemic. Additional research is required to fully comprehend the impact of SARS-CoV-2 infection on glucose tolerance and insulin sensitivity. Therefore, this article delves deeper into the current literature and links the perceived relationship between SARS-CoV-2 and diabetes. In addition, the article highlights the necessity for further research to fully grasp the mechanisms that SARS-CoV-2 utilises to induce new-onset diabetes. Where understanding and consensus are reached, therapeutic interventions to prevent the onset of diabetes could be proposed. Lastly, we propose advocating for the regular screening of diabetes and pre-diabetes, particularly for the high-risk population with a history of COVID-19 infection.
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Affiliation(s)
- Praise Tatenda Nhau
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda 6139, South Africa;
| | - Mlindeli Gamede
- Human Physiology Department, University of Pretoria, Pretoria 0028, South Africa;
| | - Ntethelelo Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda 6139, South Africa;
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3
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Pandey S, Chmelir T, Chottova Dvorakova M. Animal Models in Diabetic Research-History, Presence, and Future Perspectives. Biomedicines 2023; 11:2852. [PMID: 37893225 PMCID: PMC10603837 DOI: 10.3390/biomedicines11102852] [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: 09/19/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
Diabetes mellitus (DM) is a very serious disease, the incidence of which has been increasing worldwide. The beginning of diabetic research can be traced back to the 17th century. Since then, animals have been experimented on for diabetic research. However, the greatest development of diabetes research occurred in the second half of the last century, along with the development of laboratory techniques. Information obtained by monitoring patients and animal models led to the finding that there are several types of DM that differ significantly from each other in the causes of the onset and course of the disease. Through different types of animal models, researchers have studied the pathophysiology of all types of diabetic conditions and discovered suitable methods for therapy. Interestingly, despite the unquestionable success in understanding DM through animal models, we did not fully succeed in transferring the data obtained from animal models to human clinical research. On the contrary, we have observed that the chances of drug failure in human clinical trials are very high. In this review, we will summarize the history and presence of animal models in the research of DM over the last hundred years. Furthermore, we have summarized the new methodological approaches, such as "organ-on-chip," that have the potential to screen the newly discovered drugs for human clinical trials and advance the level of knowledge about diabetes, as well as its therapy, towards a personalized approach.
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Affiliation(s)
- Shashank Pandey
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic;
- Department of Pharmacology and Toxicology, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
| | - Tomas Chmelir
- Department of Physiology, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic;
| | - Magdalena Chottova Dvorakova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic;
- Department of Physiology, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic;
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4
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Rampanelli E, Nieuwdorp M. Gut microbiome in type 1 diabetes: the immunological perspective. Expert Rev Clin Immunol 2023; 19:93-109. [PMID: 36401835 DOI: 10.1080/1744666x.2023.2150612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Type 1 diabetes (T1D) is a prevalent, and yet uncurable, autoimmune disease targeting insulin-producing pancreatic β-cells. Despite a known genetic component in T1D onset, genetics alone cannot explain the alarming worldwide rise in T1D incidence, which is attributed to a growing impact of environmental factors, including perturbations of the gut microbiome. AREAS COVERED Intestinal commensal bacteria plays a crucial role in host physiology in health and disease by regulating endocrine and immune functions. An aberrant gut microbiome structure and metabolic function have been documented prior and during T1D onset. In this review, we summarize and discuss the current studies depicting the taxonomic profile and role of the gut microbial communities in murine models of T1D, diabetic patients and human interventional trials. EXPERT OPINION Compelling evidence have shown that the intestinal microbiota is instrumental in driving differentiation and functions of immune cells. Therefore, any alterations in the intestinal microbiome composition or microbial metabolite production, particularly early in life, may impact disease susceptibility and amplify inflammatory responses and hence accelerate the course of T1D pathogenesis.
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Affiliation(s)
- Elena Rampanelli
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands.,Amsterdam Institute for Infection and Immunity (AII), Amsterdam, The Netherlands.,Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM) Institute, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM) Institute, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands.,Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
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5
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Geerling E, Hameed M, Weger-Lucarelli J, Pinto AK. Metabolic syndrome and aberrant immune responses to viral infection and vaccination: Insights from small animal models. Front Immunol 2022; 13:1015563. [PMID: 36532060 PMCID: PMC9747772 DOI: 10.3389/fimmu.2022.1015563] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/08/2022] [Indexed: 12/05/2022] Open
Abstract
This review outlines the propensity for metabolic syndrome (MetS) to induce elevated disease severity, higher mortality rates post-infection, and poor vaccination outcomes for viral pathogens. MetS is a cluster of conditions including high blood glucose, an increase in circulating low-density lipoproteins and triglycerides, abdominal obesity, and elevated blood pressure which often overlap in their occurrence. MetS diagnoses are on the rise, as reported cases have increased by greater than 35% since 1988, resulting in one-third of United States adults currently diagnosed as MetS patients. In the aftermath of the 2009 H1N1 pandemic, a link between MetS and disease severity was established. Since then, numerous studies have been conducted to illuminate the impact of MetS on enhancing virally induced morbidity and dysregulation of the host immune response. These correlative studies have emphasized the need for elucidating the mechanisms by which these alterations occur, and animal studies conducted as early as the 1940s have linked the conditions associated with MetS with enhanced viral disease severity and poor vaccine outcomes. In this review, we provide an overview of the importance of considering overall metabolic health in terms of cholesterolemia, glycemia, triglyceridemia, insulin and other metabolic molecules, along with blood pressure levels and obesity when studying the impact of metabolism-related malignancies on immune function. We highlight the novel insights that small animal models have provided for MetS-associated immune dysfunction following viral infection. Such animal models of aberrant metabolism have paved the way for our current understanding of MetS and its impact on viral disease severity, dysregulated immune responses to viral pathogens, poor vaccination outcomes, and contributions to the emergence of viral variants.
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Affiliation(s)
- Elizabeth Geerling
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Muddassar Hameed
- Department of Biomedical Science and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - James Weger-Lucarelli
- Department of Biomedical Science and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - Amelia K. Pinto
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, United States
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6
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Wang SC, Liao JY. Epidemiologic Implication of the Association between Herpes Simplex Virus Infection and the Risk of Type 1 Diabetes Mellitus: A Nationwide Case-Control Study in Taiwan. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19137832. [PMID: 35805493 PMCID: PMC9265894 DOI: 10.3390/ijerph19137832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 02/05/2023]
Abstract
Enterovirus infection is a known risk factor for type 1 diabetes (T1DM). Whether infection with other viruses induces T1DM remains undetermined. This study investigated the association between human herpesvirus (HHV) infection and the development of T1DM, using the data from Taiwan’s National Health Insurance Research Database. Patients with T1DM and age- and sex-matched controls were included. Subjects with HHV infection were subgrouped into those with histories of varicella-zoster virus, herpes simplex virus (HSV), Epstein-Barr virus, and human cytomegalovirus infections. The odds ratio of the risk of T1DM was calculated using a multivariable conditional logistic regression model. Atopic diseases, autoimmune thyroid diseases, and history of enterovirus infection served as adjusted comorbidities. Our findings suggested a significant association between HSV infection and the risk of T1DM (adjusted odds ratio: 1.21; 95% CI: 1.01–1.47, p = 0.048), while infection with other HHVs was not. The result of HSV infection remained significant when subjects were restricted to age ≤ 18 years (adjusted odds ratio: 1.35; 95% CI: 1.08–1.70, p = 0.010). We found a history of HSV infection might be an independent predictive risk factor for T1DM. This could be potentially helpful to the practice in public health.
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Affiliation(s)
- Shao-Chang Wang
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan;
| | - Jung-Yu Liao
- Department of Public Health, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 2106)
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7
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Bauer W, Gyenesei A, Krętowski A. The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children. Int J Mol Sci 2021; 22:7493. [PMID: 34299114 PMCID: PMC8305179 DOI: 10.3390/ijms22147493] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3-5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.
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Affiliation(s)
- Witold Bauer
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
| | - Attila Gyenesei
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
- Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland; (A.G.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Białystok, Marii Skłodowskiej-Curie 24a, 15-276 Białystok, Poland
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8
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Pearson JA, Wong FS, Wen L. Inflammasomes and Type 1 Diabetes. Front Immunol 2021; 12:686956. [PMID: 34177937 PMCID: PMC8219953 DOI: 10.3389/fimmu.2021.686956] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/17/2021] [Indexed: 01/10/2023] Open
Abstract
Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes.
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Affiliation(s)
- James Alexander Pearson
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Li Wen
- Section of Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
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9
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Shakeel-u-Rehman, Bhat KA, Lone SH, Malik FA. Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of D-(+)-pinitol. ARAB J CHEM 2019. [DOI: 10.1016/j.arabjc.2015.10.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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10
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Lalwani A, Warren J, Liuwantara D, Hawthorne WJ, O'Connell PJ, Gonzalez FJ, Stokes RA, Chen J, Laybutt DR, Craig ME, Swarbrick MM, King C, Gunton JE. β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes. Cell Rep 2019; 27:2370-2384.e6. [PMID: 31116982 PMCID: PMC6661122 DOI: 10.1016/j.celrep.2019.04.086] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 01/31/2019] [Accepted: 04/18/2019] [Indexed: 12/28/2022] Open
Abstract
The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D.
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Affiliation(s)
- Amit Lalwani
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Joanna Warren
- Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - David Liuwantara
- National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Wayne J Hawthorne
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Philip J O'Connell
- National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
| | - Rebecca A Stokes
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
| | - Jennifer Chen
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
| | - D Ross Laybutt
- Islet Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Maria E Craig
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The Children's Hospital at Westmead, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Kensington, NSW, Australia
| | - Michael M Swarbrick
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia
| | - Cecile King
- Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jenny E Gunton
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia.
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11
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Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab Res Rev 2018; 34:e3043. [PMID: 29929213 PMCID: PMC6220847 DOI: 10.1002/dmrr.3043] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/06/2018] [Accepted: 06/14/2018] [Indexed: 12/17/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease, which is characterized by the destruction of islet β cells in the pancreas triggered by genetic and environmental factors. In past decades, extensive familial and genome-wide association studies have revealed more than 50 risk loci in the genome. However, genetic susceptibility cannot explain the increased incidence of T1D worldwide, which is very likely attributed by the growing impact of environmental factors, especially gut microbiome. Recently, the role of gut microbiome in the pathogenesis of T1D has been uncovered by the increasing evidence from both human subjects and animal models, strongly indicating that gut microbiome might be a pivotal hub of T1D-triggering factors, especially environmental factors. In this review, we summarize the current aetiological and mechanism studies of gut microbiome in T1D. A better understanding of the role of gut microbiome in T1D may provide us with powerful prognostic and therapeutic tools in the near future.
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Affiliation(s)
- Peilin Zheng
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
| | - Zhixia Li
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina
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12
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Marré ML, Piganelli JD. Environmental Factors Contribute to β Cell Endoplasmic Reticulum Stress and Neo-Antigen Formation in Type 1 Diabetes. Front Endocrinol (Lausanne) 2017; 8:262. [PMID: 29033899 PMCID: PMC5626851 DOI: 10.3389/fendo.2017.00262] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 09/20/2017] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which immune-mediated targeting and destruction of insulin-producing pancreatic islet β cells leads to chronic hyperglycemia. There are many β cell proteins that are targeted by autoreactive T cells in their native state. However, recent studies have demonstrated that many β cell proteins are recognized as neo-antigens following posttranslational modification (PTM). Although modified neo-antigens are well-established targets of pathology in other autoimmune diseases, the effects of neo-antigens in T1D progression and the mechanisms by which they are generated are not well understood. We have demonstrated that PTM occurs during endoplasmic reticulum (ER) stress, a process to which β cells are uniquely susceptible due to the high rate of insulin production in response to dynamic glucose sensing. In the context of genetic susceptibility to autoimmunity, presentation of these modified neo-antigens may activate autoreactive T cells and cause pathology. However, inherent β cell ER stress and protein PTM do not cause T1D in every genetically susceptible individual, suggesting the contribution of additional factors. Indeed, many environmental factors, such as viral infection, chemicals, or inflammatory cytokines, are associated with T1D onset, but the mechanisms by which these factors lead to disease onset remain unknown. Since these environmental factors also cause ER stress, exposure to these factors may enhance production of neo-antigens, therefore boosting β cell recognition by autoreactive T cells and exacerbating T1D pathogenesis. Therefore, the combined effects of physiological ER stress and the stress that is induced by environmental factors may lead to breaks in peripheral tolerance, contribute to antigen spread, and hasten disease onset. This Hypothesis and Theory article summarizes what is currently known about ER stress and protein PTM in autoimmune diseases including T1D and proposes a role for environmental factors in breaking immune tolerance to β cell antigens through neo-antigen formation.
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Affiliation(s)
- Meghan L Marré
- Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jon D Piganelli
- Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States
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13
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Bergamin CS, Dib SA. Enterovirus and type 1 diabetes: What is the matter? World J Diabetes 2015; 6:828-839. [PMID: 26131324 PMCID: PMC4478578 DOI: 10.4239/wjd.v6.i6.828] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 01/30/2015] [Accepted: 04/09/2015] [Indexed: 02/05/2023] Open
Abstract
A complex interaction of genetic and environmental factors can trigger the immune-mediated mechanism responsible for type 1 diabetes mellitus (T1DM) establishment. Environmental factors may initiate and possibly sustain, accelerate, or retard damage to β-cells. The role of environmental factors in this process has been exhaustive studied and viruses are among the most probable ones, especially enteroviruses. Improvements in enterovirus detection methods and randomized studies with patient follow-up have confirmed the importance of human enterovirus in the pathogenesis of T1DM. The genetic risk of T1DM and particular innate and acquired immune responses to enterovirus infection contribute to a tolerance to T1DM-related autoantigens. However, the frequency, mechanisms, and pathways of virally induced autoimmunity and β-cell destruction in T1DM remain to be determined. It is difficult to investigate the role of enterovirus infection in T1DM because of several concomitant mechanisms by which the virus damages pancreatic β-cells, which, consequently, may lead to T1DM establishment. Advances in molecular and genomic studies may facilitate the identification of pathways at earlier stages of autoimmunity when preventive and therapeutic approaches may be more effective.
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Pane JA, Coulson BS. Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes. Diabetologia 2015; 58:1149-59. [PMID: 25794781 DOI: 10.1007/s00125-015-3562-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 03/04/2015] [Indexed: 02/07/2023]
Abstract
Viruses are considered to be potential key modulators of type 1 diabetes mellitus, with several possible mechanisms proposed for their modes of action. Here we discuss the evidence for virus involvement, including pancreatic infection and the induction of T cell-mediated molecular mimicry. A particular focus of this review is the further possibility that virus infection triggers bystander activation of pre-existing autoreactive lymphocytes. In this scenario, the virus triggers dendritic cell maturation and proinflammatory cytokine secretion by engaging pattern recognition receptors. These proinflammatory cytokines provoke bystander autoreactive lymphocyte activation in the presence of cognate autoantigen, which leads to enhanced beta cell destruction. Importantly, this mechanism does not necessarily involve pancreatic virus infection, and its virally non-specific nature suggests that it might represent a means commonly employed by multiple viruses. The ability of viruses specifically associated with type 1 diabetes, including group B coxsackievirus, rotavirus and influenza A virus, to induce these responses is also examined. The elucidation of a mechanism shared amongst several viruses for accelerating progression to type 1 diabetes would facilitate the identification of important targets for disease intervention.
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Affiliation(s)
- Jessica A Pane
- Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC, 3010, Australia
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15
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Dhuria RS, Singh G, Kaur A, Kaur R, Kaur T. Current status and patent prospective of animal models in diabetic research. Adv Biomed Res 2015; 4:117. [PMID: 26261819 PMCID: PMC4513317 DOI: 10.4103/2277-9175.157847] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/15/2014] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is a heterogeneous complex metabolic disorder with multiple etiology which characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. The widespread occurrence of diabetes throughout the world has increased dramatically over the past few years. For better understanding, appropriate animal models that closely mimic the changes in humans needed, as vital tool for understanding the etiology and pathogenesis of the disease at the cellular/molecular level and for preclinical testing of drugs. This review aims to describe the animal models of type-1 diabetes (T1Ds) and T2Ds to mimic the causes and progression of the disease in humans. And also we highlight patent applications published in the last few years related to animal models in diabetes as an important milestone for future therapies that are aim to treating diabetes with specific symptoms and complications.
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Affiliation(s)
- Radhey S. Dhuria
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Gurpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Anudeep Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Ramandeep Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Tanurajvir Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
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16
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Precechtelova J, Borsanyiova M, Sarmirova S, Bopegamage S. Type I diabetes mellitus: genetic factors and presumptive enteroviral etiology or protection. J Pathog 2014; 2014:738512. [PMID: 25574400 PMCID: PMC4276674 DOI: 10.1155/2014/738512] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 07/14/2014] [Accepted: 11/09/2014] [Indexed: 02/06/2023] Open
Abstract
We review type 1 diabetes and host genetic components, as well as epigenetics and viruses associated with type 1 diabetes, with added emphasis on the enteroviruses, which are often associated with triggering the disease. Genus Enterovirus is classified into twelve species of which seven (Enterovirus A, Enterovirus B, Enterovirus C, and Enterovirus D and Rhinovirus A, Rhinovirus B, and Rhinovirus C) are human pathogens. These viruses are transmitted mainly by the fecal-oral route; they may also spread via the nasopharyngeal route. Enterovirus infections are highly prevalent, but these infections are usually subclinical or cause a mild flu-like illness. However, infections caused by enteroviruses can sometimes be serious, with manifestations of meningoencephalitis, paralysis, myocarditis, and in neonates a fulminant sepsis-like syndrome. These viruses are often implicated in chronic (inflammatory) diseases as chronic myocarditis, chronic pancreatitis, and type 1 diabetes. In this review we discuss the currently suggested mechanisms involved in the viral induction of type 1 diabetes. We recapitulate current basic knowledge and definitions.
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Affiliation(s)
- Jana Precechtelova
- Enterovirus Laboratory, Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia
| | - Maria Borsanyiova
- Enterovirus Laboratory, Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia
| | - Sona Sarmirova
- Enterovirus Laboratory, Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia
| | - Shubhada Bopegamage
- Enterovirus Laboratory, Faculty of Medicine, Slovak Medical University, Limbova 12, 83303 Bratislava, Slovakia
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17
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Precechtelova J, Borsanyiova M, Stipalova D, Sarmirova S, Gomolcak P, Berakova K, Bopegamage S. Pathophysiology of the pancreas after oral infection of genetically diverse mice with coxsackievirus B4-E2. Arch Virol 2014; 160:103-15. [DOI: 10.1007/s00705-014-2236-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 09/17/2014] [Indexed: 12/11/2022]
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18
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Honeyman MC, Laine D, Zhan Y, Londrigan S, Kirkwood C, Harrison LC. Rotavirus infection induces transient pancreatic involution and hyperglycemia in weanling mice. PLoS One 2014; 9:e106560. [PMID: 25181416 PMCID: PMC4152295 DOI: 10.1371/journal.pone.0106560] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 08/08/2014] [Indexed: 12/16/2022] Open
Abstract
Rotavirus is a ubiquitous double-stranded RNA virus responsible for most cases of infantile gastroenteritis. It infects pancreatic islets in vitro and is implicated as a trigger of autoimmune destruction of islet beta cells leading to type 1 diabetes, but pancreatic pathology secondary to rotavirus infection in vivo has not been documented. To address this issue, we inoculated 3 week-old C57Bl/6 mice at weaning with rhesus rotavirus, which is closely related to human rotaviruses and known to infect mouse islets in vitro. Virus was quantified in tissues by culture-isolation and enzyme-linked immunosorbent assay. A requirement for viral double stranded RNA was investigated in toll-like receptor 3 (TLR3)-deficient mice. Cell proliferation and apoptosis, and insulin expression, were analyzed by immunohistochemistry. Following rotavirus inoculation by gavage, two phases of mild, transient hyperglycemia were observed beginning after 2 and 8 days. In the first phase, widespread apoptosis of pancreatic cells was associated with a decrease in pancreas mass and insulin production, without detectable virus in the pancreas. These effects were mimicked by injection of the double-stranded RNA mimic, polyinosinic-polycytidylic acid, and were TLR3-dependent. By the second phase, the pancreas had regenerated but islets were smaller than normal and viral antigen was then detected in the pancreas for several days. These findings directly demonstrate pathogenic effects of rotavirus infection on the pancreas in vivo, mediated initially by the interaction of rotavirus double-stranded RNA with TLR3.
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Affiliation(s)
- Margo C. Honeyman
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - David Laine
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Yifan Zhan
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Sarah Londrigan
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Carl Kirkwood
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Leonard C. Harrison
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- * E-mail:
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Vojdani A. A Potential Link between Environmental Triggers and Autoimmunity. Autoimmune Dis 2014; 2014:437231. [PMID: 24688790 PMCID: PMC3945069 DOI: 10.1155/2014/437231] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 11/19/2013] [Accepted: 11/21/2013] [Indexed: 12/11/2022] Open
Abstract
Autoimmune diseases have registered an alarming rise worldwide in recent years. Accumulated evidence indicates that the immune system's ability to distinguish self from nonself is negatively impacted by genetic factors and environmental triggers. Genetics is certainly a factor, but since it normally takes a very long time for the human genetic pattern to change enough to register on a worldwide scale, increasingly the attention of studies has been focused on the environmental factors of a rapidly changing and evolving civilization. New technology, new industries, new inventions, new chemicals and drugs, and new foods and diets are constantly and rapidly being introduced in this fast-paced ever-changing world. Toxicants, infections, epitope spreading, dysfunctions of immune homeostasis, and dietary components can all have an impact on the body's delicate immune recognition system. Although the precise etiology and pathogenesis of many autoimmune diseases are still unknown, it would appear from the collated studies that there are common mechanisms in the immunopathogenesis of multiple autoimmune reactivities. Of particular interest is the citrullination of host proteins and their conversion to autoantigens by the aforementioned environmental triggers. The identification of these specific triggers of autoimmune reactivity is essential then for the development of new therapies for autoimmune diseases.
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Affiliation(s)
- Aristo Vojdani
- Immunosciences Lab., Inc., 822 S. Robertson Boulevard, Suite 312, Los Angeles, CA 90035, USA
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20
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Coppieters KT, Boettler T, von Herrath M. Virus infections in type 1 diabetes. Cold Spring Harb Perspect Med 2013; 2:a007682. [PMID: 22315719 DOI: 10.1101/cshperspect.a007682] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The precise etiology of type 1 diabetes (T1D) is still unknown, but viruses have long been suggested as a potential environmental trigger for the disease. However, despite decades of research, the body of evidence supporting a relationship between viral infections and initiation or acceleration of islet autoimmunity remains largely circumstantial. The most robust association with viruses and T1D involves enterovirus species, of which some strains have the ability to induce or accelerate disease in animal models. Several hypotheses have been formulated to mechanistically explain how viruses may affect islet autoimmunity and β-cell decay. The recent observation that certain viral infections, when encountered at the right time and infectious dose, can prevent autoimmune diabetes illustrates that potential relationships may be more complex than previously thought. Here, we provide a concise summary of data obtained in mouse models and humans, and identify future avenues toward a better characterization of the association between viruses and T1D.
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Affiliation(s)
- Ken T Coppieters
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
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21
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Oxidative stress and redox modulation potential in type 1 diabetes. Clin Dev Immunol 2011; 2011:593863. [PMID: 21647409 PMCID: PMC3102468 DOI: 10.1155/2011/593863] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 03/09/2011] [Indexed: 12/21/2022]
Abstract
Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreatic β-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.
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22
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Van Belle TL, Coppieters KT, Von Herrath MG. Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies. Physiol Rev 2011; 91:79-118. [DOI: 10.1152/physrev.00003.2010] [Citation(s) in RCA: 673] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.
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Affiliation(s)
- Tom L. Van Belle
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
| | - Ken T. Coppieters
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
| | - Matthias G. Von Herrath
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
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23
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Jaïdane H, Sauter P, Sane F, Goffard A, Gharbi J, Hober D. Enteroviruses and type 1 diabetes: towards a better understanding of the relationship. Rev Med Virol 2010; 20:265-80. [PMID: 20629044 DOI: 10.1002/rmv.647] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Environmental factors, especially viruses, are involved in the initiation or the acceleration of type 1 diabetes (T1D) pathogenesis. Epidemiological data strongly suggest that enteroviruses, such as coxsackievirus B4 (CV-B4), can be associated with T1D. It has been demonstrated that enterovirus infections were significantly more prevalent in at risk individuals, such as siblings of diabetic patients, when they developed anti-beta-cell autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects. The isolation of CV-B4 from the pancreas of diabetic patients strengthened the hypothesis of a relationship between the virus and the disease. Studies performed in vitro and in vivo in animal models helped to discover mechanisms of the infection of pancreas and other tissues, potentially able to play a role in the pathogenesis of T1D. Interestingly, it cannot be excluded that enteroviruses behave as half-devil half-angel since experimental studies suggest that, in certain conditions, these agents would be able to protect individuals against the disease. All of the plausible mechanisms by which enterovirus may be related to T1D will be reviewed here.
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Affiliation(s)
- Hela Jaïdane
- Laboratoire de Virologie/EA3610 Pathogenèse Virale du Diabète de Type 1, Faculté de Médecine, Université de Lille Nord de France, CHRU Lille, Centre de Biologie et Pathologie et Parc Eurasanté, Lille Cedex, France
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24
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Tracy S, Drescher KM, Jackson JD, Kim K, Kono K. Enteroviruses, type 1 diabetes and hygiene: a complex relationship. Rev Med Virol 2010; 20:106-16. [PMID: 20049905 PMCID: PMC7169204 DOI: 10.1002/rmv.639] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system mounts an attack on the host's insulin‐producing β cells. Because most cases of T1D cannot be attributed only to individual genetics, it is strongly inferred that there is a significant environmental contribution, such as infection, impacting disease development. The human enteroviruses (HEV) are common picornaviruses often implicated as triggers of human T1D, although precisely which of the numerous HEV may be involved in human T1D development is unknown. Experiments using non‐obese diabetic (NOD) mice, commonly used to model T1D, show that induction of T1D by HEV infection in NOD mice is a multifactorial process involving both the virus and the host. Interestingly, results demonstrate that HEV infection of NOD mice can also induce long‐term protection from T1D under certain conditions, suggesting that a similar mechanism may occur in humans. Based upon both experimental animal and observational human studies, we postulate that HEV have a dual role in T1D development and can either cause or prevent autoimmune disease. Whichever outcome occurs depends upon multiple variables in the host‐virus equation, many of which can be deduced from results obtained from NOD mouse studies. We propose that the background to the sharply rising T1D incidences observed in the 20th century correlates with increased levels of hygiene in human societies. Viewing T1D in this perspective suggests that potential preventative options could be developed. Copyright © 2009 John Wiley & Sons, Ltd.
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Affiliation(s)
- S Tracy
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, USA.
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25
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Abstract
Enteroviruses are believed to contribute to the pathogenesis of type 1 diabetes mellitus (T1DM). In this Review, the interplay between infection with enteroviruses, the immune system and host genes is discussed. Data from retrospective and prospective epidemiological studies strongly suggest the involvement of enteroviruses, such as coxsackievirus B, in the development of T1DM. Enteroviral RNA and/or proteins can be detected in tissues of patients with T1DM. Isolation of coxsackievirus B4 from the pancreas of patients with T1DM or the presence of enteroviral components in their islets strengthens the hypothesis of a relationship between the virus and the disease. Enteroviruses can play a part in the early phase of T1DM through the infection of beta cells and the activation of innate immunity and inflammation. In contrast with its antiviral role, virus-induced interferon alpha can be deleterious, acting as an initiator of the autoimmunity directed against beta cells. Enteroviruses, through persistent and/or successive infections, can interact with the adaptive immune system. Host genes, such as IFIH1, that influence susceptibility to T1DM are associated with antiviral activities. An increased activity of the IFIH1 protein may promote the development of T1DM. An improved knowledge of the pathogenic mechanisms of enterovirus infections should help to uncover preventive strategies for T1DM.
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Affiliation(s)
- Didier Hober
- Laboratoire de Virologie/EA3610 "Pathogenèse Virale du Diabète de Type 1", Faculté de Médecine, Université Lille 2, CHRU Lille, Centre de Biologie et Pathologie et Institut Hippocrate Parc Eurasanté, Boulevard du Prof J Leclercq, 59037 Lille Cedex, France
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26
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Jaïdane H, Sané F, Gharbi J, Aouni M, Romond MB, Hober D. Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models. Diabetes Metab Res Rev 2009; 25:591-603. [PMID: 19621354 DOI: 10.1002/dmrr.995] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The role of enteroviruses, in particular type B coxsackieviruses (CV-B), in type 1 diabetes (T1D) pathogenesis is supported by epidemiological, clinical and experimental observations.The investigation of T1D pathogenesis benefits from the contribution of animal models called spontaneously diabetic. Among these animals the non-obese diabetic (NOD) mouse and the bio-breeding diabetes-prone (BBDP) rat present a genetic susceptibility manifested by the expression of an autoimmune diabetes similar to the pathology observed in human beings. Other models whose genetic predisposition is less known are of considerable contribution as well. Numerous major observations relative to several aspects of T1D pathogenesis in the context of CV-B infections, such as susceptibility, diabetogenicity, pancreatotropism, mechanisms of beta cells destruction and others, have been deduced thanks to investigations with animal models. Despite their limits, these models are necessary in improving our knowledge of the role of enteroviruses, like CV-B4, in the pathogenesis of T1D, and the recent advances ensuing from their contribution may have important therapeutic and preventive spin-offs.
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Affiliation(s)
- H Jaïdane
- Laboratoire de Virologie/UPRES EA3610 Pathogenèse virale du diabète de type 1, Faculté de Médecine, Université Lille 2, CHRU Lille, Centre de Biologie Pathologie et Eurasanté, CHRU Lille, 59037 Lille, France
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27
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Akatsuka H, Yano Y, Gabazza EC, Morser J, Sasaki R, Suzuki T, Fujiwara R, Katsuki A, Takei Y, Sumida Y. A case of fulminant type 1 diabetes with coxsackie B4 virus infection diagnosed by elevated serum levels of neutralizing antibody. Diabetes Res Clin Pract 2009; 84:e50-2. [PMID: 19362384 DOI: 10.1016/j.diabres.2009.03.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2008] [Revised: 09/26/2008] [Accepted: 03/12/2009] [Indexed: 10/20/2022]
Abstract
A 39-year-old woman with hyperglycemia and ketonuria but with normal HbA1c level was diagnosed as having fulminant type 1 diabetes. The patient had 8-fold increase in the plasma titer of coxsackie B4 virus neutralizing antibody. Infection with coxsackie B4 virus was associated with fulminant type 1 diabetes.
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Affiliation(s)
- Hajime Akatsuka
- Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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28
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Jaïdane H, Hober D. Role of coxsackievirus B4 in the pathogenesis of type 1 diabetes. DIABETES & METABOLISM 2008; 34:537-48. [PMID: 18951821 DOI: 10.1016/j.diabet.2008.05.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Revised: 05/23/2008] [Accepted: 05/23/2008] [Indexed: 11/28/2022]
Abstract
Environmental factors, especially viruses, are thought to play an important role in the initiation or acceleration of the pathogenesis of type 1 diabetes (T1D). Data from retrospective and prospective epidemiological studies strongly suggest that enteroviruses, such as coxsackievirus B4 (CV-B4), may be associated with the development of T1D. It has also been shown that enterovirus infections are significantly more prevalent in at-risk individuals such as the siblings of diabetic patients, when they develop anti-beta-cell autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects. The isolation of CV-B4 from the pancreas of diabetic patients supports the hypothesis of a relationship between the virus and the disease. Furthermore, studies performed in vitro and in vivo in animal models have increased our knowledge of the role of CV-B4 in T1D by helping to clarify the pathogenic mechanisms of the infection that can lead to beta-cell destruction, including direct virus-induced beta-cell lysis, molecular mimicry, 'bystander activation' and viral persistence. The role of enteroviruses as the sole agents in T1D, and a causal link between these agents and T1D, have not yet been established, although arguments that support such a role for these viruses in the pathogenesis of the disease cannot be ignored.
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Affiliation(s)
- H Jaïdane
- Laboratoire de virologie/UPRES EA3610, faculté de médecine, université Lille-2, CHRU de Lille, centre de biologie pathologie et parc Eurasanté, 59037 Lille, France
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29
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Zhou M, Li F. Complete nucleotide sequence of a coxsackievirus B4 strain that establishes infection in ICR mice pancreas and induces glucose intolerance. Anat Rec (Hoboken) 2008; 291:601-9. [PMID: 18384052 DOI: 10.1002/ar.20690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Some coxsackievirus B serotypes are potentially diabetogenic. Previous studies revealed that the virulence and the tissue damage varied with the genetics of the virus strain as well as with the genetics of the mice. A single amino acid variation can alter virulence and tropism in both murine and in vitro models. However, the genetic determinants of this phenomenon have not been determined. In this study, infections with a laboratory strain of coxsackievirus B4 resulted in a diabetes-like syndrome in ICR mice, characterized by chronic pancreatic inflammation together with dysregulation in glucose metabolism, loss of pancreatic acinar tissue and persistent infection in islets. To characterize the genetic determinants involved in the mouse pancreas adaptation, the laboratory strain of coxsackievirus B4 was cloned for molecular characterization. Comparing the whole genome sequence of this virus strain with the other coxsackievirus B4 strains revealed some differences. Altogether 15 nucleotides were changed, resulting in 10 amino acid substitutions, which might be responsible for the pathogenic phenotype of this strain in mice.
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Affiliation(s)
- Mi Zhou
- Department of Pathogeniobiology, Norman Bethune College of Medical Sciences, Jilin University, Changchun, People' Republic of China
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30
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van der Werf N, Kroese FGM, Rozing J, Hillebrands JL. Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 2007; 23:169-83. [PMID: 17103489 DOI: 10.1002/dmrr.695] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
During the last decades, the incidence of type 1 diabetes (T1D) has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetical factors environmental perturbations (including viral infections) are also involved in the pathogenesis of T1D. T1D has been associated with viral infections including enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus (CMV). Although correlations between clinical presentation with T1D and the occurrence of a viral infection that precedes the development of overt disease have been recognized, causalities between viruses and the diabetogenic process are still elusive and difficult to prove in humans. The use of experimental animal models is therefore indispensable, and indeed more insight in the mechanism by which viruses can modulate diabetogenesis has been provided by studies in rodent models for T1D such as the biobreeding (BB) rat, nonobese diabetic (NOD) mouse or specific transgenic mouse strains. Data from experimental animals as well as in vitro studies indicate that various viruses are clearly able to modulate the development of T1D via different mechanisms, including direct beta-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells and molecular mimicry. Data obtained in rodents and in vitro systems have improved our insight in the possible role of viral infections in the pathogenesis of human T1D. Future studies will hopefully reveal which human viruses are causally involved in the induction of T1D and this knowledge may provide directions on how to deal with viral infections in diabetes-susceptible individuals in order to delay or even prevent the diabetogenic process.
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Affiliation(s)
- Nienke van der Werf
- Department of Cell Biology, Immunology Section, University Medical Center Groningen, University of Groningen, The Netherlands
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31
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Chehadeh W, Lobert PE, Sauter P, Goffard A, Lucas B, Weill J, Vantyghem MC, Alm G, Pigny P, Hober D. Viral protein VP4 is a target of human antibodies enhancing coxsackievirus B4- and B3-induced synthesis of alpha interferon. J Virol 2006; 79:13882-91. [PMID: 16254324 PMCID: PMC1280186 DOI: 10.1128/jvi.79.22.13882-13891.2005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Coxsackievirus B4 (CVB4)-induced production of alpha interferon (IFN-alpha) by peripheral blood mononuclear cells (PBMC) is enhanced in vitro by nonneutralizing anti-CVB4 antibodies from healthy subjects and, to a higher extent, from patients with insulin-dependent diabetes mellitus. In this study, we focused on identification of the viral target of these antibodies in CVB systems. High levels of IFN-alpha were obtained in supernatants of PBMC incubated with CVB4E2 or CVB3 and plasma from healthy subjects and, to a higher extent, from patients. The VP4 capsid proteins dissociated by heating at 56 degrees C from CVB4E2 (VP4(CVB4)) and CVB3 (VP4(CVB3)) but not H antigen preincubated with plasma from healthy subjects or patients inhibited the plasma-dependent enhancement of CVB4E2- and CVB3-induced IFN-alpha synthesis. There was no cross-reaction between VP4(CVB4) and VP4(CVB3) in the inhibiting effect. IFN-alpha levels in culture supernatants showed dose-dependent correlation with anti-VP4 antibodies eluted from plasma specimens using VP4-coated plates. There were higher index values for anti-VP4 antibodies detected by enzyme-linked immunosorbent assay (ELISA) and higher proportions of positive detection in 40 patients than in 40 healthy subjects (80% versus 15% for anti-VP4(CVB4)). There was no relationship between the levels of anti-CVB neutralizing antibodies and the detection of anti-VP4 antibodies by ELISA. The CVB plasma-induced IFN-alpha levels obtained in PBMC cultures in the anti-VP4 antibody-positive groups were significantly higher than those obtained in the anti-VP4 antibody-negative groups regardless of the titers of anti-CVB neutralizing antibodies. These results show that VP4 is the target of antibodies involved in the plasma-dependent enhancement of CVB4E2- and CVB3-induced IFN-alpha synthesis by PBMC.
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Affiliation(s)
- Wassim Chehadeh
- Service de Virologie/ UPRES EA3610, Faculté de Médecine, Université Lille 2, Bâtiment Paul Boulanger, CHRU Lille, 59037 Lille, France
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32
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Roivainen M. Enteroviruses: new findings on the role of enteroviruses in type 1 diabetes. Int J Biochem Cell Biol 2005; 38:721-5. [PMID: 16226050 DOI: 10.1016/j.biocel.2005.08.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2005] [Revised: 08/25/2005] [Accepted: 08/30/2005] [Indexed: 10/25/2022]
Abstract
Common enterovirus infections appear to initiate or facilitate the pathogenetic processes leading to type 1 diabetes, and sometimes also precipitate the clinical disease. It is not known in detail how enterovirus infections bring about the loss of insulin-producing beta-cells, a phenomenon characteristic of the disease. Recent results from studies on pancreases from human autopsies and cultured human islets support the idea that during systemic enterovirus infections, the virus may reach pancreatic islets and cause direct beta-cell damage. Although individual enteroviruses (EV) exhibited differences in their beta-cell tropism in the cultured human islets, all serotypes studied contained highly destructive strains. The final confirmation on the role of enteroviruses in type 1 diabetes can only be obtained from intervention studies. If the association holds true then it would be possible to reduce the risk of developing type 1 diabetes by preventing enterovirus infections with a multivalent enterovirus vaccine that could be given to children soon after birth.
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Affiliation(s)
- Merja Roivainen
- Enterovirus Laboratory, National Public Health Institute, Helsinki, Finland.
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33
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Al-Hello H, Davydova B, Smura T, Kaialainen S, Ylipaasto P, Saario E, Hovi T, Rieder E, Roivainen M. Phenotypic and genetic changes in coxsackievirus B5 following repeated passage in mouse pancreas in vivo. J Med Virol 2005; 75:566-74. [PMID: 15714484 DOI: 10.1002/jmv.20303] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Common enterovirus infections appear to initiate or facilitate the pathogenetic processes leading to type 1 diabetes, and also sometimes precipitate the clinical disease. In experimental infection of mice, coxsackieviruses have shown to have a strong affinity for the exocrine tissue, while even in lethal cases, the islets remain unaffected. The virus strain most intensively studied in this respect is the diabetogenic variant E2 of coxsackievirus B4. In addition, it is known that all six serotypes of coxsackie B viruses can be made diabetogenic by repeated passages in either mouse pancreas in vivo or in cultured mouse beta-cells in vitro. However, the genetic determinants of the phenomenon have not been determined. In the present study, a laboratory strain of coxsackievirus B5 was passaged repeatedly in mouse pancreas in vivo. After 15 passages, the virus phenotype was clearly changed and infection of the variant resulted in a diabetes-like syndrome in mice characterized by chronic pancreatic inflammation together with dysregulation in glucose metabolism, loss of pancreatic acinar tissue, and mild insulitis. In order to characterize the genetic determinants involved in mouse pancreas adaptation, the passaged virus variant together with the parental virus strain was cloned for molecular characterization. The whole genome sequencing of both virus strains revealed only limited differences. Altogether, eight nucleotides were changed resulting in five amino acid substitutions, of which three were located in the capsid proteins.
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Affiliation(s)
- Haider Al-Hello
- Enterovirus Laboratory, National Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland
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34
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35
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Yap IS, Giddings G, Pocock E, Chantler JK. Lack of islet neogenesis plays a key role in beta-cell depletion in mice infected with a diabetogenic variant of coxsackievirus B4. J Gen Virol 2003; 84:3051-3068. [PMID: 14573810 DOI: 10.1099/vir.0.19150-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Group B coxsackieviruses (CVBs) have a well-established association with type 1 diabetes but the mechanism of depletion of beta-cell mass following infection has not yet been defined. In this report we show that the major difference in pathogenesis between the E2 diabetogenic strain of CVB4 and the prototypic JVB strain in SJL mice is not in tropism for islet cells but in the degree of damage inflicted on the exocrine pancreas and the resulting capacity for regeneration of both acinar and islet tissue by the host. Both strains replicated to a high titre in acinar tissue up to day 3 post-infection (p.i.), while the islets of Langerhans were largely spared. However, the pancreas in the JVB-infected animals then regenerated and many small islets were seen throughout the tissue by day 10 p.i. In contrast, the acinar tissue in E2-infected mice became increasingly necrotic until all that remained by day 21 p.i. were large islets containing varying numbers of dead cells, caught up in strands of connective tissue. Surviving beta cells were found to synthesize little insulin, although islet amyloid polypeptide was detected and glucagon synthesis in alpha cells appeared normal or enhanced. Our results suggest that the key to CVB-E2-induced damage lies in the exocrine tissue and prevention of islet neogenesis rather than from direct effects on existing islets.
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Affiliation(s)
- I S Yap
- The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4
| | - G Giddings
- The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4
| | - E Pocock
- The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4
| | - J K Chantler
- The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4
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36
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Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N. Coxsackievirus-mediated hyperglycemia is enhanced by reinfection and this occurs independent of T cells. Virology 2003; 314:510-20. [PMID: 14554080 DOI: 10.1016/s0042-6822(03)00462-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The induction of autoimmunity by viruses has been hypothesized to occur by a number of mechanisms. Coxsackievirus B4 (CB4) induces hyperglycemia in SJL mice resembling diabetes in humans. While virus is effectively cleared within 2 weeks, hyperglycemia does not appear until about 8-12 weeks postinfection at a time when replicative virus is no longer detectable. In SJL mice, reinfection with CB4 enhanced the development of hyperglycemia. As predicted, the immune system responded more rapidly to the second infection and virus was cleared more swiftly. However, while infiltrating T cells were found within the pancreas, depletion of the CD4 T cell population prior to secondary infection or use of CD8 knock-out mice had no effect on the development of virus-mediated hyperglycemia. In conclusion, enhanced hyperglycemia induced by CB4 occurs independent of the T cell response.
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Affiliation(s)
- Marc S Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 123, Canada
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37
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Davydova B, Härkönen T, Kaialainen S, Hovi T, Vaarala O, Roivainen M. Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice. J Med Virol 2003; 69:510-20. [PMID: 12601759 DOI: 10.1002/jmv.10339] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the non-obese diabetic mice, an animal model for human autoimmune insulin-dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization-activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune response to virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta-cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA-2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4-dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non-obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non-obese diabetic mice.
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MESH Headings
- Adoptive Transfer
- Amino Acid Sequence
- Animals
- Antibodies, Viral/blood
- Antigens, Viral/chemistry
- Antigens, Viral/genetics
- Antigens, Viral/immunology
- Autoantigens/immunology
- Coxsackievirus Infections/immunology
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/prevention & control
- Disease Models, Animal
- Enterovirus B, Human/immunology
- Epitope Mapping
- Female
- Humans
- Immunization
- Incidence
- Islets of Langerhans/immunology
- Mice
- Mice, Inbred NOD
- Molecular Sequence Data
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Affiliation(s)
- B Davydova
- Enterovirus Laboratory, National Public Health Institute (KTL), Helsinki, Finland
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38
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Härkönen T, Paananen A, Lankinen H, Hovi T, Vaarala O, Roivainen M. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. J Med Virol 2003; 69:426-40. [PMID: 12526055 DOI: 10.1002/jmv.10306] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Molecular mimicry is one of the mechanisms by which enterovirus infections have been postulated to have a role in the pathogenesis of type 1 diabetes. Immunogenic epitopes in enterovirus capsid protein VP1 and procapsid protein VP0 have sequence similarities with diabetes-associated epitopes in tyrosine phosphatase IA-2/IAR and heat shock protein 60. In the present study, documented enterovirus infection was shown to induce humoral responses, that in 7% and 1% of patients cross-reacted with the known diabetes-associated epitopes in tyrosine phosphatase IAR and heat shock protein 60, respectively. In contrast, none of the children vaccinated against poliomyelitis had antibodies to the diabetes-associated epitope of tyrosine phosphatases IA-2/IAR. The antibody response studied in serum samples from six patients with coxsackievirus A9 infection was mainly targeted to capsid protein VP1. Coxsackievirus A9 infection induced antibodies cross-reacted with one epitope in heat shock protein 60, but not with epitopes derived from other autoantigens. Most diabetic children had high levels of antibodies to both coxsackievirus and poliovirus derived VP1 peptides but the pattern of reactivity did not differ from that seen in healthy children. The reactivity of linear epitopes derived from autoantigens was low in general and associated with the presence of multiple autoantibodies in the patients. Some linear auto-epitopes derived from tyrosine phosphatase IA-2, glutamic acid decarboxylase 65, preproinsulin, and heat shock protein 60 were recognized by sera from diabetic patients, but not by sera from healthy children. In conclusion, enteroviruses may induce immune responses that react with islet cell autoantigens, which is a concern when a putative inactivated enterovirus vaccine is considered.
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MESH Headings
- Adolescent
- Amino Acid Sequence
- Antibodies, Viral/blood
- Antibodies, Viral/immunology
- Autoantigens/chemistry
- Autoantigens/immunology
- Capsid Proteins/chemistry
- Capsid Proteins/immunology
- Chaperonin 60/chemistry
- Chaperonin 60/immunology
- Child
- Child, Preschool
- Cross Reactions
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 1/virology
- Enterovirus B, Human/immunology
- Enterovirus Infections/immunology
- Enterovirus Infections/virology
- Epitope Mapping
- Female
- Humans
- Infant
- Male
- Membrane Proteins/chemistry
- Membrane Proteins/immunology
- Molecular Sequence Data
- Peptides/chemistry
- Peptides/immunology
- Poliovirus Vaccine, Inactivated/administration & dosage
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Protein Tyrosine Phosphatases/chemistry
- Protein Tyrosine Phosphatases/immunology
- Receptor-Like Protein Tyrosine Phosphatases, Class 8
- Vaccination
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Affiliation(s)
- Taina Härkönen
- Enterovirus Laboratory, National Public Health Institute (KTL), Helsinki, Finland
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39
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Salminen K, Sadeharju K, Lönnrot M, Vähäsalo P, Kupila A, Korhonen S, Ilonen J, Simell O, Knip M, Hyöty H. Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J Med Virol 2003; 69:91-8. [PMID: 12436483 DOI: 10.1002/jmv.10260] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Enterovirus infections have been associated with the manifestation of clinical type 1 diabetes in a number of reports, and recent prospective studies have suggested that enterovirus infections may initiate the autoimmune process, leading to the disease. In the present study, we analyzed the role of enterovirus infections in a Finnish birth cohort study, Diabetes Prediction and Prevention (DIPP), in which all newborn infants are screened for diabetes-associated HLA-DQB1 alleles, and those with an increased genetic risk are invited for prospective follow-up. Enterovirus infections were diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR) from serum samples taken from birth every 3-6 months. Case children included 41 infants who became positive for diabetes-associated autoantibodies during the observation. Control children comprised altogether 196 infants who remained autoantibody negative and were matched for the time of birth, sex, and HLA-DQB1 alleles. Enterovirus infections were more frequent in case children than in control children (P = 0.004), and the average enterovirus antibody levels were also higher in the case children (P = 0.003). Enterovirus infections were particularly frequent during the 6-month period preceding the first detection of autoantibodies: 51% of the case children compared with 28% of the control children had an infection in that time interval (P = 0.003). There was no difference in the frequency of adenovirus infections between the groups (P = 0.9). The present results imply that enterovirus infections are associated with the appearance of beta-cell autoantibodies. A possible causal relationship is supported by the clustering of infections to the time when autoantibodies appeared.
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Affiliation(s)
- Kimmo Salminen
- Juvenile Diabetes Research Foundation Center for Prevention of Type 1 Diabetes in Finland
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40
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Abstract
Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed.
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Affiliation(s)
- Hee-Sook Jun
- Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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41
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Akerblom HK, Vaarala O, Hyöty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. AMERICAN JOURNAL OF MEDICAL GENETICS 2002; 115:18-29. [PMID: 12116173 DOI: 10.1002/ajmg.10340] [Citation(s) in RCA: 178] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes.
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42
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Olson JK, Croxford JL, Miller SD. Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease. Viral Immunol 2002; 14:227-50. [PMID: 11572634 DOI: 10.1089/088282401753266756] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Virus infections have been implicated in the initiation of multiple human autoimmune diseases. This article focuses on reviewing the role of viruses in initiation, progression, and perpetuation of autoimmune diseases. Various mechanisms by which virus infections can induce autoimmune responses including molecular mimicry, epitope spreading, direct bystander activation, and release of cryptic epitopes are discussed. Evidence implicating virus infections in the pathogenesis of various human autoimmune diseases is reviewed. Last, the characteristics of animal models that have been developed for the study of the potential role of viruses in the initiation and progression of autoimmune disease are reviewed.
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Affiliation(s)
- J K Olson
- Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois 60611, USA
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43
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Rouse BT, Deshpande S. Viruses and autoimmunity: an affair but not a marriage contract. Rev Med Virol 2002; 12:107-13. [PMID: 11921306 PMCID: PMC7169138 DOI: 10.1002/rmv.347] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2001] [Indexed: 11/09/2022]
Abstract
Viruses are considered as causative agents and contributors to lesion expression in autoimmune disease, notions best supported by studies in animal model systems. This review discusses relationships between virus infection and autoimmunity focusing on mechanisms by which they could induce autoreactivity. The popular idea of molecular mimicry is viewed skeptically with the reviewers taking the viewpoint that viruses contribute to autoimmunity mainly by inducing several nonspecific inflammatory events that together are sufficient to trigger autoreactivity in genetically receptive hosts.
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Affiliation(s)
- Barry T Rouse
- Department of Microbiology, The University of Tennessee, Knoxville, TN 37996-0845, USA.
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44
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Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N. Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J Clin Invest 2002. [DOI: 10.1172/jci0211198] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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45
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Abstract
Type 1 (insulin-dependent) diabetes is a typical organ-specific autoimmune disease where insulin-producing beta cells are destroyed by immune mediated mechanisms. The risk of the disease is modulated by genetic factors, mainly genes coding for human leukocyte antigens (HLA), but environmental factors are needed to trigger the process in genetically susceptible individuals. Possible viral triggers of the disease have been sought for years but their identification has been very difficult. Recently, considerable progress has been made by employing new research methods which have supported the idea that the group of enteroviruses may be particularly important in the pathogenesis. An association between enterovirus infections and type 1 diabetes was first reported 30 years ago and since then evaluated in several studies. Recent molecular studies have considerably strengthened this hypothesis by showing that enterovirus genome is present in the blood of diabetic patients. In addition, the first prospective studies have suggested that enterovirus infections may initiate the beta-cell damaging process several years before clinical diabetes is diagnosed. Ecological studies have also indicated similarities in the epidemiology of type 1 diabetes and poliomyelitis - a well-known enterovirus disease. Experimental models, like enterovirus-infected mice or in vitro-cultured beta cells, have provided important information about possible mechanisms, but still it is not known how beta cells are destroyed in human beings. The ongoing prospective studies will answer many open questions, and should the association still hold true, intervention trials will be needed to confirm causality. Even if enterovirus infections were not associated with all diabetes cases but rather with a subgroup of them, this would offer attractive possibilities to prevent the disease or part of it, for example, by an enterovirus vaccine.
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Affiliation(s)
- Heikki Hyöty
- JDRF Center for Prevention of Type 1 Diabetes, Tampere, Finland.
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46
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Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N. Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J Clin Invest 2002; 109:79-87. [PMID: 11781353 PMCID: PMC150813 DOI: 10.1172/jci11198] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral infection and the subsequent activation of T cells specific for islet antigen has not been elucidated. These T cells could become activated through exposure to sequestered antigens released by damaged beta cells, or they could have responded to factors secreted by the inflammatory response itself. To distinguish between these possibilities, we treated mice harboring a diabetogenic T cell repertoire with either the islet-damaging agent streptozotocin (STZ) or poly I:C, which nonspecifically activates T cells. Significantly, only treatment of mice with STZ resulted in IDDM and mimicked the effects observed following CB4 infection. Furthermore, antigen-presenting cells from STZ-treated mice were shown to directly activate autoreactive T cells and induce diabetes. Therefore, the primary role of CB4 in the precipitation of IDDM is to damage tissue, causing release and presentation of sequestered islet antigen. These events stimulate autoreactive T cells and thereby initiate disease.
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MESH Headings
- Animals
- Antigen Presentation
- Autoantigens
- Autoimmunity
- Coxsackievirus Infections/complications
- Coxsackievirus Infections/immunology
- Coxsackievirus Infections/pathology
- Diabetes Mellitus, Experimental/etiology
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 1/etiology
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Enterovirus B, Human/pathogenicity
- Humans
- Islets of Langerhans/immunology
- Islets of Langerhans/pathology
- Lymphocyte Activation
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Poly I-C/toxicity
- Streptozocin/toxicity
- T-Lymphocytes/immunology
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Affiliation(s)
- Marc S Horwitz
- Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
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Roivainen M, Ylipaasto P, Ustinov J, Hovi T, Otonkoski T. Screening enteroviruses for beta-cell tropism using foetal porcine beta-cells. J Gen Virol 2001; 82:1909-1916. [PMID: 11457997 DOI: 10.1099/0022-1317-82-8-1909] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Primary adult human insulin-producing beta-cells are susceptible to infection by prototype strains of coxsackieviruses (CV) and infection may result in impaired beta-cell function and/or cell death, as shown for coxsackie B virus (CVB) types 4 and 5, or have no apparent immediate adverse effects, as shown for CVA-9. Because of the limited availability of human pancreatic beta-cells, the aim of this study was to find out if foetal porcine pancreatic islets could be used as a substitute in enterovirus (EV) screening. These cells resemble human beta-cells in several biological properties. CVB infection resulted in a rapid progressive decline of insulin content and reponsiveness to insulin release. The amount of virus inoculum sufficient for this destruction was small, corresponding to only 55 infectious units per pancreas. In contrast to CVBs, CVA-9 replicated poorly, and sometimes not at all, in foetal porcine beta-cells. The first signs of functional impairment and cell destruction, if present at all, were seen only after 1-3 weeks of incubation. Furthermore, CVA-16, several strains of echoviruses and human parechovirus type 1 were unable to replicate in foetal porcine pancreatic beta-cells. Based on these results, foetal porcine islets are somewhat more sensitive to CVB infection than adult human islets, whereas many other human EV strains do not infect porcine beta-cells. Therefore, foetal porcine beta-cells cannot be used for systematic screening of human EV strains and isolates for beta-cell tropism, but they might provide a useful model for detailed studies on the interaction of CVBs with beta-cells.
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Affiliation(s)
- Merja Roivainen
- Enterovirus Laboratory, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland1
| | - Petri Ylipaasto
- Enterovirus Laboratory, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland1
| | - Jarkko Ustinov
- Transplantation Laboratory, Haartman Institute and Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland2
| | - Tapani Hovi
- Enterovirus Laboratory, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland1
| | - Timo Otonkoski
- Transplantation Laboratory, Haartman Institute and Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland2
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Horwitz MS, Fine C, Ilic A, Sarvetnick N. Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration. J Autoimmun 2001; 16:211-7. [PMID: 11334485 DOI: 10.1006/jaut.2000.0486] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The induction of autoimmunity by viruses has been attributed to numerous mechanisms. Coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) in mice resembling the final step of disease progression in humans. Following viral infection, autoreactive lymphocytes are activated through exposure to damaged islets consequently precipitating IDDM. However, the viral and host requirements leading up to this final step have yet to be elucidated. We provide evidence that disease induction requires a pre-existing accumulation of beta-cell specific autoreactive T cells within the pancreas, as well as the infection of islet beta-cells. Therefore, the primary role of CB4 in the development of IDDM is to infect tissue, resulting in the presentation of sequestered islet antigen, the stimulation of preexisting autoreactive T cells, and the initiation of disease.
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Affiliation(s)
- M S Horwitz
- Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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49
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Heitmeier MR, Arnush M, Scarim AL, Corbett JA. Pancreatic beta-cell damage mediated by beta-cell production of interleukin-1. A novel mechanism for virus-induced diabetes. J Biol Chem 2001; 276:11151-8. [PMID: 11108714 DOI: 10.1074/jbc.m009159200] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Viral infection is one environmental factor that may initiate beta-cell damage during the development of autoimmune diabetes. Formed during viral replication, double-stranded RNA (dsRNA) activates the antiviral response in infected cells. In combination, synthetic dsRNA (polyinosinic-polycytidylic acid, poly(I-C)) and interferon (IFN)-gamma stimulate inducible nitric-oxide synthase (iNOS) expression, inhibit insulin secretion, and induce islet degeneration. Interleukin-1 (IL-1) appears to mediate dsRNA + IFN-gamma-induced islet damage in a nitric oxide-dependent manner, as the interleukin-1 receptor antagonist protein prevents dsRNA + IFN-gamma-induced iNOS expression, inhibition of insulin secretion, and islet degeneration. IL-1beta is synthesized as an inactive precursor protein that requires cleavage by the IL-1beta-converting enzyme (ICE) for activation. dsRNA and IFN-gamma stimulate IL-1beta expression and ICE activation in primary beta-cells, respectively. Selective ICE inhibition attenuates dsRNA + IFN-gamma-induced iNOS expression by primary beta-cells. In addition, poly(I-C) + IFN-gamma-induced iNOS expression and nitric oxide production by human islets are prevented by interleukin-1 receptor antagonist protein, indicating that human islets respond to dsRNA and IFN-gamma in a manner similar to rat islets. These studies provide biochemical evidence for a novel mechanism by which viral infection may initiate beta-cell damage during the development of autoimmune diabetes. The viral replicative intermediate dsRNA stimulates beta-cell production of pro-IL-1beta, and following cleavage to its mature form by IFN-gamma-activated ICE, IL-1 then initiates beta-cell damage in a nitric oxide-dependent fashion.
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Affiliation(s)
- M R Heitmeier
- Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA
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Flodström M, Horwitz MS, Maday A, Balakrishna D, Rodriguez E, Sarvetnick N. A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. Virology 2001; 281:205-15. [PMID: 11277693 DOI: 10.1006/viro.2000.0801] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic beta-cell maintenance. Mice deficient in NOS2 (NOS2-/- mice) and their wild-type (wt) counterparts were injected with CB4, after which both groups developed severe pancreatitis, hepatitis, and hypoglycemia within 3 days. Within 4 to 7 days postinfection (p.i.), most of the NOS2-/- mice died and at a strikingly higher mortality rate than wt mice. Histological examination of pancreata from both infected NOS2-/- and infected wt mice revealed early and complete destruction of the pancreatic acinar tissue, but intact, insulin-stained islets. When examined up to 8 weeks p.i., neither surviving NOS2-/-mice nor surviving wt mice developed hyperglycemia. However, the clearance of infectious CB4 was different between the mice. The spleens of NOS2-/- survivors were cleared of infectious virus with kinetics similar to that of wt mice, but the livers, pancreata, kidneys, and hearts of the NOS2-/- groups cleared virus more slowly than those of the wt group. This delayed clearance was particularly prominent in the livers of infected NOS2-/- mice, which also showed prolonged histopathological features of viral hepatitis. Taken together, this outcome suggests that NOS2 (and NO) is not required for the prevention of pancreatic beta-cell depletion after CB4 infection. Instead the critical actions of NOS2 apparently occur early in the host immune response, allowing mice to survive and clear virus. Moreover, the data support the existence of an organ-specific dependency on NO for a rapid clearance of CB4.
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Affiliation(s)
- M Flodström
- Department of Immunology, The Scripps Research Institute, 10 550 North Torrey Pines Road, La Jolla, California 92037, USA
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