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Rodriguez-Calvo T, Laiho JE, Oikarinen M, Akhbari P, Flaxman C, Worthington T, Apaolaza P, Kaddis JS, Kusmartseva I, Tauriainen S, Campbell-Thompson M, Atkinson MA, von Herrath M, Hyöty H, Morgan NG, Pugliese A, Richardson SJ. Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes. Diabetologia 2025; 68:1197-1210. [PMID: 40090995 PMCID: PMC12069150 DOI: 10.1007/s00125-025-06384-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/19/2024] [Indexed: 03/19/2025]
Abstract
AIMS/HYPOTHESIS Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. METHODS Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb+, n=20; AAb++, n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. RESULTS Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1+ cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1+ donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb++ and T1D-ICI groups (94.9%, p<0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1+ compared with VP1- donors (45.8% vs 16%, p<0.001). CONCLUSIONS/INTERPRETATION We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one of multiple mechanisms driving islet cell HLA-I hyperexpression.
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Affiliation(s)
- Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maarit Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Pouria Akhbari
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Christine Flaxman
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Thomas Worthington
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Paola Apaolaza
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | | | - Martha Campbell-Thompson
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Matthias von Herrath
- Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
- Division of Endocrine, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Noel G Morgan
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Alberto Pugliese
- Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sarah J Richardson
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
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Richardson SJ, Rodriguez-Calvo T, Laiho JE, Kaddis JS, Nyalwidhe JO, Kusmartseva I, Morfopoulou S, Petrosino JF, Plagnol V, Maedler K, Morris MA, Nadler JL, Atkinson MA, von Herrath M, Lloyd RE, Hyoty H, Morgan NG, Pugliese A. Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue. Diabetologia 2025; 68:1226-1241. [PMID: 40090994 PMCID: PMC12069141 DOI: 10.1007/s00125-025-06401-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/03/2024] [Indexed: 03/19/2025]
Abstract
AIMS/HYPOTHESIS Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes. METHODS The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, n=41) or with only insulin-deficient islets (T1D-IDI, n=42); donors without diabetes who are AAb-negative (ND, n=83); and rare donors without diabetes expressing a single AAb (AAb+, n=22) or multiple AAbs (AAb++, n=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors. RESULTS Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (p<0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb+ 24.6%; AAb++ 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], p<0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), p=0.076; EV-PCR/HLA-I, p=0.016; proteomics/HLA-I, p<0.0001; VP1/proteomics, p=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (p<0.001), 26.7% of AAb+ (p=0.006), 28.6% of AAb++ (p=0.023) and 0% of T1D-IDI (p<0.001) donors. CONCLUSIONS/INTERPRETATION The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb++ donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas.
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Affiliation(s)
- Sarah J Richardson
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Julius O Nyalwidhe
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Sofia Morfopoulou
- Division of Infection and Immunity, University College London, London, UK
| | | | | | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Margaret A Morris
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
- Autoimmunity and Primary Immunodeficiency Disease Section, Autoimmunity and Mucosal Immunology Branch, DAIT NIAD NIH DHHS, Rockville, MD, USA
| | - Jerry L Nadler
- UC Davis School of Medicine, Sacramento, CA, USA
- ACOS-Research Northern California VA Health System, Mather, CA, USA
| | - Mark A Atkinson
- Diabetes Institute, Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Matthias von Herrath
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Heikki Hyoty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
- Department of Paediatrics, Tampere University Hospital, Tampere, Finland
| | - Noel G Morgan
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Alberto Pugliese
- Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA.
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Nikola L, Iva L. Gut microbiota as a modulator of type 1 diabetes: A molecular perspective. Life Sci 2024; 359:123187. [PMID: 39488260 DOI: 10.1016/j.lfs.2024.123187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 10/04/2024] [Accepted: 10/24/2024] [Indexed: 11/04/2024]
Abstract
Type 1 diabetes (T1D) is defined as an autoimmune metabolic disorder, characterized by destruction of pancreatic β-cells and high blood sugar levels. If left untreated, T1D results in severe health complications, including cardiovascular and kidney disease, as well as nerve damage, with ultimately grave consequences. Besides the role of genetic and certain environmental factors in T1D development, in the last decade, one new player emerged to affect T1D pathology as well, and that is a gut microbiota. Dysbiosis of gut bacteria can contribute to T1D by gut barrier disruption and the activation of autoimmune response, leading to the destruction of insulin producing cells, causing the development and aggravation of T1D symptoms. The relationship between gut microbiota and diabetes is complex and varies between individuals and additional research is needed to fully understand the effects of gut microbiome alternations in T1D pathogenesis. Therefore, the goal of this review is to understand the current knowledge in underlying molecular mechanism of gut microbiota effects, which leads to the new approaches for further studies in the prevention and treatment of T1D.
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Affiliation(s)
- Lukic Nikola
- Laboratory for Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinca", National Institute of the Republic of Serbia, University of Belgrade, Serbia
| | - Lukic Iva
- Laboratory for Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinca", National Institute of the Republic of Serbia, University of Belgrade, Serbia.
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Veronese-Paniagua DA, Hernandez-Rincon DC, Taylor JP, Tse HM, Millman JR. Coxsackievirus B infection invokes unique cell-type specific responses in primary human pancreatic islets. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.23.604861. [PMID: 39211206 PMCID: PMC11361082 DOI: 10.1101/2024.07.23.604861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Coxsackievirus B (CVB) infection has long been considered an environmental factor precipitating Type 1 diabetes (T1D), an autoimmune disease marked by loss of insulin-producing β cells within pancreatic islets. Previous studies have shown CVB infection negatively impacts islet function and viability but do not report on how virus infection individually affects the multiple cell types present in human primary islets. Therefore, we hypothesized that the various islet cell populations have unique transcriptional responses to CVB infection. Here, we performed single-cell RNA sequencing on human cadaveric islets treated with either CVB or poly(I:C), a viral mimic, for 24 and 48 hours. Our global analysis reveals CVB differentially induces dynamic transcriptional changes associated with multiple cell processes and functions over time whereas poly(I:C) promotes an immune response that progressively increases with treatment duration. At the single-cell resolution, we find CVB infects all islet cell types at similar rates yet induces unique cell-type specific transcriptional responses with β, α, and ductal cells having the strongest response. Sequencing and functional data suggest that CVB negatively impacts mitochondrial respiration and morphology in distinct ways in β and α cells, while also promoting the generation of reactive oxygen species. We also observe an increase in the expression of the long-noncoding RNA MIR7-3HG in β cells with high viral titers and reveal its knockdown reduces gene expression of viral proteins as well as apoptosis in stem cell-derived islets. Together, these findings demonstrate a cell-specific transcriptional, temporal, and functional response to CVB infection and provide new insights into the relationship between CVB infection and T1D.
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Jeremiah SS, Moin ASM, Butler AE. Virus-induced diabetes mellitus: revisiting infection etiology in light of SARS-CoV-2. Metabolism 2024; 156:155917. [PMID: 38642828 DOI: 10.1016/j.metabol.2024.155917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 04/22/2024]
Abstract
Diabetes mellitus (DM) is comprised of two predominant subtypes: type 1 diabetes mellitus (T1DM), accounting for approximately 5 % of cases worldwide and resulting from autoimmune destruction of insulin-producing β-cells, and type 2 (T2DM), accounting for approximately 95 % of cases globally and characterized by the inability of pancreatic β-cells to meet the demand for insulin due to a relative β-cell deficit in the setting of peripheral insulin resistance. Both types of DM involve derangement of glucose metabolism and are metabolic diseases generally considered to be initiated by a combination of genetic and environmental factors. Viruses have been reported to play a role as infectious etiological factors in the initiation of both types of DM in predisposed individuals. Among the reported viral infections causing DM in humans, the most studied include coxsackie B virus, cytomegalovirus and hepatitis C virus. The recent COVID-19 pandemic has highlighted the diabetogenic potential of SARS-CoV-2, rekindling interest in the field of virus-induced diabetes (VID). This review discusses the reported mechanisms of viral-induced DM, addressing emerging concepts in VID, as well as highlighting areas where knowledge is lacking, and further investigation is warranted.
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Affiliation(s)
| | - Abu Saleh Md Moin
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
| | - Alexandra E Butler
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
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Isaacs SR, Roy A, Dance B, Ward EJ, Foskett DB, Maxwell AJ, Rawlinson WD, Kim KW, Craig ME. Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins. Lancet Diabetes Endocrinol 2023:S2213-8587(23)00122-5. [PMID: 37390839 DOI: 10.1016/s2213-8587(23)00122-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/19/2023] [Accepted: 04/19/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND Enteroviruses are routinely detected with molecular methods within large cohorts that are at risk of type 1 diabetes. We aimed to examine the association between enteroviruses and either islet autoimmunity or type 1 diabetes. METHODS For this systematic review and meta-analysis, we searched PubMed and Embase for controlled observational studies from inception until Jan 1, 2023. Cohort or case-control studies were eligible if enterovirus RNA or protein were detected in individuals with outcomes of islet autoimmunity or type 1 diabetes. Studies in pregnancy or other types of diabetes were excluded. Data extraction and appraisal involved author contact and deduplication, which was done independently by three reviewers. Study quality was assessed with the Newcastle-Ottawa Scale and National Health and Medical Research Council levels of evidence. Pooled and subgroup meta-analyses were done in RevMan version 5.4, with random effects models and Mantel-Haenszel odds ratios (ORs; 95% CIs). The study is registered with PROSPERO, CRD42021278863. FINDINGS The search returned 3266 publications, with 897 full texts screened. Following deduplication, 113 eligible records corresponded to 60 studies (40 type 1 diabetes; nine islet autoimmunity; 11 both), comprising 12077 participants (5981 cases; 6096 controls). Study design and quality varied, generating substantial statistical heterogeneity. Meta-analysis of 56 studies showed associations between enteroviruses and islet autoimmunity (OR 2·1, 95% CI 1·3-3·3; p=0·002; n=18; heterogeneity χ2/df 2·69; p=0·0004; I2=63%), type 1 diabetes (OR 8·0, 95% CI 4·9-13·0; p<0·0001; n=48; χ2/df 6·75; p<0·0001; I2=85%), or within 1 month of type 1 diabetes (OR 16·2, 95% CI 8·6-30·5; p<0·0001; n=28; χ2/df 3·25; p<0·0001; I2=69%). Detection of either multiple or consecutive enteroviruses was associated with islet autoimmunity (OR 2·0, 95% CI 1·0-4·0; p=0·050; n=8). Detection of Enterovirus B was associated with type 1 diabetes (OR 12·7, 95% CI 4·1-39·1; p<0·0001; n=15). INTERPRETATION These findings highlight the association between enteroviruses and islet autoimmunity or type 1 diabetes. Our data strengthen the rationale for vaccine development targeting diabetogenic enterovirus types, particularly those within Enterovirus B. Prospective studies of early life are needed to elucidate the role of enterovirus timing, type, and infection duration on the initiation of islet autoimmunity and the progression to type 1 diabetes. FUNDING Environmental Determinants of Islet Autoimmunity, European Association for the Study of Diabetes, JDRF, Australian National Health and Medical Research Council, and University of New South Wales.
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Affiliation(s)
- Sonia R Isaacs
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Anju Roy
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Brieana Dance
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Emily J Ward
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Dylan B Foskett
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Anna J Maxwell
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - William D Rawlinson
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Ki Wook Kim
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Maria E Craig
- Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia; Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, Sydney, NSW, Australia; Specialty of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
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Root-Bernstein R, Chiles K, Huber J, Ziehl A, Turke M, Pietrowicz M. Clostridia and Enteroviruses as Synergistic Triggers of Type 1 Diabetes Mellitus. Int J Mol Sci 2023; 24:ijms24098336. [PMID: 37176044 PMCID: PMC10179352 DOI: 10.3390/ijms24098336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/24/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
What triggers type 1 diabetes mellitus (T1DM)? One common assumption is that triggers are individual microbes that mimic autoantibody targets such as insulin (INS). However, most microbes highly associated with T1DM pathogenesis, such as coxsackieviruses (COX), lack INS mimicry and have failed to induce T1DM in animal models. Using proteomic similarity search techniques, we found that COX actually mimicked the INS receptor (INSR). Clostridia were the best mimics of INS. Clostridia antibodies cross-reacted with INS in ELISA experiments, confirming mimicry. COX antibodies cross-reacted with INSR. Clostridia antibodies further bound to COX antibodies as idiotype-anti-idiotype pairs conserving INS-INSR complementarity. Ultraviolet spectrometry studies demonstrated that INS-like Clostridia peptides bound to INSR-like COX peptides. These complementary peptides were also recognized as antigens by T cell receptor sequences derived from T1DM patients. Finally, most sera from T1DM patients bound strongly to inactivated Clostridium sporogenes, while most sera from healthy individuals did not; T1DM sera also exhibited evidence of anti-idiotype antibodies against idiotypic INS, glutamic acid decarboxylase, and protein tyrosine phosphatase non-receptor (islet antigen-2) antibodies. These results suggest that T1DM is triggered by combined enterovirus-Clostridium (and possibly combined Epstein-Barr-virus-Streptococcal) infections, and the probable rate of such co-infections approximates the rate of new T1DM diagnoses.
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Affiliation(s)
| | - Kaylie Chiles
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
| | - Jack Huber
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Alison Ziehl
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Miah Turke
- Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
| | - Maja Pietrowicz
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
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Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, Mason J, Sattar N, McMurray JJV, McInnes IB, Khunti K, Cambridge G. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 2023:S0140-6736(23)00457-9. [PMID: 37156255 DOI: 10.1016/s0140-6736(23)00457-9] [Citation(s) in RCA: 307] [Impact Index Per Article: 153.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/21/2023] [Accepted: 02/28/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases. METHODS In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex. FINDINGS Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. INTERPRETATION Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases. FUNDING Research Foundation Flanders.
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Affiliation(s)
- Nathalie Conrad
- Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven, Leuven Belgium; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; Deep Medicine, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
| | - Shivani Misra
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Jan Y Verbakel
- Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven, Leuven Belgium; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Geert Verbeke
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University and Katholieke Universiteit Leuven, Leuven, Belgium
| | - Geert Molenberghs
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University and Katholieke Universiteit Leuven, Leuven, Belgium
| | - Peter N Taylor
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Justin Mason
- Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, UK
| | - Naveed Sattar
- College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Iain B McInnes
- College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Geraldine Cambridge
- Department of Rheumatology, Division of Medicine, University College London, London, UK
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9
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Bélteky M, Milletich PL, Ahrens AP, Triplett EW, Ludvigsson J. Infant gut microbiome composition correlated with type 1 diabetes acquisition in the general population: the ABIS study. Diabetologia 2023; 66:1116-1128. [PMID: 36964264 DOI: 10.1007/s00125-023-05895-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 01/17/2023] [Indexed: 03/26/2023]
Abstract
AIMS/HYPOTHESIS While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. METHODS Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3±5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. RESULTS Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. CONCLUSIONS/INTERPRETATION This investigation suggests that microbial biomarkers for type 1 diabetes may be present as early as 1 year of age, as reflected in the taxonomic and functional differences of the microbial communities. The possibility of preventing disease onset by altering or promoting a 'healthy' gut microbiome is appealing. DATA AVAILABILITY The forward and reverse 16S raw sequencing data generated in this study are available through the NCBI Sequence Read Archive under BioProject PRJNA875929. Associated sample metadata used for statistical comparison are available in the source data file. R codes used for statistical comparisons and figure generation are available at: https://github.com/PMilletich/T1D_Pipeline .
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Affiliation(s)
- Malin Bélteky
- Crown Princess Victoria's Children's Hospital, Region Östergötland, Linköping, Sweden
| | - Patricia L Milletich
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, USA
| | - Angelica P Ahrens
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, USA
| | - Eric W Triplett
- Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, USA.
| | - Johnny Ludvigsson
- Crown Princess Victoria's Children's Hospital, Region Östergötland, Linköping, Sweden
- Division of Pediatrics, Linköping University, Linköping, Sweden
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10
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Morse ZJ, Simister RL, Crowe SA, Horwitz MS, Osborne LC. Virus induced dysbiosis promotes type 1 diabetes onset. Front Immunol 2023; 14:1096323. [PMID: 36742327 PMCID: PMC9892191 DOI: 10.3389/fimmu.2023.1096323] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.
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Affiliation(s)
- Zachary J Morse
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Rachel L Simister
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Sean A Crowe
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Marc S Horwitz
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lisa C Osborne
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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12
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Krogvold L, Genoni A, Puggioni A, Campani D, Richardson SJ, Flaxman CS, Edwin B, Buanes T, Dahl-Jørgensen K, Toniolo A. Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study. Diabetologia 2022; 65:2108-2120. [PMID: 35953727 PMCID: PMC9630231 DOI: 10.1007/s00125-022-05779-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/14/2022] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS Enterovirus (EV) infection of pancreatic islet cells is one possible factor contributing to type 1 diabetes development. We have reported the presence of EV genome by PCR and of EV proteins by immunohistochemistry in pancreatic sections. Here we explore multiple human virus species in the Diabetes Virus Detection (DiViD) study cases using innovative methods, including virus passage in cell cultures. METHODS Six recent-onset type 1 diabetes patients (age 24-35) were included in the DiViD study. Minimal pancreatic tail resection was performed under sterile conditions. Eleven live cases (age 43-83) of pancreatic carcinoma without diabetes served as control cases. In the present study, we used EV detection methods that combine virus growth in cell culture, gene amplification and detection of virus-coded proteins by immunofluorescence. Pancreas homogenates in cell culture medium were incubated with EV-susceptible cell lines for 3 days. Two to three blind passages were performed. DNA and RNA were extracted from both pancreas tissue and cell cultures. Real-time PCR was used for detecting 20 different viral agents other than EVs (six herpesviruses, human polyomavirus [BK virus and JC virus], parvovirus B19, hepatitis B virus, hepatitis C virus, hepatitis A virus, mumps, rubella, influenza A/B, parainfluenza 1-4, respiratory syncytial virus, astrovirus, norovirus, rotavirus). EV genomes were detected by endpoint PCR using five primer pairs targeting the partially conserved 5' untranslated region genome region of the A, B, C and D species. Amplicons were sequenced. The expression of EV capsid proteins was evaluated in cultured cells using a panel of EV antibodies. RESULTS Samples from six of six individuals with type 1 diabetes (cases) and two of 11 individuals without diabetes (control cases) contained EV genomes (p<0.05). In contrast, genomes of 20 human viruses other than EVs could be detected only once in an individual with diabetes (Epstein-Barr virus) and once in an individual without diabetes (parvovirus B19). EV detection was confirmed by immunofluorescence of cultured cells incubated with pancreatic extracts: viral antigens were expressed in the cytoplasm of approximately 1% of cells. Notably, infection could be transmitted from EV-positive cell cultures to uninfected cell cultures using supernatants filtered through 100 nm membranes, indicating that infectious agents of less than 100 nm were present in pancreases. Due to the slow progression of infection in EV-carrying cell cultures, cytopathic effects were not observed by standard microscopy but were recognised by measuring cell viability. Sequences of 5' untranslated region amplicons were compatible with EVs of the B, A and C species. Compared with control cell cultures exposed to EV-negative pancreatic extracts, EV-carrying cell cultures produced significantly higher levels of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP1). CONCLUSIONS/INTERPRETATION Sensitive assays confirm that the pancreases of all DiViD cases contain EVs but no other viruses. Analogous EV strains have been found in pancreases of two of 11 individuals without diabetes. The detected EV strains can be passaged in series from one cell culture to another in the form of poorly replicating live viruses encoding antigenic proteins recognised by multiple EV-specific antibodies. Thus, the early phase of type 1 diabetes is associated with a low-grade infection by EVs, but not by other viral agents.
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Affiliation(s)
- Lars Krogvold
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, Oslo, Norway.
| | - Angelo Genoni
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Anna Puggioni
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Daniela Campani
- Department of Surgical, Medical and Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy
| | - Sarah J Richardson
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK
| | - Christine S Flaxman
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK
| | - Bjørn Edwin
- Department for HPB Surgery, Oslo University Hospital, Oslo, Norway
| | - Trond Buanes
- Department for HPB Surgery, Oslo University Hospital, Oslo, Norway
| | - Knut Dahl-Jørgensen
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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13
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Nekoua MP, Alidjinou EK, Hober D. Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2022; 18:503-516. [PMID: 35650334 PMCID: PMC9157043 DOI: 10.1038/s41574-022-00688-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
Abstract
Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.
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Affiliation(s)
| | | | - Didier Hober
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, Lille, France.
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14
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Tiamani K, Luo S, Schulz S, Xue J, Costa R, Khan Mirzaei M, Deng L. The role of virome in the gastrointestinal tract and beyond. FEMS Microbiol Rev 2022; 46:6608358. [PMID: 35700129 PMCID: PMC9629487 DOI: 10.1093/femsre/fuac027] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 01/11/2023] Open
Abstract
The human gut virome is comprised of diverse commensal and pathogenic viruses. The colonization by these viruses begins right after birth through vaginal delivery, then continues through breastfeeding, and broader environmental exposure. Their constant interaction with their bacterial hosts in the body shapes not only our microbiomes but us. In addition, these viruses interact with the immune cells, trigger a broad range of immune responses, and influence different metabolic pathways. Besides its key role in regulating the human gut homeostasis, the intestinal virome contributes to disease development in distant organs, both directly and indirectly. In this review, we will describe the changes in the gut virome through life, health, and disease, followed by discussing the interactions between the virome, the microbiome, and the human host as well as providing an overview of their contribution to gut disease and disease of distant organs.
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Affiliation(s)
| | | | - Sarah Schulz
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, 85764 Neuherberg, Germany,Chair of Microbial Disease Prevention, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Jinling Xue
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, 85764 Neuherberg, Germany,Chair of Microbial Disease Prevention, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Rita Costa
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, 85764 Neuherberg, Germany,Chair of Microbial Disease Prevention, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Mohammadali Khan Mirzaei
- Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, 85764 Neuherberg, Germany,Chair of Microbial Disease Prevention, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Li Deng
- Corresponding author: Institute of Virology, Helmholtz Centre Munich — German Research Centre for Environmental Health, 85764 Neuherberg, Germany; Chair of Prevention of Microbial Diseases, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany. E-mail:
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15
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Environmental Factors and the Risk of Developing Type 1 Diabetes-Old Disease and New Data. BIOLOGY 2022; 11:biology11040608. [PMID: 35453807 PMCID: PMC9027552 DOI: 10.3390/biology11040608] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022]
Abstract
Simple Summary Despite many studies, the risk factors of type 1 diabetes (T1DM) in children and adolescents are still not fully understood and remain a big challenge. Therefore, an extensive online search for scientific research on factors related to diabetes has been performed for the identification of new factors of unexplained etiology. A better understanding of the role of viral, bacterial, and yeast-like fungi infections related to the risk of T1DM in children and adolescents and the identification of new risk factors, especially those spread by the droplet route, is of great importance for people and families with diabetes. Abstract The incidence of type 1 diabetes (T1D) is increasing worldwide. The onset of T1D usually occurs in childhood and is caused by the selective destruction of insulin-producing pancreatic islet cells (β-cells) by autoreactive T cells, leading to insulin deficiency. Despite advanced research and enormous progress in medicine, the causes of T1D are still not fully understood. Therefore, an extensive online search for scientific research on environmental factors associated with diabetes and the identification of new factors of unexplained etiology has been carried out using the PubMed, Cochrane, and Embase databases. The search results were limited to the past 11 years of research and discovered 143 manuscripts published between 2011 and 2022. Additionally, 21 manuscripts from between 2000 and 2010 and 3 manuscripts from 1974 to 2000 were referenced for historical reference as the first studies showcasing a certain phenomenon or mechanism. More and more scientists are inclined to believe that environmental factors are responsible for the increased incidence of diabetes. Research results show that higher T1D incidence is associated with vitamin D deficiency, a colder climate, and pollution of the environment, as well as the influence of viral, bacterial, and yeast-like fungi infections. The key viral infections affecting the risk of developing T1DM are rubella virus, mumps virus, Coxsackie virus, cytomegalovirus, and enterovirus. Since 2020, i.e., from the beginning of the COVID-19 pandemic, more and more studies have been looking for a link between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and diabetes development. A better understanding of the role of viral, bacterial, and yeast-like fungi infections related to the risk of T1DM in children and adolescents and the identification of new risk factors, especially those spread by the droplet route, is of great importance for people and families with diabetes.
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Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin deficiency and resultant hyperglycemia. Complex interactions of genetic and environmental factors trigger the onset of autoimmune mechanisms responsible for development of autoimmunity to β cell antigens and subsequent development of T1D. A potential role of virus infections has long been hypothesized, and growing evidence continues to implicate enteroviruses as the most probable triggering viruses. Recent studies have strengthened the association between enteroviruses and development of autoimmunity in T1D patients, potentially through persistent infections. Enterovirus infections may contribute to different stages of disease development. We review data from both human cohort studies and experimental research exploring the potential roles and molecular mechanisms by which enterovirus infections can impact disease outcome.
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Affiliation(s)
- Richard E. Lloyd
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Manasi Tamhankar
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University Hospital, Malmö 214 28, Sweden
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Zhang Z, Ma P, Ahmed R, Wang J, Akin D, Soto F, Liu BF, Li P, Demirci U. Advanced Point-of-Care Testing Technologies for Human Acute Respiratory Virus Detection. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2103646. [PMID: 34623709 DOI: 10.1002/adma.202103646] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/25/2021] [Indexed: 04/14/2023]
Abstract
The ever-growing global threats to human life caused by the human acute respiratory virus (RV) infections have cost billions of lives, created a significant economic burden, and shaped society for centuries. The timely response to emerging RVs could save human lives and reduce the medical care burden. The development of RV detection technologies is essential for potentially preventing RV pandemic and epidemics. However, commonly used detection technologies lack sensitivity, specificity, and speed, thus often failing to provide the rapid turnaround times. To address this problem, new technologies are devised to address the performance inadequacies of the traditional methods. These emerging technologies offer improvements in convenience, speed, flexibility, and portability of point-of-care test (POCT). Herein, recent developments in POCT are comprehensively reviewed for eight typical acute respiratory viruses. This review discusses the challenges and opportunities of various recognition and detection strategies and discusses these according to their detection principles, including nucleic acid amplification, optical POCT, electrochemistry, lateral flow assays, microfluidics, enzyme-linked immunosorbent assays, and microarrays. The importance of limits of detection, throughput, portability, and specificity when testing clinical samples in resource-limited settings is emphasized. Finally, the evaluation of commercial POCT kits for both essential RV diagnosis and clinical-oriented practices is included.
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Affiliation(s)
- Zhaowei Zhang
- Oil Crops Research Institute of Chinese Academy of Agricultural Sciences, National Reference Laboratory for Agricultural Testing (Biotoxin), Key Laboratory of Biology and Genetic Improvement of Oil Crops, Key Laboratory of Detection for Mycotoxins, Ministry of Agriculture and Rural Affairs, Wuhan, 430062, P. R. China
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
| | - Peng Ma
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics & Molecular Imaging Key Laboratory Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Rajib Ahmed
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
| | - Jie Wang
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
| | - Demir Akin
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
| | - Fernando Soto
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
| | - Bi-Feng Liu
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics & Molecular Imaging Key Laboratory Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, P. R. China
| | - Peiwu Li
- Oil Crops Research Institute of Chinese Academy of Agricultural Sciences, National Reference Laboratory for Agricultural Testing (Biotoxin), Key Laboratory of Biology and Genetic Improvement of Oil Crops, Key Laboratory of Detection for Mycotoxins, Ministry of Agriculture and Rural Affairs, Wuhan, 430062, P. R. China
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford School of Medicine, Palo Alto, CA, 94304, USA
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Buschard K. The etiology and pathogenesis of type 1 diabetes - A personal, non-systematic review of possible causes, and interventions. Front Endocrinol (Lausanne) 2022; 13:876470. [PMID: 36093076 PMCID: PMC9452747 DOI: 10.3389/fendo.2022.876470] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
In this review after a lifelong research career, my personal opinion on the development of type 1 diabetes (T1D) from its very start to clinical manifestation will be described. T1D is a disease of an increased intestinal permeability and a reduced pancreas volume. I am convinced that virus might be the initiator and that this virus could persist on strategically significant locations. Furthermore, intake of gluten is important both in foetal life and at later ages. Disturbances in sphingolipid metabolism may also be of crucial importance. During certain stages of T1D, T cells take over resulting in the ultimate destruction of beta cells, which manifests T1D as an autoimmune disease. Several preventive and early treatment strategies are mentioned. All together this review has more new theories than usually, and it might also be more speculative than ordinarily. But without new ideas and theories advancement is difficult, even though everything might not hold true during the continuous discovery of the etiology and pathogenesis of T1D.
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19
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Houeiss P, Luce S, Boitard C. Environmental Triggering of Type 1 Diabetes Autoimmunity. Front Endocrinol (Lausanne) 2022; 13:933965. [PMID: 35937815 PMCID: PMC9353023 DOI: 10.3389/fendo.2022.933965] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
- *Correspondence: Christian Boitard,
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20
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Oikarinen S, Krogvold L, Edwin B, Buanes T, Korsgren O, Laiho JE, Oikarinen M, Ludvigsson J, Skog O, Anagandula M, Frisk G, Hyöty H, Dahl-Jørgensen K. Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study. Diabetologia 2021; 64:2491-2501. [PMID: 34390364 PMCID: PMC8494699 DOI: 10.1007/s00125-021-05525-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/22/2021] [Indexed: 02/05/2023]
Abstract
AIMS/HYPOTHESIS The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24-35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported. METHODS In the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals. RESULTS All six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EV-negative in all individuals. Sequencing the 5' untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines. CONCLUSIONS/INTERPRETATION EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.
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Affiliation(s)
- Sami Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
| | - Lars Krogvold
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Bjørn Edwin
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- The Intervention Centre, Department of HPB Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Trond Buanes
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo University Hospital, Oslo, Norway
- Division of Cancer, Surgery and Transplantation, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maarit Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Johnny Ludvigsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Oskar Skog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Mahesh Anagandula
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Gun Frisk
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Knut Dahl-Jørgensen
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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21
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Quinn LM, Wong FS, Narendran P. Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality. Front Immunol 2021; 12:737964. [PMID: 34659229 PMCID: PMC8518604 DOI: 10.3389/fimmu.2021.737964] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.
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Affiliation(s)
- Lauren M Quinn
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F Susan Wong
- Department of Diabetes, University Hospitals of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Parth Narendran
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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22
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Morse ZJ, Horwitz MS. Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes. Front Immunol 2021; 12:751337. [PMID: 34721424 PMCID: PMC8554326 DOI: 10.3389/fimmu.2021.751337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
In addition to genetic predisposition, environmental determinants contribute to a complex etiology leading to onset of type 1 diabetes (T1D). Multiple studies have established the gut as an important site for immune modulation that can directly impact development of autoreactive cell populations against pancreatic self-antigens. Significant efforts have been made to unravel how changes in the microbiome function as a contributor to autoimmune responses and can serve as a biomarker for diabetes development. Large-scale longitudinal studies reveal that common environmental exposures precede diabetes pathology. Virus infections, particularly those associated with the gut, have been prominently identified as risk factors for T1D development. Evidence suggests recent-onset T1D patients experience pre-existing subclinical enteropathy and dysbiosis leading up to development of diabetes. The start of these dysbiotic events coincide with detection of virus infections. Thus viral infection may be a contributing driver for microbiome dysbiosis and disruption of intestinal homeostasis prior to T1D onset. Ultimately, understanding the cross-talk between viral infection, the microbiome, and the immune system is key for the development of preventative measures against T1D.
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Affiliation(s)
| | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
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23
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Faulkner CL, Luo YX, Isaacs S, Rawlinson WD, Craig ME, Kim KW. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies. Rev Med Virol 2021; 31:1-14. [PMID: 33378601 PMCID: PMC8518965 DOI: 10.1002/rmv.2209] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022]
Abstract
Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the 'virome') and IA/T1D using metagenomic next-generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta-analysis of human observational studies from Medline and EMBASE (published 2000-June 2020), without language restriction. Inclusion criteria were as follows: cohort and case-control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle-Ottawa scale were used for study appraisal. Meta-analysis for exposure to specific viruses was performed using random-effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case-control, nine nested case-control) included 1,425 participants (695 cases, 730 controls) and examined IA (n = 1,023) or T1D (n = 402). Meta-analysis identified small but significant associations between IA and number of stool samples positive for all enteroviruses (OR 1.14, 95% CI 1.00-1.29, p = 0.05; heterogeneity χ2 = 1.51, p = 0.68, I2 = 0%), consecutive positivity for enteroviruses (1.55, 1.09-2.20, p = 0.01; χ2 = 0.19, p = 0.91, I2 = 0%) and number of stool samples positive specifically for enterovirus B (1.20, 1.01-1.42, p = 0.04; χ2 = 0.03, p = 0.86, I2 = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent sampling and follow-up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.
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Affiliation(s)
- Clare L. Faulkner
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Yi Xuan Luo
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Sonia Isaacs
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - William D. Rawlinson
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- School of Medical SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Faculty of ScienceSchool of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Maria E. Craig
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- Institute of Endocrinology and DiabetesChildren's Hospital at WestmeadSydneyNew South WalesAustralia
- Discipline of Child and Adolescent HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Ki Wook Kim
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
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24
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Moody R, Wilson K, Flanagan KL, Jaworowski A, Plebanski M. Adaptive Immunity and the Risk of Autoreactivity in COVID-19. Int J Mol Sci 2021; 22:ijms22168965. [PMID: 34445670 PMCID: PMC8396528 DOI: 10.3390/ijms22168965] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/03/2021] [Accepted: 08/17/2021] [Indexed: 12/14/2022] Open
Abstract
While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body's adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection.
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Affiliation(s)
- Rhiane Moody
- School of Health and Biomedical Science, RMIT University, Bundoora, VIC 3083, Australia; (R.M.); (K.W.); (K.L.F.); (A.J.)
| | - Kirsty Wilson
- School of Health and Biomedical Science, RMIT University, Bundoora, VIC 3083, Australia; (R.M.); (K.W.); (K.L.F.); (A.J.)
| | - Katie L. Flanagan
- School of Health and Biomedical Science, RMIT University, Bundoora, VIC 3083, Australia; (R.M.); (K.W.); (K.L.F.); (A.J.)
- Tasmanian Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Launceston, TAS 7250, Australia
- School of Medicine, University of Tasmania, Launceston, TAS 7250, Australia
- Department of Immunology and Pathology, Monash University, Melbourne, VIC 3004, Australia
| | - Anthony Jaworowski
- School of Health and Biomedical Science, RMIT University, Bundoora, VIC 3083, Australia; (R.M.); (K.W.); (K.L.F.); (A.J.)
| | - Magdalena Plebanski
- School of Health and Biomedical Science, RMIT University, Bundoora, VIC 3083, Australia; (R.M.); (K.W.); (K.L.F.); (A.J.)
- Correspondence:
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25
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Isaacs SR, Foskett DB, Maxwell AJ, Ward EJ, Faulkner CL, Luo JYX, Rawlinson WD, Craig ME, Kim KW. Viruses and Type 1 Diabetes: From Enteroviruses to the Virome. Microorganisms 2021; 9:microorganisms9071519. [PMID: 34361954 PMCID: PMC8306446 DOI: 10.3390/microorganisms9071519] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022] Open
Abstract
For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.
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Affiliation(s)
- Sonia R. Isaacs
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Dylan B. Foskett
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Anna J. Maxwell
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Emily J. Ward
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Clare L. Faulkner
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Jessica Y. X. Luo
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - William D. Rawlinson
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
- Faculty of Science, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Maria E. Craig
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Institute of Endocrinology and Diabetes, Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Ki Wook Kim
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Correspondence: ; Tel.: +61-2-9382-9096
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26
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Fuhri Snethlage CM, Nieuwdorp M, Hanssen NMJ. Faecal microbiota transplantation in endocrine diseases and obesity. Best Pract Res Clin Endocrinol Metab 2021; 35:101483. [PMID: 33414033 DOI: 10.1016/j.beem.2020.101483] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The prevalence of type 1 (T1D) and type 2 diabetes mellitus (T2D) has greatly increased worldwide over the last century. Although the exact pathophysiology of both these conditions is distinct and still largely unknown, T1D as well as T2D, have been linked to distinct perturbations of the gut microbiome. Faecal microbiota transplantation (FMT) is a potent, and if performed well, a safe method to modulate the composition of the gut microbiome and thus positively influences the course of these hyperglycaemic conditions in humans. In this review, we provide an overview of how FMT is commonly performed and summarise how this procedure may reduce the insulin-resistance driving T2D, and the underlying auto-immunity driving T1D. Insights derived from FMT studies in T1D and T2D may help identify beneficial microbiota and associated metabolites that may serve as future treatments for these conditions.
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Affiliation(s)
- Coco M Fuhri Snethlage
- Amsterdam Diabetes Centrum, Internal and Vascular Medicine, Amsterdam UMC, Location AMC, the Netherlands
| | - Max Nieuwdorp
- Amsterdam Diabetes Centrum, Internal and Vascular Medicine, Amsterdam UMC, Location AMC, the Netherlands
| | - Nordin M J Hanssen
- Amsterdam Diabetes Centrum, Internal and Vascular Medicine, Amsterdam UMC, Location AMC, the Netherlands.
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27
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Type I interferons as key players in pancreatic β-cell dysfunction in type 1 diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:1-80. [PMID: 33832648 DOI: 10.1016/bs.ircmb.2021.02.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet inflammation (insulitis) and specific pancreatic β-cell destruction by an immune attack. Although the precise underlying mechanisms leading to the autoimmune assault remain poorly understood, it is well accepted that insulitis takes place in the context of a conflicting dialogue between pancreatic β-cells and the immune cells. Moreover, both host genetic background (i.e., candidate genes) and environmental factors (e.g., viral infections) contribute to this inadequate dialogue. Accumulating evidence indicates that type I interferons (IFNs), cytokines that are crucial for both innate and adaptive immune responses, act as key links between environmental and genetic risk factors in the development of T1D. This chapter summarizes some relevant pathways involved in β-cell dysfunction and death, and briefly reviews how enteroviral infections and genetic susceptibility can impact insulitis. Moreover, we present the current evidence showing that, in β-cells, type I IFN signaling pathway activation leads to several outcomes, such as long-lasting major histocompatibility complex (MHC) class I hyperexpression, endoplasmic reticulum (ER) stress, epigenetic changes, and induction of posttranscriptional as well as posttranslational modifications. MHC class I overexpression, when combined with ER stress and posttranscriptional/posttranslational modifications, might lead to sustained neoantigen presentation to immune system and β-cell apoptosis. This knowledge supports the concept that type I IFNs are implicated in the early stages of T1D pathogenesis. Finally, we highlight the promising therapeutic avenues for T1D treatment directed at type I IFN signaling pathway.
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28
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Ruohtula T, Kondrashova A, Lehtonen J, Oikarinen S, Hämäläinen AM, Niemelä O, Peet A, Tillmann V, Nieminen JK, Ilonen J, Knip M, Vaarala O, Hyöty H. Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life. Front Immunol 2021; 11:567046. [PMID: 33643278 PMCID: PMC7905218 DOI: 10.3389/fimmu.2020.567046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 12/29/2020] [Indexed: 11/13/2022] Open
Abstract
Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.
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Affiliation(s)
| | - Anita Kondrashova
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jussi Lehtonen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Sami Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anu-Maaria Hämäläinen
- Department of Pediatrics, Jorvi Hospital, Helsinki University Hospital, Espoo, Finland
| | - Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland
| | - Aleksandr Peet
- Department of Pediatrics, University of Tartu and Tartu University Hospital, Tartu, Estonia
| | - Vallo Tillmann
- Department of Pediatrics, University of Tartu and Tartu University Hospital, Tartu, Estonia
| | - Janne K Nieminen
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, University of Turku, Turku, Finland
| | - Mikael Knip
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Folkhälsan Research Center, Helsinki, Finland.,Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Outi Vaarala
- Clinicum, University of Helsinki, Helsinki, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
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Wang K, Ye F, Chen Y, Xu J, Zhao Y, Wang Y, Lan T. Association Between Enterovirus Infection and Type 1 Diabetes Risk: A Meta-Analysis of 38 Case-Control Studies. Front Endocrinol (Lausanne) 2021; 12:706964. [PMID: 34557158 PMCID: PMC8453141 DOI: 10.3389/fendo.2021.706964] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The association between enterovirus infection and type 1 diabetes (T1D) is controversial, and this meta-analysis aimed to explore the correlation. METHODS PubMed, Embase, Web of Science, and Cochrane Database were searched from inception to April 2020. Studies were included if they could provide sufficient information to calculate odds ratios and 95% confidence intervals. All analyses were performed using STATA 15.1. RESULTS Thirty-eight studies, encompassing 5921 subjects (2841 T1D patients and 3080 controls), were included. The pooled analysis showed that enterovirus infection was associated with T1D (P < 0.001). Enterovirus infection was correlated with T1D in the European (P < 0.001), African (P = 0.002), Asian (P = 0.001), Australian (P = 0.011), and Latin American (P = 0.002) populations, but no conclusion could be reached for North America. The association between enterovirus infection and T1D was detected in blood and tissue samples (both P < 0.001); no association was found in stool samples. CONCLUSION Our findings suggest that enterovirus infection is associated with T1D.
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Affiliation(s)
- Kan Wang
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
- *Correspondence: Kan Wang, ; Fei Ye,
| | - Fei Ye
- First Department of Neurology, Affiliated Jinhua Hospital, Jinhua Municipal Central Hospital, Zhejiang University School of Medicine, Jinhua, China
- *Correspondence: Kan Wang, ; Fei Ye,
| | - Yong Chen
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Jianxin Xu
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Yufang Zhao
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Yeping Wang
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Tian Lan
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
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Elhag DA, Kumar M, Al Khodor S. Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes. Int J Mol Sci 2020; 22:ijms22010125. [PMID: 33374418 PMCID: PMC7795494 DOI: 10.3390/ijms22010125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.
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31
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Stafford JD, Shaheen ZR, Yeo CT, Corbett JA. Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects β-cells from virally mediated lysis. J Biol Chem 2020; 295:16655-16664. [PMID: 32972972 PMCID: PMC7864063 DOI: 10.1074/jbc.ra120.014851] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/06/2020] [Indexed: 12/15/2022] Open
Abstract
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide-dependent manner.
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Affiliation(s)
- Joshua D Stafford
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Zachary R Shaheen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Bélteky M, Wahlberg J, Ludvigsson J. Maternal respiratory infections in early pregnancy increases the risk of type 1 diabetes. Pediatr Diabetes 2020; 21:1193-1201. [PMID: 32621562 DOI: 10.1111/pedi.13075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/28/2020] [Accepted: 06/28/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND/OBJECTIVE Is exposure to maternal infections and use of antibiotics in the prenatal period associated with increased risk of T1D, regardless of genetic risk? METHODS Data on infections and use of antibiotics during pregnancy were collected from questionnaires at birth from parents to 16 292 children in the All Babies in Southeast Sweden (ABIS) cohort and validated against national diagnosis registers. As of November 2017, 137 ABIS children had developed T1D, 72 boys and 65 girls (0.8% of the original cohort). RESULTS More cases were born in spring and summer than fall and winter. However, onset of T1D appeared to be more common in either summer or winter. In univariate analyses, respiratory tract infection in the first trimester (P = .002) and gastroenteritis during pregnancy (P = .04) were associated with later risk of T1D in the offspring. Other types of infection or antibiotic treatment were not associated with an increased risk. In a multiple logistic regression model, a mother with an autoimmune disease (P < .001), father with T1D (P < .001) and respiratory tract infection during the first trimester (P = .005) remained as risk factors for T1D in the offspring. In children with neutral HLA alleles antibiotic treatment may increase the risk of T1D (P = .01, OR 3.46, 95% CI 1.25-9.55). CONCLUSIONS In the general population there seems to be an association between seasonal maternal respiratory tract infection in the first trimester of pregnancy and later risk of T1D in the offspring. HLA may play a role for the effect of exposure to infections and antibiotics.
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Affiliation(s)
- Malin Bélteky
- Crown Princess Victoria's Children´s Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Jeanette Wahlberg
- Department of Endocrinology Region Östergötland, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Johnny Ludvigsson
- Crown Princess Victoria's Children´s Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Andersson Svärd A, Kaur S, Trôst K, Suvitaival T, Lernmark Å, Maziarz M, Pociot F, Overgaard AJ. Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort. Metabolomics 2020; 16:109. [PMID: 33033923 PMCID: PMC7544716 DOI: 10.1007/s11306-020-01730-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 09/25/2020] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet beta cells resulting in total loss of insulin production. Recent studies have suggested that the destruction may be interrelated to plasma lipids. OBJECTIVES Specific lipids have previously been shown to be decreased in children who develop T1D before four years of age. Disturbances of plasma lipids prior to clinical diagnosis of diabetes, if true, may provide a novel way to improve prediction, and monitor disease progression. METHODS A lipidomic approach was utilized to analyze plasma from 67 healthy adolescent subjects (10-15 years of age) with or without islet autoantibodies but all with increased genetic risk for T1D. The study subjects were enrolled at birth in the Diabetes Prediction in Skåne (DiPiS) study and after 10-15 years of follow-up we performed the present cross-sectional analysis. HLA-DRB345, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genotypes were determined using next generation sequencing. Lipidomic profiles were determined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Lipidomics data were analyzed according to genotype. RESULTS Variation in levels of several specific phospholipid species were related to level of autoimmunity but not development of T1D. Five glycosylated ceramides were increased in insulin autoantibody (IAA) positive adolescent subjects compared to adolescent subjects without this autoantibody. Additionally, HLA genotypes seemed to influence levels of long chain triacylglycerol (TG). CONCLUSION Lipidomic profiling of adolescent subjects in high risk of T1D may improve sub-phenotyping in this high risk population.
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Affiliation(s)
- Agnes Andersson Svärd
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden.
| | - Simranjeet Kaur
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Kajetan Trôst
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Tommi Suvitaival
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Åke Lernmark
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden
| | - Marlena Maziarz
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden
| | - Flemming Pociot
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Sane F, Bertin A, Sioofy-Khojine AB, Oikarinen S, Alidjinou EK, Veijola R, Toppari J, Ilonen J, Knip M, Engelmann I, Hyöty H, Hober D. Enhancing and neutralizing anti-coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes. Diabetes Metab Res Rev 2020; 36:e3305. [PMID: 32118346 DOI: 10.1002/dmrr.3305] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/03/2020] [Accepted: 02/25/2020] [Indexed: 01/12/2023]
Abstract
BACKGROUND Studies in prospective cohorts have suggested that enterovirus infections are associated with the appearance of islet autoantibodies that precede later appearance of type 1 diabetes (T1D). It was shown that in addition to an antibody-mediated anti-coxsackievirus (CV)-B neutralizing activity of serum from patients with T1D, there was also enhancing anti-CV-B activity in vitro. In this study, the patterns of enhancing and neutralizing anti-CV activities were analysed from consecutive serum samples collected from children who were followed from birth until they developed T1D in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and compared to those in non-diabetic control children. METHODS The titres of serum neutralizing activity were analysed against those CVs which were detected in the stools in these children (CV-B3, CV-B5 or CV-A4) using plaque assay. The enhancing activity of these serum samples was analysed by measuring interferon-alpha (INF-α) production in cultures of peripheral blood mononuclear cells (PBMC) inoculated with a mixture of these viruses and diluted serum. RESULTS A sustained anti-CV enhancing activity was observed in consecutive serum samples in patients with T1D. The pattern of responses differed between children who developed T1D and control children. In patients, the anti-CV enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralising activities were more balanced or the neutralizing activity was largely predominant. CONCLUSIONS Evaluating the anti-enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D.
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MESH Headings
- Adolescent
- Antibodies, Neutralizing/blood
- Antibodies, Neutralizing/immunology
- Autoantibodies/blood
- Autoantibodies/immunology
- Biomarkers/blood
- Child
- Child, Preschool
- Coxsackievirus Infections/immunology
- Coxsackievirus Infections/virology
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/virology
- Enterovirus B, Human/immunology
- Enterovirus B, Human/isolation & purification
- Female
- Finland/epidemiology
- Follow-Up Studies
- Humans
- Immunoglobulin G/blood
- Immunoglobulin G/immunology
- Infant
- Infant, Newborn
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/virology
- Male
- Prognosis
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Affiliation(s)
- Famara Sane
- Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France
| | - Antoine Bertin
- Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France
| | - Amir-Babak Sioofy-Khojine
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Sami Oikarinen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Enagnon K Alidjinou
- Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France
| | - Riitta Veijola
- Department of Paediatrics, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Toppari
- Department of Pediatrics, Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku University Hospital, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Mikael Knip
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Tampere Centre for Child Health Research, Tampere University Hospital, Tampere, Finland
- Folkhälsan Research Centre, Helsinki, Finland
| | - Ilka Engelmann
- Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Didier Hober
- Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France
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Poma AM, Genoni A, Broccolo F, Denaro M, Pugliese A, Basolo F, Toniolo A. Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes. Microorganisms 2020; 8:microorganisms8071031. [PMID: 32664675 PMCID: PMC7409211 DOI: 10.3390/microorganisms8071031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022] Open
Abstract
Enterovirus (EV) infection of insulin-producing pancreatic beta cells is associated with type 1 diabetes (T1D), but little is known about the mechanisms that lead the virus to cause a persistent infection and, possibly, to induce beta cell autoimmunity. A cell line susceptible to most enterovirus types was infected with EV isolates from cases of T1D and, for comparison, with a replication-competent strain of coxsackievirus B3. The transcription of immune-related genes and secretion of cytokines was evaluated in infected vs. uninfected cells. Acutely infected cells showed the preserved transcription of type I interferon (IFN) pathways and the enhanced transcription/secretion of IL6, IL8, LIF, MCP1, and TGFB1. On the other hand, infection by defective EV strains obtained from diabetic subjects suppressed IFN pathways and the transcription of most cytokines, while enhancing the expression of IL8, IL18, IL32, and MCP1. IL18 and IL32 are known for their pathogenic role in autoimmune diabetes. Thus, the cytokine profile of AV3 cells infected by diabetes-derived EV strains closely matches that observed in patients at the early stages of T1D. The concordance of our results with clinically verified information reinforces the hypothesis that the immune changes observed in type 1 diabetic patients are due to a hardly noticeable virus infection.
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Affiliation(s)
- Anello Marcello Poma
- Department of Surgical, Medical, Molecular Pathology and Clinical Area, University of Pisa, 56126 Pisa, Italy; (M.D.); (F.B.)
- Correspondence:
| | - Angelo Genoni
- Medical Microbiology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (A.G.); (A.T.)
| | - Francesco Broccolo
- Medical Microbiology, Department of Medical Sciences, University Milano Bicocca, 20126 Milano, Italy;
| | - Maria Denaro
- Department of Surgical, Medical, Molecular Pathology and Clinical Area, University of Pisa, 56126 Pisa, Italy; (M.D.); (F.B.)
| | - Alberto Pugliese
- Diabetes Research Institute, University of Miami, Miami, FL 33136, USA;
| | - Fulvio Basolo
- Department of Surgical, Medical, Molecular Pathology and Clinical Area, University of Pisa, 56126 Pisa, Italy; (M.D.); (F.B.)
| | - Antonio Toniolo
- Medical Microbiology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (A.G.); (A.T.)
- Global Virus Network, 21100 Varese, Italy
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Andersson Svärd A, Maziarz M, Ramelius A, Lundgren M, Lernmark Å, Elding Larsson H. Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies. J Transl Autoimmun 2020; 3:100052. [PMID: 32743532 PMCID: PMC7388396 DOI: 10.1016/j.jtauto.2020.100052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/02/2020] [Indexed: 12/18/2022] Open
Abstract
The risk for type 1 diabetes is strongly associated with HLA-DQ and the appearance of beta cell autoantibodies against either insulin, glutamate decarboxylase (GAD65), insulinoma-associated protein-2 (IA-2), or zinc transporter 8 (ZnT8). Prolonged exposure to autoantibodies may be related to T cell exhaustion known to occur in chronic infections or autoimmune disorders. It was hypothesized that autoantibody exposure may affect HLA-DQ expression on peripheral blood cells and thereby contribute to T cell exhaustion thought to be associated with the pathogenesis of type 1 diabetes. The aim of this study was to determine whether autoantibody exposure as an expression of autoimmunity burden was related to peripheral blood cell HLA-DQ cell surface expression in either 1) a cross-sectional analysis or 2) cumulative as area under the trajectory of autoantibodies during long term follow-up in the Diabetes Prediction in Skåne (DiPiS) study. Children (n = 67), aged 10–15 years were analyzed for complete blood count, HLA-DQ cell surface median fluorescence intensity (MFI), autoantibody frequency, and HLA genotypes by Next Generation Sequencing. Decreased HLA-DQ cell surface MFI with an increasing number of autoantibodies was observed in CD16+, CD14+CD16−, CD4+ and CD8+ cells but not in CD19+ cells and neutrophils. HLA-DQ cell surface MFI was associated with HLA-DQ2/8 in CD4+ T cells, marginally in CD14+CD16− monocytes and CD8+ T cells. These associations appeared to be related to autoimmunity burden. The results suggest that HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
PBMC HLA-DQ surface expression in beta cell autoimmunity is poorly understood. Children, 10–15 years of age without or with beta cell autoantibodies were analyzed. HLA-DQ cell surface expression decreased with increasing number of autoantibodies. HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
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Affiliation(s)
- Agnes Andersson Svärd
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Marlena Maziarz
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Anita Ramelius
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Markus Lundgren
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
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Kim KW, Allen DW, Briese T, Couper JJ, Barry SC, Colman PG, Cotterill AM, Davis EA, Giles LC, Harrison LC, Harris M, Haynes A, Horton JL, Isaacs SR, Jain K, Lipkin WI, McGorm K, Morahan G, Morbey C, Pang ICN, Papenfuss AT, Penno MAS, Sinnott RO, Soldatos G, Thomson RL, Vuillermin P, Wentworth JM, Wilkins MR, Rawlinson WD, Craig ME. Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes. Pediatr Diabetes 2020; 21:271-279. [PMID: 31800147 DOI: 10.1111/pedi.12952] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 11/07/2019] [Accepted: 11/10/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. METHODS Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. RESULTS Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of samples and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. CONCLUSIONS We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.
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Affiliation(s)
- Ki Wook Kim
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Digby W Allen
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Thomas Briese
- Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| | - Jennifer J Couper
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Simon C Barry
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Peter G Colman
- Department of Diabetes and Endocrinology, The Royal Melbourne Hospital Victoria, Melbourne, Victoria, Australia
| | - Andrew M Cotterill
- Department of Endocrinology, Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - Elizabeth A Davis
- Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Lynne C Giles
- School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Leonard C Harrison
- Walter and Eliza Hall Institute and Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Mark Harris
- Department of Endocrinology, Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - Aveni Haynes
- Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Jessica L Horton
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Sonia R Isaacs
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Komal Jain
- Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| | - Walter I Lipkin
- Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| | - Kelly McGorm
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Grant Morahan
- Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia
| | - Claire Morbey
- Hunter Diabetes Centre, Newcastle, New South Wales, Australia
| | - Ignatius C N Pang
- School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Anthony T Papenfuss
- Walter and Eliza Hall Institute and Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Megan A S Penno
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Richard O Sinnott
- Department of Computing and Information Systems, University of Melbourne, Melbourne, Victoria, Australia
| | - Georgia Soldatos
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Rebecca L Thomson
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Peter Vuillermin
- School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - John M Wentworth
- Walter and Eliza Hall Institute and Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Marc R Wilkins
- School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales, Australia
| | - William D Rawlinson
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.,Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Maria E Craig
- School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
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Norris JM, Johnson RK, Stene LC. Type 1 diabetes-early life origins and changing epidemiology. Lancet Diabetes Endocrinol 2020; 8:226-238. [PMID: 31999944 PMCID: PMC7332108 DOI: 10.1016/s2213-8587(19)30412-7] [Citation(s) in RCA: 194] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022]
Abstract
Type 1 diabetes is a chronic, immune-mediated disease characterised by the destruction of insulin-producing cells. Standardised registry data show that type 1 diabetes incidence has increased 3-4% over the past three decades, supporting the role of environmental factors. Although several factors have been associated with type 1 diabetes, none of the associations are of a magnitude that could explain the rapid increase in incidence alone. Moreover, evidence of changing prevalence of these exposures over time is insufficient. Multiple factors could simultaneously explain the changing type 1 diabetes incidence, or the magnitude of observed associations could have been underestimated because of exposure measurement error, or the mismodelling of complex exposure-time-response relationships. The identification of environmental factors influencing the risk of type 1 diabetes and increased understanding of the cause at the individual level, regardless of the ability to explain the changing incidence at the population level, is important because of the implications for prevention.
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Affiliation(s)
- Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA.
| | - Randi K Johnson
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Lars C Stene
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
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39
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Dean JW, Peters LD, Fuhrman CA, Seay HR, Posgai AL, Stimpson SE, Brusko MA, Perry DJ, Yeh WI, Newby BN, Haller MJ, Muir AB, Atkinson MA, Mathews CE, Brusko TM. Innate inflammation drives NK cell activation to impair Treg activity. J Autoimmun 2020; 108:102417. [PMID: 32035746 PMCID: PMC7086400 DOI: 10.1016/j.jaut.2020.102417] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 12/17/2022]
Abstract
IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We investigated the influence of these cytokines on immune cells involved in human T1D progression: natural killer (NK) cells, regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTL). NK cells from T1D patients exhibited higher surface CD226 versus controls and lower CD25 compared to first-degree relatives and controls. Changes in NK cell phenotype towards terminal differentiation were associated with cytomegalovirus (CMV) seropositivity, while possession of IL18RAP, IFIH1, and IL2RA T1D-risk variants impacted NK cell activation as evaluated by immuno-expression quantitative trait loci (eQTL) analyses. IL-12 and IL-18 stimulated NK cells from healthy donors exhibited enhanced specific killing of myelogenous K562 target cells. Moreover, activated NK cells increased expression of NKG2A, NKG2D, CD226, TIGIT and CD25, which enabled competition for IL-2 upon co-culture with Tregs, resulting in Treg downregulation of FOXP3, production of IFNγ, and loss of suppressive function. We generated islet-autoreactive CTL "avatars", which upon exposure to IL-12 and IL-18, upregulated IFNγ and Granzyme-B leading to increased lymphocytotoxicity of a human β-cell line in vitro. These results support a model for T1D pathogenesis wherein IL-12 and IL-18 synergistically enhance CTL and NK cell cytotoxic activity and disrupt immunoregulation by Tregs.
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MESH Headings
- Adolescent
- Adult
- Biomarkers
- Cells, Cultured
- Child
- Cytokines/metabolism
- Cytotoxicity, Immunologic
- Diabetes Mellitus, Type 1/etiology
- Diabetes Mellitus, Type 1/metabolism
- Disease Susceptibility
- Female
- Humans
- Immunity, Innate
- Immunophenotyping
- Inflammation/immunology
- Inflammation/metabolism
- Inflammation/pathology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Lymphocyte Activation/immunology
- Lymphocyte Count
- Male
- Middle Aged
- Models, Biological
- Phenotype
- Quantitative Trait Loci
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Young Adult
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Affiliation(s)
- Joseph W Dean
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Infectious Disease and Immunology, University of Florida, Gainesville, FL, USA
| | - Leeana D Peters
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Christopher A Fuhrman
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; NanoString Technologies, Seattle, WA, USA
| | - Howard R Seay
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; BD Biosciences, Ashland, OR, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Scott E Stimpson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Maigan A Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Daniel J Perry
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Wen-I Yeh
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; BD Biosciences, Ashland, OR, USA
| | - Brittney N Newby
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Fate Therapeutics, San Diego, CA, USA
| | - Michael J Haller
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Andrew B Muir
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Mark A Atkinson
- Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - Clayton E Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA; Department of Pediatrics, University of Florida, Gainesville, FL, USA.
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40
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Vehik K, Lynch KF, Wong MC, Tian X, Ross MC, Gibbs RA, Ajami NJ, Petrosino JF, Rewers M, Toppari J, Ziegler AG, She JX, Lernmark A, Akolkar B, Hagopian WA, Schatz DA, Krischer JP, Hyöty H, Lloyd RE. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nat Med 2019; 25:1865-1872. [PMID: 31792456 PMCID: PMC6898786 DOI: 10.1038/s41591-019-0667-0] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 10/25/2019] [Indexed: 12/17/2022]
Abstract
Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect β cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.
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Affiliation(s)
- Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
| | - Kristian F Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Matthew C Wong
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Xiangjun Tian
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Matthew C Ross
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Richard A Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Nadim J Ajami
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph F Petrosino
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, USA
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Anette G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany
- Forschergruppe Diabetes, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- Forschergruppe Diabetes e.V, Munich, Germany
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ake Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University Hospital, Malmö, Sweden
| | - Beena Akolkar
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | | | - Desmond A Schatz
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Jeffrey P Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Richard E Lloyd
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
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41
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Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2019; 15:635-650. [PMID: 31534209 DOI: 10.1038/s41574-019-0254-y] [Citation(s) in RCA: 279] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/13/2019] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.
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Affiliation(s)
- Jorma Ilonen
- Institue of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland.
| | - Johanna Lempainen
- Institue of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland
- Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland
| | - Riitta Veijola
- Department of Paediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
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42
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Kanduc D, Shoenfeld Y. Human Papillomavirus Epitope Mimicry and Autoimmunity: The Molecular Truth of Peptide Sharing. Pathobiology 2019; 86:285-295. [PMID: 31593963 DOI: 10.1159/000502889] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 08/22/2019] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To define the cross-reactivity potential and the consequent autoimmunity intrinsic to viral versus human peptide sharing. METHODS Using human papillomavirus (HPV) infection/active immunization as a research model, the experimentally validated HPV L1 epitopes catalogued at the Immune Epitope DataBase were analyzed for peptide sharing with the human proteome. RESULTS The final data show that the totality of the immunoreactive HPV L1 epi-topes is mostly composed by peptides present in human proteins. CONCLUSIONS Immunologically, the high extent of peptide sharing between the HPV L1 epitopes and human proteins invites to revise the concept of the negative selection of self-reactive lymphocytes. Pathologically, the data highlight a cross-reactive potential for a spectrum of autoimmune diseases that includes ovarian failure, systemic lupus erythematosus (SLE), breast cancer and sudden death, among others. Therapeutically, analyzing already validated immunoreactive epitopes filters out the peptide sharing possibly exempt of self-reactivity, defines the effective potential for pathologic autoimmunity, and allows singling out peptide epitopes for safe immunotherapeutic protocols.
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Affiliation(s)
- Darja Kanduc
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy,
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Affiliated to Tel-Aviv, University School of Medicine, Ramat Gan, Israel.,I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian, Federation, Sechenov University, Moscow, Russian Federation
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43
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Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses 2019; 11:v11080762. [PMID: 31430946 PMCID: PMC6723519 DOI: 10.3390/v11080762] [Citation(s) in RCA: 342] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 07/27/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.
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Dunne JL, Richardson SJ, Atkinson MA, Craig ME, Dahl-Jørgensen K, Flodström-Tullberg M, Hyöty H, Insel RA, Lernmark Å, Lloyd RE, Morgan NG, Pugliese A. Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia 2019; 62:744-753. [PMID: 30675626 PMCID: PMC6450860 DOI: 10.1007/s00125-019-4811-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.
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Affiliation(s)
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
| | - Mark A Atkinson
- Departments of Pathology and Pediatrics, University of Florida, College of Medicine, Gainesville, FL, USA
| | - Maria E Craig
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Knut Dahl-Jørgensen
- Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Heikki Hyöty
- Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | | | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
| | - Richard E Lloyd
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Noel G Morgan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK
| | - Alberto Pugliese
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
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Bano A, Pera A, Almoukayed A, Clarke THS, Kirmani S, Davies KA, Kern F. CD28 null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection. F1000Res 2019; 8. [PMID: 30984377 PMCID: PMC6436193 DOI: 10.12688/f1000research.17119.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2019] [Indexed: 01/03/2023] Open
Abstract
Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28
null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28
null CD4 T cells.
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Affiliation(s)
- Aalia Bano
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
| | - Alejandra Pera
- Department of Immunology, Maimonides Institute for Biomedical Research (IMIBIC), Reina Sofia Hospital, University of Cordoba, Av. Menendez Pidal, 14004, Cordoba, Spain
| | - Ahmad Almoukayed
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
| | - Thomas H S Clarke
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
| | - Sukaina Kirmani
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
| | - Kevin A Davies
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
| | - Florian Kern
- Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK
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46
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Kahrs CR, Chuda K, Tapia G, Stene LC, Mårild K, Rasmussen T, Rønningen KS, Lundin KEA, Kramna L, Cinek O, Størdal K. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ 2019; 364:l231. [PMID: 30760441 PMCID: PMC6372922 DOI: 10.1136/bmj.l231] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To determine whether infection with human enterovirus or adenovirus, both common intestinal viruses, predicts development of coeliac disease. DESIGN Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016. SETTING Norwegian population. PARTICIPANTS Children carrying the HLA genotype DR4-DQ8/DR3-DQ2 conferring increased risk of coeliac disease. EXPOSURES Enterovirus and adenovirus detected using real time polymerase chain reaction in monthly stool samples from age 3 to 36 months. MAIN OUTCOME MEASURE Coeliac disease diagnosed according to standard criteria. Coeliac disease antibodies were tested in blood samples taken at age 3, 6, 9, and 12 months and then annually. Adjusted odds ratios from mixed effects logistic regression model were used to assess the relation between viral infections before development of coeliac disease antibodies and coeliac disease. RESULTS Among 220 children, and after a mean of 9.9 (SD 1.6) years, 25 children were diagnosed as having coeliac disease after screening and were matched to two controls each. Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls (adjusted odds ratio 1.49, 95% confidence interval 1.07 to 2.06; P=0.02). The association was restricted to infections after introduction of gluten. High quantity samples (>100 000 copies/μL) (adjusted odds ratio 2.11, 1.24 to 3.60; P=0.01) and long lasting infections (>2 months) (2.16, 1.16 to 4.04; P=0.02) gave higher risk estimates. Both the commonly detected enterovirus species Enterovirus A and Enterovirus B were significantly associated with coeliac disease. The association was not found for infections during or after development of coeliac disease antibodies. Adenovirus was not associated with coeliac disease. CONCLUSIONS In this longitudinal study, a higher frequency of enterovirus, but not adenovirus, during early childhood was associated with later coeliac disease. The finding adds new information on the role of viral infections in the aetiology of coeliac disease.
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Affiliation(s)
- Christian R Kahrs
- Department of Pediatrics, Østfold Hospital Trust, Grålum, Norway
- Norwegian Institute of Public Health, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Katerina Chuda
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - German Tapia
- Norwegian Institute of Public Health, Oslo, Norway
| | - Lars C Stene
- Norwegian Institute of Public Health, Oslo, Norway
| | - Karl Mårild
- Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Trond Rasmussen
- Department of IT and e-health, Division of Institute Resources, Norwegian Institute of Public Health, Oslo, Norway
| | | | - Knut E A Lundin
- Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
| | - Lenka Kramna
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Ondrej Cinek
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Ketil Størdal
- Department of Pediatrics, Østfold Hospital Trust, Grålum, Norway
- Norwegian Institute of Public Health, Oslo, Norway
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47
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Kim KW, Horton JL, Pang CNI, Jain K, Leung P, Isaacs SR, Bull RA, Luciani F, Wilkins MR, Catteau J, Lipkin WI, Rawlinson WD, Briese T, Craig ME. Higher abundance of enterovirus A species in the gut of children with islet autoimmunity. Sci Rep 2019; 9:1749. [PMID: 30741981 PMCID: PMC6370883 DOI: 10.1038/s41598-018-38368-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 12/19/2018] [Indexed: 12/16/2022] Open
Abstract
Enteroviruses (EVs) are prime candidate environmental triggers of islet autoimmunity (IA), with potential as vaccine targets for type 1 diabetes prevention. However, the use of targeted virus detection methods and the selective focus on EVs by most studies increases the risk for substantial investigation bias and an overestimated association between EV and type 1 diabetes. Here we performed comprehensive virome-capture sequencing to examine all known vertebrate-infecting viruses without bias in 182 specimens (faeces and plasma) collected before or at seroconversion from 45 case children with IA and 48 matched controls. From >2.6 billion reads, 28 genera of viruses were detected and 62% of children (58/93) were positive for ≥1 vertebrate-infecting virus. We identified 129 viruses as differentially abundant between the gut of cases and controls, including 5 EV-A types significantly more abundant in the cases. Our findings further support EV’s hypothesised contribution to IA and corroborate the proposal that viral load may be an important parameter in disease pathogenesis. Furthermore, our data indicate a previously unrecognised association of IA with higher EV-A abundance in the gut of children and provide a catalog of viruses to be interrogated further to determine a causal link between virus infection and type 1 diabetes.
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Affiliation(s)
- Ki Wook Kim
- School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, Australia.,Virology Research Laboratory, Prince of Wales Hospital Randwick, Sydney, Australia
| | - Jessica L Horton
- School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, Australia.,Virology Research Laboratory, Prince of Wales Hospital Randwick, Sydney, Australia
| | - Chi Nam Ignatius Pang
- School of Biotechnology and Biomedical Sciences, University of New South Wales Faculty of Science, Sydney, Australia
| | - Komal Jain
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, USA
| | - Preston Leung
- Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales Faculty of Medicine, Sydney, Australia
| | - Sonia R Isaacs
- School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, Australia.,Virology Research Laboratory, Prince of Wales Hospital Randwick, Sydney, Australia
| | - Rowena A Bull
- Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales Faculty of Medicine, Sydney, Australia
| | - Fabio Luciani
- Systems Medicine, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales Faculty of Medicine, Sydney, Australia
| | - Marc R Wilkins
- School of Biotechnology and Biomedical Sciences, University of New South Wales Faculty of Science, Sydney, Australia
| | - Jacki Catteau
- Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Sydney, Australia
| | - W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, USA.,Department of Pathology and Neurology, College of Physicians & Surgeons, Columbia University, New York, USA
| | - William D Rawlinson
- School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, Australia.,Virology Research Laboratory, Prince of Wales Hospital Randwick, Sydney, Australia.,Serology and Virology Division, South Eastern Area Laboratory Services Microbiology, Prince of Wales Hospital, Sydney, Australia
| | - Thomas Briese
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, USA.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA
| | - Maria E Craig
- School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, Australia. .,Virology Research Laboratory, Prince of Wales Hospital Randwick, Sydney, Australia. .,Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Sydney, Australia. .,Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia.
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48
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Rogal J, Zbinden A, Schenke-Layland K, Loskill P. Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 2019; 140:101-128. [PMID: 30359630 DOI: 10.1016/j.addr.2018.10.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/10/2018] [Accepted: 10/19/2018] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) ranks among the severest global health concerns of the 21st century. It encompasses a group of chronic disorders characterized by a dysregulated glucose metabolism, which arises as a consequence of progressive autoimmune destruction of pancreatic beta-cells (type 1 DM), or as a result of beta-cell dysfunction combined with systemic insulin resistance (type 2 DM). Human cohort studies have provided evidence of genetic and environmental contributions to DM; yet, these studies are mostly restricted to investigating statistical correlations between DM and certain risk factors. Mechanistic studies, on the other hand, aimed at re-creating the clinical picture of human DM in animal models. A translation to human biology is, however, often inadequate owing to significant differences between animal and human physiology, including the species-specific glucose regulation. Thus, there is an urgent need for the development of advanced human in vitro models with the potential to identify novel treatment options for DM. This review provides an overview of the technological advances in research on DM-relevant stem cells and their integration into microphysiological environments as provided by the organ-on-a-chip technology.
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Affiliation(s)
- Julia Rogal
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
| | - Aline Zbinden
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany
| | - Katja Schenke-Layland
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany; Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, 675 Charles E. Young Drive South, MRL 3645, Los Angeles, CA, USA.
| | - Peter Loskill
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
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49
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Wook Kim K, Allen DW, Briese T, Couper JJ, Barry SC, Colman PG, Cotterill AM, Davis EA, Giles LC, Harrison LC, Harris M, Haynes A, Horton JL, Isaacs SR, Jain K, Lipkin WI, Morahan G, Morbey C, Pang ICN, Papenfuss AT, Penno MAS, Sinnott RO, Soldatos G, Thomson RL, Vuillermin PJ, Wentworth JM, Wilkins MR, Rawlinson WD, Craig ME. Distinct Gut Virome Profile of Pregnant Women With Type 1 Diabetes in the ENDIA Study. Open Forum Infect Dis 2019; 6:ofz025. [PMID: 30815502 PMCID: PMC6386807 DOI: 10.1093/ofid/ofz025] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/05/2019] [Accepted: 01/15/2019] [Indexed: 12/11/2022] Open
Abstract
Background The importance of gut bacteria in human physiology, immune regulation, and disease pathogenesis is well established. In contrast, the composition and dynamics of the gut virome are largely unknown; particularly lacking are studies in pregnancy. We used comprehensive virome capture sequencing to characterize the gut virome of pregnant women with and without type 1 diabetes (T1D), longitudinally followed in the Environmental Determinants of Islet Autoimmunity study. Methods In total, 61 pregnant women (35 with T1D and 26 without) from Australia were examined. Nucleic acid was extracted from serial fecal specimens obtained at prenatal visits, and viral genomes were sequenced by virome capture enrichment. The frequency, richness, and abundance of viruses were compared between women with and without T1D. Results Two viruses were more prevalent in pregnant women with T1D: picobirnaviruses (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.0–17.1; P = .046) and tobamoviruses (OR, 3.2; 95% CI, 1.1–9.3; P = .037). The abundance of 77 viruses significantly differed between the 2 maternal groups (≥2-fold difference; P < .02), including 8 Enterovirus B types present at a higher abundance in women with T1D. Conclusions These findings provide novel insight into the composition of the gut virome during pregnancy and demonstrate a distinct profile of viruses in women with T1D.
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Affiliation(s)
- Ki Wook Kim
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
| | - Digby W Allen
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
| | - Thomas Briese
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York
| | - Jennifer J Couper
- Adelaide Medical School, Faculty and Health and Medical Sciences, University of Adelaide Robinson Research Institute, Australia
| | - Simon C Barry
- Adelaide Medical School, Faculty and Health and Medical Sciences, University of Adelaide Robinson Research Institute, Australia
| | - Peter G Colman
- Department of Diabetes and Endocrinology, The Royal Melbourne Hospital Victoria, Australia
| | | | | | - Lynne C Giles
- School of Public Health, University of Adelaide, Australia
| | - Leonard C Harrison
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Mark Harris
- Children's Health Queensland Hospital and Health Service, Australia
| | - Aveni Haynes
- Telethon Kids Institute, The University of Western Australia, Perth
| | - Jessica L Horton
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
| | - Sonia R Isaacs
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
| | - Komal Jain
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York
| | - Walter Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York
| | - Grant Morahan
- Centre for Diabetes Research, The Harry Perkins Institute for Medical Research, Perth, Australia
| | | | - Ignatius C N Pang
- School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, Australia
| | - Anthony T Papenfuss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Megan A S Penno
- Adelaide Medical School, Faculty and Health and Medical Sciences, University of Adelaide Robinson Research Institute, Australia
| | - Richard O Sinnott
- Department of Computing and Information Systems, University of Melbourne, Australia
| | - Georgia Soldatos
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Rebecca L Thomson
- Adelaide Medical School, Faculty and Health and Medical Sciences, University of Adelaide Robinson Research Institute, Australia
| | | | - John M Wentworth
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Marc R Wilkins
- School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, Australia
| | - William D Rawlinson
- Serology and Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia
| | - Maria E Craig
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia
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50
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Hyöty H, Leon F, Knip M. Developing a vaccine for type 1 diabetes by targeting coxsackievirus B. Expert Rev Vaccines 2018; 17:1071-1083. [PMID: 30449209 DOI: 10.1080/14760584.2018.1548281] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Virus infections have long been considered as a possible cause of type 1 diabetes (T1D). One virus group, enteroviruses (EVs), has been studied extensively, and clinical development of a vaccine against T1D-associated EV types has started. AREAS COVERED Epidemiological studies have indicated an association between EVs and T1D. These viruses have a strong tropism for insulin-producing β-cells; the destruction of these cells leads to T1D. The exact mechanisms by which EVs could cause T1D are not known, but direct infection of β-cells and virus-induced inflammation may play a role. Recent studies have narrowed down the epidemiological association to a subset of EVs: group B coxsackieviruses (CVBs). These findings have prompted efforts to develop vaccines against CVBs. Prototype CVB vaccines have prevented both infection and CVB-induced diabetes in mice. This review summarizes recent progress in the field and the specifics of what could constitute the first human vaccine developed for a chronic autoimmune disease. EXPERT COMMENTARY Manufacturing of a clinical CVB vaccine as well as preclinical studies are currently in progress in order to enable clinical testing of the first CVB vaccine. Ongoing scientific research projects can significantly facilitate this effort by providing insights into the mechanisms of the CVB-T1D association.
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Affiliation(s)
- Heikki Hyöty
- a Faculty of Medicine and Life Sciences, Department of Virology , University of Tampere , Tampere , Finland.,b Fimlab Laboratories , Pirkanmaa Hospital District , Tampere , Finland
| | | | - Mikael Knip
- d Children's Hospital , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.,e Diabetes and Obesity Research Program , University of Helsinki , Helsinki , Finland.,f Folkhälsan Research Center , Helsinki , Finland.,g Center for Child Health Research , Tampere University Hospital , Tampere , Finland
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