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Bastea LI, Liu X, Fleming AK, Pandey V, Döppler H, Edenfield BH, Krishna M, Zhang L, Thompson EA, Grandgenett PM, Hollingsworth MA, Fairweather D, Clemens D, Storz P. Coxsackievirus and adenovirus receptor expression facilitates enteroviral infections to drive the development of pancreatic cancer. Nat Commun 2024; 15:10547. [PMID: 39627248 PMCID: PMC11615305 DOI: 10.1038/s41467-024-55043-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/26/2024] [Indexed: 12/06/2024] Open
Abstract
The development of pancreatic cancer requires both, acquisition of an oncogenic mutation in KRAS as well as an inflammatory insult. However, the physiological causes for pancreatic inflammation are less defined. We show here that oncogenic KRas-expressing pre-neoplastic lesion cells upregulate coxsackievirus (CVB) and adenovirus receptor (CAR). This facilitates infections from enteroviruses such as CVB3, which can be detected in approximately 50% of pancreatic cancer patients. Moreover, using an animal model we show that a one-time pancreatic infection with CVB3 in control mice is transient, but in the presence of oncogenic KRas drives chronic inflammation and rapid development of pancreatic cancer. We further demonstrate that a knockout of CAR in pancreatic lesion cells blocks these CVB3-induced effects. Our data demonstrate that KRas-caused lesions promote the development of pancreatic cancer by enabling certain viral infections.
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Affiliation(s)
- Ligia I Bastea
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Xiang Liu
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Alicia K Fleming
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Veethika Pandey
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Heike Döppler
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | | | - Murli Krishna
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Lizhi Zhang
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, 55905, USA
| | - E Aubrey Thompson
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - DeLisa Fairweather
- Department of Cardiovascular Diseases, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Dahn Clemens
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
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Viswanathan A, Wood JR, Hatipoglu BA. What Is a Honeymoon in Type 1, Can It Go into Remission? Endocrinol Metab Clin North Am 2023; 52:175-185. [PMID: 36754493 DOI: 10.1016/j.ecl.2022.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Type 1 diabetes is a chronic autoimmune disorder that results in destruction of insulin-producing cells in the pancreas. The autoimmune process is thought to be waxing and waning resulting in variable endogenous insulin secretion ability. An example of this is the honeymoon phase or partial remission phase of type 1 diabetes, during which optimal control of blood glucoses can be maintained with significantly reduced exogenous insulin, and occasionally exogenous insulin can be temporarily discontinued altogether. Understanding this phase is important because even fairly small amounts of endogenous insulin secretion is associated with reduced risk of severe hypoglycemia and microvascular complications.
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Affiliation(s)
- Anuradha Viswanathan
- Section for Pediatric Endocrinology, Cleveland Clinic Children's, 9500 Euclid Avenue, R Building- R-3, Cleveland, OH 44195, USA.
| | - Jamie R Wood
- University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Betul A Hatipoglu
- University Hospitals Cleveland Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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Association between Pediatric Adenovirus Infection and Type 1 Diabetes. CHILDREN 2022; 9:children9101494. [PMID: 36291430 PMCID: PMC9600003 DOI: 10.3390/children9101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/16/2022] [Accepted: 09/23/2022] [Indexed: 12/05/2022]
Abstract
Background: Viruses are among the inducers of type 1 diabetes (T1D) as they are implicated in the initiation of β-cell destruction. This study aimed to explore the link between adenoviruses’ infection, inflammatory biomarkers, and the development of T1D. Methods: The study population included 80 children with T1D and 40 healthy controls (2–16 years old). The T1D group was further clustered into two groups according to time of T1D diagnosis: a group of children who were diagnosed during the first year of life and a second group who were diagnosed after the first year of life. Adenovirus DNA, anti-adenovirus IgG, cytokines, and lipid profiles were screened in the different groups. The results were statistically assessed using one-way analysis of variance (ANOVA) and LSD t-test. Results: Positive adenovirus PCR was detected in 2.5% and 20% of normal and T1D children, respectively. Moreover, the positive PCR results for adenovirus were found significantly higher in the T1D group, who were diagnosed during the first year of life (33.4%), in comparison to those diagnosed after the first year of life (12%). Anti-adenoviruses IgG was found in 12.5% and 40% of healthy controls and diabetic children, respectively. Seropositive results were found to be higher in newly diagnosed children (46.7%) in comparison to those previously diagnosed with T1D (36%). Body mass index (BMI), IFN-γ, IL-15, adiponectin, lipid profile, and microalbuminuria were significantly increased in T1D adenoviruses-positive children compared to children who were negative for adenoviruses. Conclusions: Adenovirus infection could be among the contributing risk factors and may play a role in the induction of T1D in children.
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Xiao Z, He F, Feng M, Liu Z, Liu Z, Li S, Wang W, Yao H, Wu J. Engineered coxsackievirus B3 containing multiple organ-specific miRNA targets showed attenuated viral tropism and protective immunity. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 103:105316. [PMID: 35718333 DOI: 10.1016/j.meegid.2022.105316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/07/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023]
Abstract
Coxsackievirus B3 (CVB3) can cause viral myocarditis, pancreatitis, and aseptic meningitis. This study aimed to construct an engineered CVB3 harboring three different tissue-specific miRNA targets (CVB3-miR3*T) to decrease the virulence of CVB3 in muscles, pancreas, and brain. CVB3-miR3*T and CVB3-miR-CON (containing three sequences not found in the human genome) were engineered and replicated in HELA cells. A viral plaque assay was used to determine the titers in HELA cells and TE671 cells (high miRNA-206 expression), MIN-6 cells (high miRNA-29a-3p expression), and mouse astrocytes (high miRNA-124-3p expression). We found that engineered CVB3 showed attenuated replication and reduced cytotoxicity, the variability of each type of cell was also increased in the CVB3-miR3*T group. Male BALB/c mice were infected to determine the LD50 and examine heart, pancreas, and brain titers and injury. Viral replication of the engineered viruses was restricted in infected mouse heart, pancreas, and brain, and viral plaques were about 100 fold lower compared with the control group. Mice immunized using CVB3-miR3*T, UV-inactivated CVB3-WT, and CVB3-miR-CON were infected with 100 × LD50 of CVB3-WT to determine neutralization. CVB3-miRT*3-preimmunized mice exhibited complete protection and remained alive after lethal virus infection, while only 5/15 were alive in the UV-inactivated mice, and all 15 mice were dead in the PBS-immunized group. The results demonstrate that miR-206-, miRNA-29a-3p-, and miRNA-124-3p-mediated CVB3 detargeting from the pancreas, heart, and brain might be a highly effective strategy for viral vaccine development.
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Affiliation(s)
- Zonghui Xiao
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Feng He
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Miao Feng
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Zhuo Liu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Zhewei Liu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Sen Li
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Wei Wang
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Hailan Yao
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China.
| | - Jianxin Wu
- Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China; Beijing Municipal Key Laboratory of Child Development and Nutriomics, Beijing, China; Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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Jimbo E, Kobayashi T, Takeshita A, Mine K, Nagafuchi S, Fukui T, Yagihashi S. Immunohistochemical detection of enteroviruses in pancreatic tissues of patients with type 1 diabetes using a polyclonal antibody against 2A protease of Coxsackievirus. J Diabetes Investig 2022; 13:435-442. [PMID: 34669264 PMCID: PMC8902398 DOI: 10.1111/jdi.13700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/12/2021] [Accepted: 10/15/2021] [Indexed: 11/29/2022] Open
Abstract
AIMS/INTRODUCTION The need for antiserum for immunohistochemical (IHC) detection of enterovirus (EV) in formaldehyde-fixed and paraffin-embedded samples is increasing. The gold standard monoclonal antibody (clone 5D8/1) against EV-envelope protein (VP1) was proven to cross-react with other proteins. Another candidate marker of EV proteins is 2A protease (2Apro ), which is encoded by the EV gene and translated by the host cells during EV replication, and participates processing proproteins to viral capsid proteins. MATERIALS AND METHODS We raised polyclonal antiserum by immunizing a rabbit with an 18-mer peptide of Coxsackievirus B1 (CVB1)-2Apro , and examined the specificity and sensitivity for EV on formaldehyde-fixed and paraffin-embedded tissue samples. RESULTS Enzyme-linked immunosorbent assay study showed a high titer of antibody for 18-mer peptide of CVB1-2Apro , cross-reacting with CVB3-2Apro peptide. IHC showed that antiserum against 2Apro reacted with CVB1-infected and VP1-positive Vero cells. Confocal laser scanning microscopy showed that antigen stained by the 2Apro antibody located in the same cell with VP1 stained by 5D8/1. IHC using 2Apro antiserum showed dense staining in the islets of EV-associated fulminant type 1 diabetes pancreas and that located in the same cell stained positive for VP1 (5D8/1). Specificity of 2Apro antiserum by IHC staining was confirmed by negative 2Apro in 14 VP1-negative non-diabetes control pancreases. CONCLUSIONS Our study provides a new polyclonal antiserum against CVB1-2Apro , which might be useful for IHC of EV-infected human tissues stored as archive of formaldehyde-fixed and paraffin-embedded tissue samples.
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Affiliation(s)
- Erika Jimbo
- Division of Immunology and Molecular MedicineOkinaka Memorial Institute for Medical ResearchTokyoJapan
| | - Tetsuro Kobayashi
- Division of Immunology and Molecular MedicineOkinaka Memorial Institute for Medical ResearchTokyoJapan
- Department of Endocrinology and MetabolismToranomon HospitalTokyoJapan
| | - Akira Takeshita
- Department of Endocrinology and MetabolismToranomon HospitalTokyoJapan
| | - Keiichiro Mine
- Division of Metabolism and EndocrinologyDepartment of Internal MedicineFaculty of MedicineSaga UniversitySagaJapan
| | - Seiho Nagafuchi
- Division of Metabolism and EndocrinologyDepartment of Internal MedicineFaculty of MedicineSaga UniversitySagaJapan
| | - Tomoyasu Fukui
- Division of Diabetes, Metabolism and EndocrinologyDepartment of MedicineShowa University School of MedicineTokyoJapan
| | - Soroku Yagihashi
- Department of Exploratory Medicine on Nature, Life, and ManToho University School of MedicineChibaJapan
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Geravandi S, Richardson S, Pugliese A, Maedler K. Localization of enteroviral RNA within the pancreas in donors with T1D and T1D-associated autoantibodies. CELL REPORTS MEDICINE 2021; 2:100371. [PMID: 34467248 PMCID: PMC8385321 DOI: 10.1016/j.xcrm.2021.100371] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/07/2021] [Accepted: 07/19/2021] [Indexed: 12/16/2022]
Abstract
Enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D), but reliable methods to ascertain localization of single infected cells in the pancreas were missing. Using a single-molecule-based fluorescent in situ hybridization (smFISH) method, we detected increased virus infection in pancreases from organ donors with T1D and with disease-associated autoantibodies (AAb+). Although virus-positive β cells are found at higher frequency in T1D pancreases, compared to control donors, but are scarce, most virus-positive cells are scattered in the exocrine pancreas. Augmented CD45+ lymphocytes in T1D pancreases show virus positivity or localization in close proximity to virus-positive cells. Many more infected cells were also found in spleens from T1D donors. The overall increased proportion of virus-positive cells in the pancreas of AAb+ and T1D organ donors suggests that enteroviruses are associated with immune cell infiltration, autoimmunity, and β cell destruction in both preclinical and diagnosed T1D.
Enterovirus-infected cells are significantly increased in AAb+ and T1D pancreases Most of the virus-positive cells are scattered within the exocrine pancreas Virus-positive β cells are rare but more in T1D compared to control donors Also elevated in T1D donors, there is more infection in spleens than in pancreases
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Affiliation(s)
- Shirin Geravandi
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.,JDRF nPOD-Virus Group
| | - Sarah Richardson
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK.,JDRF nPOD-Virus Group
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology and Metabolism, Miami, FL, USA.,Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA.,JDRF nPOD-Virus Group
| | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.,JDRF nPOD-Virus Group
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Rajendran S, Quesada-Masachs E, Zilberman S, Graef M, Kiosses WB, Chu T, Benkahla MA, Lee JHM, von Herrath M. IL-17 is expressed on beta and alpha cells of donors with type 1 and type 2 diabetes. J Autoimmun 2021; 123:102708. [PMID: 34358764 DOI: 10.1016/j.jaut.2021.102708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE IL-17 is an important effector cytokine driving immune-mediated destruction in autoimmune diseases such as psoriasis. Blockade of the IL-17 pathway after the initiation of insulitis was effective in delaying or preventing the onset of type 1 diabetes (T1D) in rodent models. Expression of IL-17 transcripts in islets from a donor with recent-onset T1D has been reported, however, studies regarding IL-17 protein expression are lacking. We aimed to study whether IL-17 is being expressed in the islets of diabetic donors. METHODS We stained human pancreatic tissues from non-diabetic (n = 5), auto-antibody positive (aab+) (n = 5), T1D (n = 6) and T2D (n = 5) donors for IL-17, Insulin, and Glucagon, and for CD45 in selected cases. High resolution images were acquired with Zeiss laser scanning confocal microscope LSM780 and analyzed with Zen blue 2.3 software. Cases stained for CD45 were also acquired with widefield slide scanner and analyzed with QuPath software. RESULTS We observed a clear cytoplasmic staining for IL-17 in insulin-containing islets of donors with T1D and T2D, accounting for an average of 7.8 ± 8.4% and 14.9 ± 16.8% of total islet area, respectively. Both beta and alpha cells were sources of IL-17, but CD45+ cells were not a major source of IL-17 in those donors. Expression of IL-17 was reduced in islets of non-diabetic donors, aab+ donors and in insulin-deficient islets of donors with T1D. CONCLUSION Our finding that IL-17 is expressed in islets of donors with T1D or T2D is quite intriguing and warrants further mechanistic studies in human islets to understand the role of IL-17 in the context of metabolic and immune stress in beta cells.
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Affiliation(s)
| | | | | | | | | | - Tiffany Chu
- La Jolla Institute for Immunology, La Jolla, CA, USA
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Vig S, Lambooij JM, Zaldumbide A, Guigas B. Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes. Front Immunol 2021; 12:669492. [PMID: 33936111 PMCID: PMC8085402 DOI: 10.3389/fimmu.2021.669492] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.
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Affiliation(s)
- Saurabh Vig
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Joost M. Lambooij
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
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9
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Allard-Chamard H, Mishra HK, Nandi M, Mayhue M, Menendez A, Ilangumaran S, Ramanathan S. Interleukin-15 in autoimmunity. Cytokine 2020; 136:155258. [PMID: 32919253 DOI: 10.1016/j.cyto.2020.155258] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022]
Abstract
Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the β chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is 'trans-presented' to responder cells that expresses the IL-2/15Rβγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions. IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.
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Affiliation(s)
- Hugues Allard-Chamard
- Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada.
| | - Hemant K Mishra
- Vet & Biomedical Sciences, University of Minnesota, Minneapolis, MN, USA
| | - Madhuparna Nandi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marian Mayhue
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Alfredo Menendez
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Subburaj Ilangumaran
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sheela Ramanathan
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
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da Silva IV, Cardoso C, Méndez-Giménez L, Camoes SP, Frühbeck G, Rodríguez A, Miranda JP, Soveral G. Aquaporin-7 and aquaporin-12 modulate the inflammatory phenotype of endocrine pancreatic beta-cells. Arch Biochem Biophys 2020; 691:108481. [PMID: 32735865 DOI: 10.1016/j.abb.2020.108481] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 02/08/2023]
Abstract
Aquaporins (AQPs) facilitate water and glycerol movement across membranes. AQP7 is the main aquaglyceroporin in pancreatic β-cells and was proposed to play a role in insulin exocytosis. Although AQP7-null mice display adult-onset obesity, impaired insulin secretion and insulin resistance, AQP7 loss-of-function homozygous mutations in humans do not correlate with obesity nor type-2 diabetes. In addition, AQP12 is upregulated in pancreatitis. However, the implication of this isoform in endocrine pancreas inflammation is still unclear. Here, we investigated AQP7 and AQP12 involvement in cellular and inflammatory processes using RIN-m5F beta cells, a model widely used for their high insulin secretion. AQP7 and AQP12 expression were directly associated with cell proliferation, adhesion and migration. While tumor necrosis factor-alpha (TNFα)-induced inflammation impaired AQP7 expression and drastically reduced insulin secretion, lipopolysaccharides (LPS) prompted AQP7 upregulation, and both TNFα and LPS upregulated AQP12. Importantly, cells overexpressing AQP12 are more resistant to inflammation, revealing lower levels of proinflammatory markers. Altogether, these data document AQP7 involvement in insulin secretion and AQP12 implication in inflammation, highlighting their fundamental role in pancreatic β-cell function.
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Affiliation(s)
- Inês Vieira da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal
| | - Carlos Cardoso
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal; Clinical Chemistry Laboratory, Dr. Joaquim Chaves, 1495-068, Algés, Portugal
| | - Leire Méndez-Giménez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, 31008, Pamplona, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008, Pamplona, Spain
| | - Sérgio Povoas Camoes
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, 31008, Pamplona, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008, Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, 31008, Pamplona, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008, Pamplona, Spain
| | - Joana Paiva Miranda
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal.
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal.
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11
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Nyalwidhe JO, Jurczyk A, Satish B, Redick S, Qaisar N, Trombly MI, Vangala P, Racicot R, Bortell R, Harlan DM, Greiner DL, Brehm MA, Nadler JL, Wang JP. Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge. Microorganisms 2020; 8:microorganisms8020295. [PMID: 32093375 PMCID: PMC7074978 DOI: 10.3390/microorganisms8020295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 01/04/2023] Open
Abstract
Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant β-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived β (SC-β) cells are insulin-producing cell clusters that closely resemble native β cells. To better understand the events precipitated by enteroviral infection of β cells, we investigated transcriptional and proteomic changes in SC-β cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-β cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following infection, and combined transcriptional and proteomic analysis revealed activation of innate immune pathways, including type I interferon (IFN), IFN-stimulated genes, nuclear factor-kappa B (NF-κB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-β cells was impaired. These transcriptional, proteomic, and functional findings are in agreement with responses in primary human islets infected with CVB ex vivo. Human SC-β cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-β cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.
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Affiliation(s)
- Julius O. Nyalwidhe
- Department of Microbiology and Molecular Cell Biology and Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (J.O.N.); (J.L.N.)
| | - Agata Jurczyk
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Basanthi Satish
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Sambra Redick
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Natasha Qaisar
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Melanie I. Trombly
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Pranitha Vangala
- Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Riccardo Racicot
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - David M. Harlan
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Dale L. Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Michael A. Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Jerry L. Nadler
- Department of Microbiology and Molecular Cell Biology and Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (J.O.N.); (J.L.N.)
- Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA
| | - Jennifer P. Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
- Correspondence: ; Tel.: +01-508-856-8414
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12
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Bergamin CS, Pérez-Hurtado E, Oliveira L, Gabbay M, Piveta V, Bittencourt C, Russo D, Carmona RDC, Sato M, Dib SA. Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background. Front Endocrinol (Lausanne) 2020; 11:555685. [PMID: 33071971 PMCID: PMC7538605 DOI: 10.3389/fendo.2020.555685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.
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Affiliation(s)
- Carla Sanchez Bergamin
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
- *Correspondence: Carla Sanchez Bergamin
| | - Elizabeth Pérez-Hurtado
- Immunology Division, Microbiology, Immunology and Parasitological Department, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Luanda Oliveira
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Monica Gabbay
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Valdecira Piveta
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Célia Bittencourt
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Denise Russo
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Rita de Cássia Carmona
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Maria Sato
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Sergio A. Dib
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
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13
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Bender C, Rajendran S, von Herrath MG. New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes. Front Endocrinol (Lausanne) 2020; 11:606434. [PMID: 33469446 PMCID: PMC7813992 DOI: 10.3389/fendo.2020.606434] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/20/2020] [Indexed: 12/31/2022] Open
Abstract
Since the establishment of the network for pancreatic organ donors with diabetes (nPOD), we have gained unprecedented insight into the pathology of human type 1 diabetes. Many of the pre-existing "dogmas", mostly derived from studies of animal models and sometimes limited human samples, have to be revised now. For example, we have learned that autoreactive CD8 T cells are present even in healthy individuals within the exocrine pancreas. Furthermore, their "attraction" to islets probably relies on beta-cell intrinsic events, such as the over-expression of MHC class I and resulting presentation of autoantigens such as (prepro)insulin. In addition, we are discovering other signs of beta-cell dysfunction, possibly at least in part due to stress, such as the over-expression of certain cytokines. This review summarizes the latest developments focusing on cytokines and autoreactive CD8 T cells in human type 1 diabetes pathogenesis.
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14
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IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes. Clin Immunol 2019; 211:108320. [PMID: 31809899 DOI: 10.1016/j.clim.2019.108320] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/27/2019] [Accepted: 11/29/2019] [Indexed: 01/03/2023]
Abstract
IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.
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15
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Yeung ML, Jia L, Yip CCY, Chan JFW, Teng JLL, Chan KH, Cai JP, Zhang C, Zhang AJ, Wong WM, Kok KH, Lau SKP, Woo PCY, Lo JYC, Jin DY, Shih SR, Yuen KY. Human tryptophanyl-tRNA synthetase is an IFN-γ-inducible entry factor for Enterovirus. J Clin Invest 2018; 128:5163-5177. [PMID: 30153112 DOI: 10.1172/jci99411] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 08/23/2018] [Indexed: 01/08/2023] Open
Abstract
Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.
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Affiliation(s)
- Man Lung Yeung
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Lilong Jia
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Cyril C Y Yip
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jasper F W Chan
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jade L L Teng
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Kwok-Hung Chan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Jian-Piao Cai
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Chaoyu Zhang
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Anna J Zhang
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wan-Man Wong
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Kin-Hang Kok
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
| | - Susanna K P Lau
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Patrick C Y Woo
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Janice Y C Lo
- Public Health Laboratory Centre, Department of Health, Hong Kong Special Administrative Region, China
| | - Dong-Yan Jin
- School of Biological Sciences, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Shin-Ru Shih
- Research Center for Emerging Viral Infection, Chang Gung University, Kwei-Shan Tao-Yuan, Taiwan, Republic of China.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Kwei-Shan Tao-Yuan, Taiwan, Republic of China
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.,Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, China.,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China.,University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China
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16
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Abstract
PURPOSE OF REVIEW Despite immense research efforts, type 1 diabetes (T1D) remains an autoimmune disease without a known trigger or approved intervention. Over the last three decades, studies have primarily focused on delineating the role of the adaptive immune system in the mechanism of T1D. The discovery of Toll-like receptors in the 1990s has advanced the knowledge on the role of the innate immune system in host defense as well as mechanisms that regulate adaptive immunity including the function of autoreactive T cells. RECENT FINDINGS Recent investigations suggest that inflammation plays a key role in promoting a large number of autoimmune disorders including T1D. Data from the LEW1.WR1 rat model of virus-induced disease and the RIP-B7.1 mouse model of diabetes suggest that innate immune signaling plays a key role in triggering disease progression. There is also evidence that innate immunity may be involved in the course of T1D in humans; however, a small number of clinical trials have shown that interfering with the function of the innate immune system following disease onset exerts only a modest effect on β-cell function. The data implying that innate immune pathways are linked with mechanisms of islet autoimmunity hold great promise for the identification of novel disease pathways that may be harnessed for clinical intervention. Nevertheless, more work needs to be done to better understand mechanisms by which innate immunity triggers β-cell destruction and assess the therapeutic value in blocking innate immunity for diabetes prevention.
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Affiliation(s)
- James C Needell
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Danny Zipris
- Innate Biotechnologies LLC, Denver, CO, 80231, USA.
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17
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Nyalwidhe JO, Gallagher GR, Glenn LM, Morris MA, Vangala P, Jurczyk A, Bortell R, Harlan DM, Wang JP, Nadler JL. Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes. J Endocr Soc 2017; 1:1272-1286. [PMID: 29264452 PMCID: PMC5686651 DOI: 10.1210/js.2017-00278] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/06/2017] [Indexed: 12/15/2022] Open
Abstract
Enteroviral infections have been associated with the development of type 1 diabetes (T1D), a chronic inflammatory disease characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Cultured human islets, including the insulin-producing beta cells, can be infected with coxsackievirus B4 (CVB4) and thus are useful for understanding cellular responses to infection. We performed quantitative mass spectrometry analysis on cultured primary human islets infected with CVB4 to identify molecules and pathways altered upon infection. Corresponding uninfected controls were included in the study for comparative protein expression analyses. Proteins were significantly and differentially regulated in human islets challenged with virus compared with their uninfected counterparts. Complementary analyses of gene transcripts in CVB4-infected primary islets over a time course validated the induction of RNA transcripts for many of the proteins that were increased in the proteomics studies. Notably, infection with CVB4 results in a considerable decrease in insulin. Genes/proteins modulated during CVB4 infection also include those involved in activation of immune responses, including type I interferon pathways linked to T1D pathogenesis and with antiviral, cell repair, and inflammatory properties. Our study applies proteomics analyses to cultured human islets challenged with virus and identifies target proteins that could be useful in T1D interventions.
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Affiliation(s)
- Julius O Nyalwidhe
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 23501.,Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, Virginia 23501
| | - Glen R Gallagher
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Lindsey M Glenn
- Department of Internal Medicine and Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23501
| | - Margaret A Morris
- Department of Internal Medicine and Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23501
| | - Pranitha Vangala
- Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Agata Jurczyk
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - David M Harlan
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Jennifer P Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Jerry L Nadler
- Department of Internal Medicine and Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23501
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18
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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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19
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Morse ZJ, Horwitz MS. Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset. Front Endocrinol (Lausanne) 2017; 8:249. [PMID: 29018409 PMCID: PMC5623193 DOI: 10.3389/fendo.2017.00249] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 09/12/2017] [Indexed: 12/25/2022] Open
Abstract
Heritable susceptibility of the autoimmune disorder, type 1 diabetes (T1D), only partially equates for the incidence of the disease. Significant evidence attributes several environmental stressors, such as vitamin D deficiency, gut microbiome, dietary antigens, and most notably virus infections in triggering the onset of T1D in these genetically susceptible individuals. Extensive epidemiological and clinical studies have provided credibility to this causal relationship. Infection by the enterovirus, coxsackievirus B, has been closely associated with onset of T1D and is considered a significant etiological agent for disease induction. Recognition of viral antigens via innate pathogen-recognition receptors induce inflammatory events which contribute to autoreactivity of pancreatic self-antigens and ultimately the destruction of insulin-secreting beta cells. The activation of these specific innate pathways and expression of inflammatory molecules, including type I and III interferon, prime the immune system to elicit either a protective regulatory response or a diabetogenic effector response. Therefore, sensing of viral antigens by retinoic acid-inducible gene I-like receptors and toll-like receptors may be detrimental to inducing autoreactivity initiated by viral stress and resulting in T1D.
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Affiliation(s)
- Zachary J. Morse
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Marc S. Horwitz,
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20
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Lundberg M, Krogvold L, Kuric E, Dahl-Jørgensen K, Skog O. Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes. Diabetes 2016; 65:3104-10. [PMID: 27422384 DOI: 10.2337/db16-0616] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 07/08/2016] [Indexed: 11/13/2022]
Abstract
A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.
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Affiliation(s)
- Marcus Lundberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Lars Krogvold
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Enida Kuric
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Knut Dahl-Jørgensen
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Oskar Skog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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21
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Schulte BM, Kers-Rebel ED, Bottino R, Piganelli JD, Galama JMD, Engelse MA, de Koning EJP, Adema GJ. Distinct activation of primary human BDCA1(+) dendritic cells upon interaction with stressed or infected β cells. Clin Exp Immunol 2016; 184:293-307. [PMID: 26888163 DOI: 10.1111/cei.12779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2016] [Indexed: 12/16/2022] Open
Abstract
Derailment of immune responses can lead to autoimmune type 1 diabetes, and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1(+) DCs towards differentially stressed pancreatic β cells. Our data show that BDCA1(+) DCs in human pancreas-draining lymph node (pdLN) suspensions and blood-derived BDCA1(+) DCs both effectively engulf β cells, thus mimicking physiological conditions. Upon uptake of enterovirus-infected, but not mock-infected cells, BDCA1(+) DCs induced interferon (IFN)-α/β responses, co-stimulatory molecules and proinflammatory cytokines and chemokines. Notably, induction of stress in β cells by ultraviolet irradiation, culture in serum-free medium or cytokine-induced stress did not provoke strong DC activation, despite efficient phagocytosis. DC activation correlated with the amount of virus used to infect β cells and required RNA within virally infected cells. DCs encountering enterovirus-infected β cells, but not those incubated with mock-infected or stressed β cells, suppressed T helper type 2 (Th2) cytokines and variably induced IFN-γ in allogeneic mixed lymphocyte reaction (MLR). Thus, stressed β cells have little effect on human BDCA1(+) DC activation and function, while enterovirus-infected β cells impact these cells significantly, which could help to explain their role in development of autoimmune diabetes in individuals at risk.
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Affiliation(s)
- B M Schulte
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - E D Kers-Rebel
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - R Bottino
- Department of Pediatrics, Diabetes Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - J D Piganelli
- Department of Pediatrics, Diabetes Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - J M D Galama
- Department of Medical Microbiology, Radboud University Medical Center, Nijmegen
| | - M A Engelse
- Department of Nephrology, Leiden University Medical Center, Leiden
| | - E J P de Koning
- Department of Nephrology, Leiden University Medical Center, Leiden.,Department of Endocrinology, Leiden University Medical Center, Leiden.,Hubrecht Institute, Utrecht, the Netherlands
| | - G J Adema
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
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22
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Santin I, Dos Santos RS, Eizirik DL. Pancreatic Beta Cell Survival and Signaling Pathways: Effects of Type 1 Diabetes-Associated Genetic Variants. Methods Mol Biol 2016; 1433:21-54. [PMID: 26936771 DOI: 10.1007/7651_2015_291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease in which pancreatic beta cells are specifically destroyed by the immune system. The disease has an important genetic component and more than 50 loci across the genome have been associated with risk of developing T1D. The molecular mechanisms by which these putative T1D candidate genes modulate disease risk, however, remain poorly characterized and little is known about their effects in pancreatic beta cells. Functional studies in in vitro models of pancreatic beta cells, based on techniques to inhibit or overexpress T1D candidate genes, allow the functional characterization of several T1D candidate genes. This requires a multistage procedure comprising two major steps, namely accurate selection of genes of potential interest and then in vitro and/or in vivo mechanistic approaches to characterize their role in pancreatic beta cell dysfunction and death in T1D. This chapter details the methods and settings used by our groups to characterize the role of T1D candidate genes on pancreatic beta cell survival and signaling pathways, with particular focus on potentially relevant pathways in the pathogenesis of T1D, i.e., inflammation and innate immune responses, apoptosis, beta cell metabolism and function.
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Affiliation(s)
- Izortze Santin
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium.
- Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, CIBERDEM, Spain.
| | - Reinaldo S Dos Santos
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
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23
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Abstract
The microbiome (or microbiota) are an ecological community of commensal, symbiotic, and pathogenic microorganisms that outnumber the cells of the human body tenfold. These microorganisms are most abundant in the gut where they play an important role in health and disease. Alteration of the homeostasis of the gut microbiota can have beneficial or harmful consequences to health. There has recently been a major increase in studies on the association of the gut microbiome composition with disease phenotypes.The nonobese diabetic (NOD) mouse is an excellent mouse model to study spontaneous type 1 diabetes development. We, and others, have reported that gut bacteria are critical modulators for type 1 diabetes development in genetically susceptible NOD mice.Here we present our standard protocol for gut microbiome analysis in NOD mice that has been routinely implemented in our research laboratory. This incorporates the following steps: (1) Isolation of total DNA from gut bacteria from mouse fecal samples or intestinal contents; (2) bacterial DNA sequencing, and (3) basic data analysis.
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Affiliation(s)
- Jian Peng
- Department of Endocrinology and Metabolism, School of Medicine, Yale University, 208020, New Haven, CT, 06520-8020, USA
| | - Youjia Hu
- Department of Endocrinology and Metabolism, School of Medicine, Yale University, 208020, New Haven, CT, 06520-8020, USA
| | - F Susan Wong
- Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Tenovus Building, Heath Park, CF14 4XN, UK
| | - Li Wen
- Department of Endocrinology and Metabolism, School of Medicine, Yale University, 208020, New Haven, CT, 06520-8020, USA.
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24
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Baden MY, Fukui K, Hosokawa Y, Iwahashi H, Imagawa A, Shimomura I. Examination of a Viral Infection Mimetic Model in Human iPS Cell-Derived Insulin-Producing Cells and the Anti-Apoptotic Effect of GLP-1 Analogue. PLoS One 2015; 10:e0144606. [PMID: 26659307 PMCID: PMC4676675 DOI: 10.1371/journal.pone.0144606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 11/21/2015] [Indexed: 12/22/2022] Open
Abstract
Aims Viral infection is associated with pancreatic beta cell destruction in fulminant type 1 diabetes mellitus. The aim of this study was to investigate the acceleration and protective mechanisms of beta cell destruction by establishing a model of viral infection in pancreatic beta cells. Methods Polyinosinic:polycytidylic acid was transfected into MIN6 cells and insulin-producing cells differentiated from human induced pluripotent stem cells via small molecule applications. Gene expression was analyzed by real-time PCR, and apoptosis was evaluated by caspase-3 activity and TUNEL staining. The anti-apoptotic effect of Exendin-4 was also evaluated. Results Polyinosinic:polycytidylic acid transfection led to elevated expression of the genes encoding IFNα, IFNβ, CXCL10, Fas, viral receptors, and IFN-inducible antiviral effectors in MIN6 cells. Exendin-4 treatment suppressed the elevated gene expression levels and reduced polyinosinic:polycytidylic acid-induced apoptosis both in MIN6 cells and in insulin-producing cells from human induced pluripotent stem cells. Glucagon-like peptide-1 receptor, protein kinase A, and phosphatidylinositol-3 kinase inhibitors counteracted the anti-apoptotic effect of Exendin-4. Conclusions Polyinosinic:polycytidylic acid transfection can mimic viral infection, and Exendin-4 exerted an anti-apoptotic effect both in MIN6 and insulin-producing cells from human induced pluripotent stem cells.
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Affiliation(s)
- Megu Yamaguchi Baden
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kenji Fukui
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yoshiya Hosokawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hiromi Iwahashi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Akihisa Imagawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- * E-mail:
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
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25
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Smura T, Natri O, Ylipaasto P, Hellman M, Al-Hello H, Piemonti L, Roivainen M. Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells. Virus Res 2015; 210:188-97. [DOI: 10.1016/j.virusres.2015.08.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/31/2015] [Accepted: 08/05/2015] [Indexed: 12/16/2022]
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26
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Neurotropic Enterovirus Infections in the Central Nervous System. Viruses 2015; 7:6051-66. [PMID: 26610549 PMCID: PMC4664993 DOI: 10.3390/v7112920] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 11/06/2015] [Accepted: 11/13/2015] [Indexed: 02/03/2023] Open
Abstract
Enteroviruses are a group of positive-sense single stranded viruses that belong to the Picornaviridae family. Most enteroviruses infect humans from the gastrointestinal tract and cause mild symptoms. However, several enteroviruses can invade the central nervous system (CNS) and result in various neurological symptoms that are correlated to mortality associated with enteroviral infections. In recent years, large outbreaks of enteroviruses occurred worldwide. Therefore, these neurotropic enteroviruses have been deemed as re-emerging pathogens. Although these viruses are becoming large threats to public health, our understanding of these viruses, especially for non-polio enteroviruses, is limited. In this article, we review recent advances in the trafficking of these pathogens from the peripheral to the central nervous system, compare their cell tropism, and discuss the effects of viral infections in their host neuronal cells.
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27
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Abstract
Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.
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Affiliation(s)
- Antje Petzold
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Michele Solimena
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- />Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Klaus-Peter Knoch
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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28
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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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29
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Gallagher GR, Brehm MA, Finberg RW, Barton BA, Shultz LD, Greiner DL, Bortell R, Wang JP. Viral infection of engrafted human islets leads to diabetes. Diabetes 2015; 64:1358-69. [PMID: 25392246 PMCID: PMC4375078 DOI: 10.2337/db14-1020] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes.
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Affiliation(s)
- Glen R Gallagher
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Michael A Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Robert W Finberg
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Bruce A Barton
- Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA
| | | | - Dale L Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Jennifer P Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
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30
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Adamczak DM, Nowak JK, Frydrychowicz M, Kaczmarek M, Sikora J. The role of Toll-like receptors and vitamin D in diabetes mellitus type 1--a review. Scand J Immunol 2014; 80:75-84. [PMID: 24845558 DOI: 10.1111/sji.12188] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 05/04/2014] [Indexed: 12/17/2022]
Abstract
It is widely accepted that type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from an interaction between immunologic, genetic and environmental factors. However, the exact mechanism leading to the development of T1DM remains incomplete. There is a large body of evidence pointing towards the important role of toll-like receptor (TLR) activation and vitamin D deficiency in T1DM pathogenesis. In this article, we review the available data on the influence of TLRs' level of activation and vitamin D status on the risk of the development of T1DM in humans and rodent models. We also summarize the current information regarding the interactions between TLRs' level of activation, vitamin D status and various environmental factors, such as enteroviral infections, the gut microbiota and breastfeeding substitution, among others. Our results stipulate that vitamin D seems to protect against T1DM by reducing the TLRs' level of activation.
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Affiliation(s)
- D M Adamczak
- Poznan University of Medical Sciences, Clinical Hospital No. 1, Poznan, Poland; Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
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31
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Alkanani AK, Hara N, Gianani R, Zipris D. Kilham Rat Virus-induced type 1 diabetes involves beta cell infection and intra-islet JAK-STAT activation prior to insulitis. Virology 2014; 468-470:19-27. [PMID: 25129435 DOI: 10.1016/j.virol.2014.07.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/17/2014] [Accepted: 07/21/2014] [Indexed: 11/24/2022]
Abstract
We used the LEW1.WR1 rat model of Kilham Rat Virus (KRV)-induced type 1 diabetes (T1D) to test the hypothesis that disease mechanisms are linked with beta cell infection and intra-islet immune activation prior to insulitis. KRV induces genes involved in type I and type II interferon pathways in islet cell lines in vitro and in islets from day-5-infected animals in vivo via mechanisms that do not involve insulitis, beta cell apoptosis, or impaired insulin expression. Immunohistochemistry studies indicated that KRV protein is expressed in beta cells 5 days following infection. KRV induces the phosphorylation of Janus Kinase 1/2 (JAK1/2) and signal transducer and activator of transcription 1 (STAT-1) in islet cells via a mechanism that could involve TLR9 and NF-κB pathways. These data demonstrate for the first time that KRV-induced islet destruction is associated with beta cell infection and intra-islet innate immune upregulation early in the disease process.
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Affiliation(s)
- Aimon K Alkanani
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States
| | - Naoko Hara
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States
| | - Roberto Gianani
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States
| | - Danny Zipris
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States.
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32
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Human rhinovirus 16 causes Golgi apparatus fragmentation without blocking protein secretion. J Virol 2014; 88:11671-85. [PMID: 25100828 PMCID: PMC4178721 DOI: 10.1128/jvi.01170-14] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The replication of picornaviruses has been described to cause fragmentation of the Golgi apparatus that blocks the secretory pathway. The inhibition of major histocompatibility complex class I upregulation and cytokine, chemokine and interferon secretion may have important implications for host defense. Previous studies have shown that disruption of the secretory pathway can be replicated by expression of individual nonstructural proteins; however the situation with different serotypes of human rhinovirus (HRV) is unclear. The expression of 3A protein from HRV14 or HRV2 did not cause Golgi apparatus disruption or a block in secretion, whereas other studies showed that infection of cells with HRV1A did cause Golgi apparatus disruption which was replicated by the expression of 3A. HRV16 is the serotype most widely used in clinical HRV challenge studies; consequently, to address the issue of Golgi apparatus disruption for HRV16, we have systematically and quantitatively examined the effect of HRV16 on both Golgi apparatus fragmentation and protein secretion in HeLa cells. First, we expressed each individual nonstructural protein and examined their cellular localization and their disruption of endoplasmic reticulum and Golgi apparatus architecture. We quantified their effects on the secretory pathway by measuring secretion of the reporter protein Gaussia luciferase. Finally, we examined the same outcomes following infection of cells with live virus. We demonstrate that expression of HRV16 3A and 3AB and, to a lesser extent, 2B caused dispersal of the Golgi structure, and these three nonstructural proteins also inhibited protein secretion. The infection of cells with HRV16 also caused significant Golgi apparatus dispersal; however, this did not result in the inhibition of protein secretion. IMPORTANCE The ability of replicating picornaviruses to influence the function of the secretory pathway has important implications for host defense. However, there appear to be differences between different members of the family and inconsistent results when comparing infection with live virus to expression of individual nonstructural proteins. We demonstrate that individual nonstructural HRV16 proteins, when expressed in HeLa cells, can both fragment the Golgi apparatus and block secretion, whereas viral infection fragments the Golgi apparatus without blocking secretion. This has major implications for how we interpret mechanistic evidence derived from the expression of single viral proteins.
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33
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Fleiner HF, Radtke M, Ryan L, Moen T, Grill V. Circulating immune mediators are closely linked in adult-onset type 1 diabetes as well as in non-diabetic subjects. Autoimmunity 2014; 47:530-7. [DOI: 10.3109/08916934.2014.938321] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Hanne Fiskvik Fleiner
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
TrondheimNorway
| | - Maria Radtke
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
TrondheimNorway
- Department of Renal Medicine, St. Olavs University Hospital
TrondheimNorway
| | - Liv Ryan
- Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology
TrondheimNorway
| | - Torolf Moen
- Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology
TrondheimNorway
| | - Valdemar Grill
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
TrondheimNorway
- Department of Endocrinology, St. Olavs University Hospital
TrondheimNorway
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34
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Chao GYC, Wallis RH, Marandi L, Ning T, Sarmiento J, Paterson AD, Poussier P. Iddm30 controls pancreatic expression of Ccl11 (Eotaxin) and the Th1/Th2 balance within the insulitic lesions. THE JOURNAL OF IMMUNOLOGY 2014; 192:3645-53. [PMID: 24646746 DOI: 10.4049/jimmunol.1302383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The autoimmune diabetic syndrome of the BioBreeding diabetes-prone (BBDP) rat is a polygenic disease that resembles in many aspects human type 1 diabetes (T1D). A successful approach to gain insight into the mechanisms underlying genetic associations in autoimmune diseases has been to identify and map disease-related subphenotypes that are under simpler genetic control than the full-blown disease. In this study, we focused on the β cell overexpression of Ccl11 (Eotaxin), previously postulated to be diabetogenic in BBDR rats, a BBDP-related strain. We tested the hypothesis that this trait is genetically determined and contributes to the regulation of diabetes in BBDP rats. Similar to the BBDR strain, we observed a time-dependent, insulitis-independent pancreatic upregulation of Ccl11 in BBDP rats when compared with T1D-resistant ACI.1u.lyp animals. Through linkage analysis of a cross-intercross of these two parental strains, this trait was mapped to a region on chromosome 12 that overlaps Iddm30. Linkage results were confirmed by phenotypic assessment of a novel inbred BBDP.ACI-Iddm30 congenic line. As expected, the Iddm30 BBDP allele is associated with a significantly higher pancreatic expression of Ccl11; however, the same allele confers resistance to T1D. Analysis of islet-infiltrating T cells in Iddm30 congenic BBDP animals revealed that overexpression of pancreatic Ccl11, a prototypical Th2 chemokine, is associated with an enrichment in Th2 CD4+ T cells within the insulitic lesions. These results indicate that, in the BBDP rat, Iddm30 controls T1D susceptibility through both the regulation of Ccl11 expression in β cells and the subsequent Th1/Th2 balance within islet-infiltrating T lymphocytes.
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Affiliation(s)
- Gary Y C Chao
- Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada
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35
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Abstract
Considerable efforts have been invested to understand the mechanisms by which pro-inflammatory cytokines mediate the demise of β-cells in type 1 diabetes but much less attention has been paid to the role of anti-inflammatory cytokines as potential cytoprotective agents in these cells. Despite this, there is increasing evidence that anti-inflammatory molecules such as interleukin (IL)-4, IL-10 and IL-13 can exert a direct influence of β-cell function and viability and that the circulating levels of these cytokines may be reduced in type 1 diabetes. Thus, it seems possible that targeting of anti-inflammatory pathways might offer therapeutic potential in this disease. In the present review, we consider the evidence implicating IL-4, IL-10 and IL-13 as cytoprotective agents in the β-cell and discuss the receptor components and downstream signaling pathways that mediate these effects.
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Affiliation(s)
- M A Russell
- Institute of Biomedical and Clinical Science; University of
Exeter Medical School; Exeter, Devon, UK
- Correspondence to: MA
Russell;
| | - N G Morgan
- Institute of Biomedical and Clinical Science; University of
Exeter Medical School; Exeter, Devon, UK
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36
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Anagandula M, Richardson SJ, Oberste MS, Sioofy-Khojine AB, Hyöty H, Morgan NG, Korsgren O, Frisk G. Infection of human islets of Langerhans with two strains of Coxsackie B virus serotype 1: assessment of virus replication, degree of cell death and induction of genes involved in the innate immunity pathway. J Med Virol 2013; 86:1402-11. [PMID: 24249667 DOI: 10.1002/jmv.23835] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2013] [Indexed: 12/13/2022]
Abstract
Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1.Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFNβ, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFNβ, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential β-cell tropism of the virus.
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Affiliation(s)
- Mahesh Anagandula
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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37
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Liu B, Hassan Z, Amisten S, King AJ, Bowe JE, Huang GC, Jones PM, Persaud SJ. The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis. Diabetologia 2013; 56:2467-76. [PMID: 23979485 DOI: 10.1007/s00125-013-3022-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 07/19/2013] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular calcium, so we investigated whether islets express this receptor and whether its activation by CCL5 increases beta cell calcium levels and insulin secretion. METHODS Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR and GPR75 was detected in islets by western blotting and immunohistochemistry. In some experiments GPR75 was downregulated by transient transfection with small interfering RNA. Real-time changes in intracellular calcium were determined by single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was determined by measuring glucose and insulin tolerance, and insulin secretion in vivo. RESULTS Mouse and human islets express GPR75 and its ligand CCL5. Exogenous CCL5 reversibly increased intracellular calcium in beta cells via GPR75, this phenomenon being dependent on phospholipase C activation and calcium influx. CCL5 also stimulated insulin secretion from mouse and human islets in vitro, and improved glucose tolerance in lean mice and in a mouse model of hyperglycaemia and insulin resistance (ob/ob). The improvement in glucose tolerance was associated with enhanced insulin secretion in vivo, without changes in insulin sensitivity. CONCLUSIONS/INTERPRETATION Although CCL5 is implicated in the pathogenesis of diabetes through activation of CCRs, it has beneficial effects on beta cells through GPR75 activation.
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Affiliation(s)
- Bo Liu
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, School of Medicine, 2.9N Hodgkin Building, King's College London, Guy's Campus, London, SE1 1UL, UK
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38
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Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) results from interplay between genetic predisposition, immune system, and environmental factors. Epidemiological and experimental data strongly suggest a role for enteroviruses in the development of T1D, but a lot of controversies and unanswered questions remained. This review focuses on issues that are fueling debate. RECENT FINDINGS Beyond HLA genes, which provide genetic susceptibility for T1D, other loci have been identified to be associated with the disease. There is a link between T1D and single-nucleotide polymorphisms (SNPs) in the interferon-induced helicase 1 (IFIH1) gene that encodes melanoma differentiation-associated protein 5 (MDA5). This protein is a cytoplasmic sensor for viruses especially coxsackieviruses B, the most incriminated enteroviruses in T1D pathogenesis. Upon viral infection, MDA5 stimulates the production of mediators of the innate antiviral immune response, which is believed to play a role in a 'bystander activation' scenario. Rare variants of IFIH1 through a lost or reduced expression of the protein are protective against T1D, whereas common IFIH1 SNPs are associated with the disease. However, a clear association has not been yet established between T1D-associated IFIH1 polymorphisms and enterovirus detection. SUMMARY Literature have accumulated a lot of evidence supporting that enteroviruses can contribute, at least in some patients, to the pathogenesis of T1D through various mechanisms. But it is still a challenge to date to prove a causal relationship between enteroviruses and T1D. Future studies may lead to a better understanding of this relationship and ultimately can help toward disease prevention.
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39
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Zipris D. The interplay between the gut microbiota and the immune system in the mechanism of type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2013; 20:265-70. [PMID: 23743644 DOI: 10.1097/med.0b013e3283628569] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Discuss recent data linking the intestinal microbiome with mechanisms of inflammation and islet destruction. RECENT FINDINGS Type 1 diabetes (T1D) is a proinflammatory disease that results in the loss of insulin-producing beta cells. How T1D is triggered is unclear; however, both genetic and environmental factors were implicated in disease mechanisms. Emerging evidence supports the notion that there is a complex interaction between the intestinal microbiome and the immune system and this cross-talk is involved in maintaining normal immune homeostasis in the gut and periphery. Under some circumstances the gut microbiota could lead to pathogenic immune responses resulting in inflammation in the intestine as well as other organs. Indeed, recent data from genetically susceptible individuals suggested that alterations in gut bacterial communities may be involved in the mechanism of islet destruction. Studies performed in animal models of T1D indicated that manipulating the gut microbiome can protect from islet destruction via mechanisms that may involve down-regulating both the adaptive and innate immune systems. SUMMARY Further work is required to identify specific bacterial communities and mechanisms involved in triggering T1D. A better knowledge of the role of the gut microbiome in islet destruction could lead to new clinical interventions to restore healthy homeostasis and prevent disease development.
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Affiliation(s)
- Danny Zipris
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045–6511 , USA.
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40
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Schneider DA, von Herrath MG. Viruses and Type 1 diabetes: a dynamic labile equilibrium. DIABETES MANAGEMENT (LONDON, ENGLAND) 2013; 3:217-223. [PMID: 24634696 PMCID: PMC3949992 DOI: 10.2217/dmt.13.17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) results from the specific immune-mediated destruction of the insulin-producing β-cells of the pancreas. In genetically susceptible individuals, a still undetermined initiating 'hit' triggers a cascade of events that eventually leads to autoreactive CD8 T cells infiltrating the pancreatic islets and, subsequently, destroying them. There is increasing evidence that viruses, especially enteroviruses, are major environmental candidates; however, despite decades of investigation, we still lack certainty with regard to the causation of T1D. Moreover, studies in animal models of diabetes suggest a protective role of certain enteroviral infections upon diabetes contraction, making the quest for viral involvement in T1D even more difficult. Analyzing the foundation and the results of the most current work in the field, this article gives a brief overview of current knowledge, as well as providing an outlook for future directions.
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Affiliation(s)
- Darius A Schneider
- Center for Type 1 Diabetes Research, 9420 Athena Circle, La Jolla, CA 92037, USA
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41
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Schulte BM, Kers-Rebel ED, Prosser AC, Galama JMD, van Kuppeveld FJM, Adema GJ. Differential susceptibility and response of primary human myeloid BDCA1(+) dendritic cells to infection with different Enteroviruses. PLoS One 2013; 8:e62502. [PMID: 23638101 PMCID: PMC3634769 DOI: 10.1371/journal.pone.0062502] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 03/22/2013] [Indexed: 12/24/2022] Open
Abstract
Coxsackie B viruses (CVBs) and echoviruses (EVs) form the Human Enterovirus-B (HEV-B) species within the family Picornaviridae. HEV-B infections are widespread and generally cause mild disease; however, severe infections occur and HEV-B are associated with various chronic diseases such as cardiomyopathy and type 1 diabetes. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system and initiate and control immune responses to invading pathogens, yet also maintain tolerance to self-antigens. We previously reported that EVs, but not CVBs, can productively infect in vitro generated monocyte-derived DCs. The interactions between HEV-B and human myeloid DCs (mDCs) freshly isolated from blood, however, remain unknown. Here, we studied the susceptibility and responses of BDCA1(+) mDC to HEV-B species and found that these mDC are susceptible to EV, but not CVB infection. Productive EV7 infection resulted in massive, rapid cell death without DC activation. Contrary, EV1 infection, which resulted in lower virus input at the same MOI, resulted in DC activation as observed by production of type I interferon-stimulated genes (ISGs), upregulation of co-stimulatory and co-inhibitory molecules (CD80, CD86, PDL1) and production of IL-6 and TNF-α, with a relative moderate decrease in cell viability. EV1-induced ISG expression depended on virus replication. CVB infection did not affect DC viability and resulted in poor induction of ISGs and CD80 induction in part of the donors. These data show for the first time the interaction between HEV-B species and BDCA1(+) mDCs isolated freshly from blood. Our data indicate that different HEV-B species can influence DC homeostasis in various ways, possibly contributing to HEV-B associated pathology.
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Affiliation(s)
- Barbara M. Schulte
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Esther D. Kers-Rebel
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Amy C. Prosser
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Jochem M. D. Galama
- Department of Medical Microbiology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Frank J. M. van Kuppeveld
- Department of Medical Microbiology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Gosse J. Adema
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences & Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- * E-mail:
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In type 1 diabetes a subset of anti-coxsackievirus B4 antibodies recognize autoantigens and induce apoptosis of pancreatic beta cells. PLoS One 2013; 8:e57729. [PMID: 23469060 PMCID: PMC3585221 DOI: 10.1371/journal.pone.0057729] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 01/25/2013] [Indexed: 02/07/2023] Open
Abstract
Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients’sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients’ sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.
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43
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Hals IK, Rokstad AM, Strand BL, Oberholzer J, Grill V. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia. J Diabetes Res 2013; 2013:374925. [PMID: 24364039 PMCID: PMC3864170 DOI: 10.1155/2013/374925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 11/08/2013] [Indexed: 01/06/2023] Open
Abstract
Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1-0.3% O2 for 8 h, followed by reoxygenation) on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8 ± 3.5% in encapsulated and 42.9 ± 5.2% in nonencapsulated islets (P < 0.2). Nonencapsulated islets released 37.7% (median) more HMGB1 compared to encapsulated islets after hypoxic culture conditions (P < 0.001). Glucose-induced insulin release was marginally affected by hypoxia. Basal oxygen consumption was equally reduced in encapsulated and nonencapsulated islets, by 22.0 ± 6.1% versus 24.8 ± 5.7%. Among 27 tested cytokines/chemokines, hypoxia increased the secretion of IL-6 and IL-8/CXCL8 in both groups of islets, whereas an increase of MCP-1/CCL2 was seen only with nonencapsulated islets. Conclusion. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation.
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Affiliation(s)
- I. K. Hals
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Postbox 8905, 7491 Trondheim, Norway
- *I. K. Hals:
| | - A. M. Rokstad
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Postbox 8905, 7491 Trondheim, Norway
| | - B. L. Strand
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Postbox 8905, 7491 Trondheim, Norway
- Department of Biotechnology, Faculty of Natural Sciences and Technology, Norwegian University of Science and Technology, 7034 Trondheim, Norway
| | - J. Oberholzer
- Department of Surgery, University of Illinois, IL at Chicago, Chicago, IL 60612, USA
| | - V. Grill
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Postbox 8905, 7491 Trondheim, Norway
- Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Postbox 3250, 7006 Trondheim, Norway
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Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG. Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 2013; 56:185-93. [PMID: 23064357 DOI: 10.1007/s00125-012-2745-4] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 09/13/2012] [Indexed: 01/12/2023]
Abstract
AIMS/HYPOTHESIS Immunohistochemical staining reveals that the enteroviral capsid protein VP1 is present at higher frequency in the insulin-containing islets of patients with recent-onset type 1 diabetes than in controls. This is consistent with epidemiological evidence suggesting that enteroviral infection may contribute to the autoimmune response in type 1 diabetes. However, immunostaining of VP1 is not definitive since the antibody widely used to detect the protein (Clone 5D8/1) might also cross-react with additional proteins under some conditions. Therefore, we sought to verify that VP1 immunopositivity correlates with additional markers of viral infection. METHODS Antigen immunoreactivity was examined in formalin-fixed, paraffin-embedded, pancreases from two different collections of type 1 diabetes and control cases: a historical collection from the UK and the nPOD (network of Pancreatic Organ donors with Diabetes) cohort from the USA. RESULTS VP1 immunoreactivity was present in ~20% of insulin-containing islets of both cohorts under stringent conditions but was absent from insulin-deficient islets. The presence of VP1 was restricted to beta cells but only a minority of these contained the antigen. The innate viral sensor, protein kinase R (PKR) was upregulated selectively in beta cells that were immunopositive for VP1. The anti-apoptotic protein myeloid cell leukaemia sequence-1 (Mcl-1) was abundant in beta cells that were immunonegative for VP1 but Mcl-1 was depleted in cells containing VP1. CONCLUSIONS/INTERPRETATION The presence of immunoreactive VP1 within beta cells in type 1 diabetes is associated with a cellular phenotype consistent with the activation of antiviral response pathways and enhanced sensitivity to apoptosis. However, definitive studies confirming whether viral infections are causal to beta cell loss in human diabetes are still awaited.
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Affiliation(s)
- S J Richardson
- Endocrine Pharmacology, University of Exeter Medical School, John Bull Building, Plymouth PL6 8BU, UK.
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