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1.
Cell Mol Life Sci ; 77(1): 179-194, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31172216

RESUMO

It has been suggested that the persistence of coxsackieviruses-B (CV-B) in pancreatic beta cells plays a role in the pathogenesis of type 1 diabetes (T1D). Yet, immunological effectors, especially natural killer (NK) cells, are supposed to clear virus-infected cells. Therefore, an evaluation of the response of NK cells to pancreatic beta cells persistently infected with CV-B4 was conducted. A persistent CV-B4 infection was established in 1.1B4 pancreatic beta cells. Infectious particles were found in supernatants throughout the culture period. The proportion of cells containing viral protein VP1 was low (< 5%), although a large proportion of cells harbored viral RNA (around 50%), whilst cell viability was preserved. HLA class I cell surface expression was downregulated in persistently infected cultures, but HLA class I mRNA levels were unchanged in comparison with mock-infected cells. The cytolytic activities of IL-2-activated non-adherent peripheral blood mononuclear cells (PBMCs) and of NK cells were higher towards persistently infected cells than towards mock-infected cells, as assessed by an LDH release assay. Impaired cytolytic activity of IL-2-activated non-adherent PBMCs from patients with T1D towards infected beta cells was observed. In conclusion, pancreatic beta cells persistently infected with CV-B4 can be lysed by NK cells, implying that impaired cytolytic activity of these effector cells may play a role in the persistence of CV-B in the host and thus in the viral pathogenesis of T1D.


Assuntos
Infecções por Coxsackievirus/complicações , Diabetes Mellitus Tipo 1/virologia , Enterovirus Humano B/imunologia , Células Secretoras de Insulina/virologia , Células Matadoras Naturais/imunologia , Adulto , Linhagem Celular , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Imunidade Celular , Células Secretoras de Insulina/imunologia , Pessoa de Meia-Idade
3.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß 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. ß 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 ß 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.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
5.
Diabetologia ; 62(5): 744-753, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30675626

RESUMO

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.


Assuntos
Antivirais/uso terapêutico , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/prevenção & controle , Pâncreas/fisiopatologia , Vacinas Virais/uso terapêutico , Imunidade Adaptativa , Autoimunidade , Bancos de Espécimes Biológicos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Infecções por Enterovirus/complicações , Infecções por Enterovirus/tratamento farmacológico , Humanos , Imunidade Inata , Células Secretoras de Insulina/metabolismo , Pâncreas/virologia , Vacinas Virais/economia
6.
Clin Exp Immunol ; 195(1): 64-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30444956

RESUMO

Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti-viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169+ macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin-specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169+ macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169+ macrophages. Tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cell signaling (NF-κB) have been found to promote the survival of infected CD169+ macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein-Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Sistema Linfático/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Vesiculovirus/fisiologia , Viroses/imunologia , Replicação Viral , Animais , Diabetes Mellitus Tipo 1/virologia , Herpesvirus Humano 4 , Interações Hospedeiro-Patógeno , Humanos , Lúpus Eritematoso Sistêmico/virologia , Sistema Linfático/virologia , Especificidade de Órgãos , Viroses/virologia
7.
Expert Rev Vaccines ; 17(12): 1071-1083, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30449209

RESUMO

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 ß-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 ß-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.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Infecções por Enterovirus/prevenção & controle , Vacinas Virais/administração & dosagem , Animais , Diabetes Mellitus Tipo 1/virologia , Desenvolvimento de Medicamentos/métodos , Enterovirus Humano B/imunologia , Infecções por Enterovirus/complicações , Infecções por Enterovirus/imunologia , Humanos , Células Secretoras de Insulina/virologia , Camundongos , Vacinas Virais/imunologia
8.
Curr Diab Rep ; 18(11): 106, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232567

RESUMO

PURPOSE OF REVIEW: To provide an overview of studies that have detected enteroviruses (EV) in samples from people with type 1 diabetes (T1D), the techniques they have used, and which challenges they have encountered. RECENT FINDINGS: Recent studies have detected EVs in serum, blood, stools, nasal swabs, and pancreas of people with T1D before or around clinical onset of disease, indicating that an association between EV infections and T1D exists. However, definitive evidence for its role as disease triggers is lacking. Recent access to human samples is starting to provide the necessary tools to define their role in disease pathogenesis. Emerging evidence suggests that chronic infections take place in the pancreas of diabetic donors. However, the development of sensitive techniques able to detect low amounts of viral protein and RNA still constitute a major challenge for the field. New evidence at the protein, RNA, and host immune response level suggests a role for EV infections in the development of autoimmunity. In the upcoming years, new technologies, collaborative efforts, and therapeutic interventions are likely to find a definitive answer for their role in disease pathogenesis.


Assuntos
Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/complicações , Enterovirus/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Interferons/metabolismo , Replicação Viral
9.
J Clin Endocrinol Metab ; 103(12): 4343-4356, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203067

RESUMO

Context: Recent studies have suggested that influenza A virus (IAV) might be involved in the etiology of diabetes. Objective and Methods: To address this question, we tested the ability of H1N1 pandemic IAV to infect, replicate, and damage human ß cells/pancreatic islets in vitro and induce pancreatic damage and/or glucose metabolism alterations in chemical and autoimmune models of ß cell damage in vivo. Moreover, we looked for direct and/or indirect evidence of correlation between IAV infection and autoimmunity/diabetes in humans. Results: Human H1N1 A/California/2009-derived viruses infected human pancreatic islets in vitro, inducing a proinflammatory response associated with substantial increases of CXCL9 and CXCL10 release. In vivo, infected mice showed a clear susceptibility to the virus, with its localization also found in extrapulmonary organs, including the pancreas. Infection was able to induce mild modifications of glycemia in C57B6 mice after chemical damage of islets but did not modulate the autoimmune damage of islets in NOD mice. One of 69 nasopharyngeal swabs collected from patients at the onset of type 1 diabetes yielded positive results for IAV. Pancreas sections from 17 organ donors available from the Network for Pancreatic Organ Donors With Diabetes showed the persistence of CXCL10-positive cells in islet autoimmunity-positive subjects; however, extremely rare cells stained for viral RNA and not preferentially in autoimmune subjects. Conclusion: Influenza H1N1 pdm strains are able to infect and replicate in mammalian pancreatic cells both in vitro and in vivo but did not cause any functional impairment consistent with diabetes.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/virologia , Adolescente , Adulto , Animais , Glicemia , Linhagem Celular , Linhagem Celular Tumoral , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Criança , Pré-Escolar , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/virologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/virologia , Cães , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/virologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pandemias , Cultura Primária de Células , RNA Viral/isolamento & purificação , Adulto Jovem
10.
J Diabetes Res ; 2018: 8475341, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186878

RESUMO

Objective: Viruses trigger and promote islet cell destruction and cause type 1 diabetes mellitus (T1DM). However, the existence of a cause-and-effect relationship is under debate. The aim of this study is to investigate the sero-epidemiological and molecular evidence on enteroviruses and respiratory viruses in patients with newly diagnosed T1DM during the cold season. Design: Forty children newly diagnosed with T1DM and 30 healthy children who presented to the clinic over the course of a year were included in the study. The IgM antibodies against enteroviruses and respiratory viruses were studied using the indirect immunofluorescence assay (IFA) test, and no CBV4-specific RNA was detected in the children. The onset times of T1DM were classified into fall-winter and spring-summer seasons and separated into cold, moderate, or warm months in terms of temperature. Results: The percentages of viral IgM antibodies against most common viruses were detected in the patients as follows: influenza B (IVB) (70%), echovirus 7 (ECHO7) (45%), parainfluenza virus 4 (PIV4) (40%), coxsackievirus A7 (CAV7) (27.5%), and H3N2 (22.5%). Compared with the control group, the above viruses had a significant association with T1DM (p ≤ 0.001, p ≤ 0.001, p = 0.035, p = 0.003, and p = 0.023, resp.). CBV4-specific RNA was not detected in any serum. A total of 75% and 95% patients were diagnosed with T1DM in the fall-winter seasons and cold-moderate months, respectively. Conclusion: Our study demonstrates the significant association between T1DM and the presence of IgM antibodies against IVB, ECHO7, PIV4, CAV7, and H3N2, and the majority of newly diagnosed T1DM appeared in the fall-winter season. It suggests that enteroviruses and respiratory viruses, in addition to seasonal variation, could play a role in the etiopathogenesis and clinical onset of T1DM.


Assuntos
Anticorpos Antivirais/imunologia , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/virologia , Enterovirus/imunologia , Imunoglobulina M/imunologia , Infecções Respiratórias/virologia , Adolescente , Fatores Etários , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Enterovirus/patogenicidade , Infecções por Enterovirus/sangue , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/imunologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Imunoglobulina M/sangue , Lactente , Masculino , Infecções Respiratórias/sangue , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/imunologia , Estudos Retrospectivos , Fatores de Risco , Estações do Ano , Fatores de Tempo , Turquia
11.
Curr Opin Pharmacol ; 43: 11-19, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30064099

RESUMO

The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is partly because much of the epidemiological evidence derives from studies of neutralising antibody generation in blood samples while less attention has been paid to the pancreatic beta cell as a site of infection. Nevertheless, recent studies have revealed that beta cells express specific enteroviral receptors and that they can sustain a productive enteroviral infection. Importantly, they can also mount antiviral responses which attenuate viral replication and may favour the establishment of a persistent enteroviral infection. Together, these responses combine to create the Trojan horse by which enteroviruses might precipitate islet autoimmunity.


Assuntos
Antivirais/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , Desenho de Drogas , Enterovirus/patogenicidade , Infecções por Enterovirus/sangue , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipoglicemiantes/efeitos adversos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/virologia , Fatores de Risco
12.
Diabetologia ; 61(9): 1996-2004, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29934759

RESUMO

AIMS/HYPOTHESIS: Case reports have linked influenza infections to the development of type 1 diabetes. We investigated whether pandemic and seasonal influenza infections were associated with subsequent increased risk of type 1 diabetes. METHODS: In this population-based registry study, we linked individual-level data from national health registries for the entire Norwegian population under the age of 30 years for the years 2006-2014 (2.5 million individuals). Data were obtained from the National Registry (population data), the Norwegian Patient Registry (data on inpatient and outpatient specialist care), the Primary Care Database, the Norwegian Prescription Database and the Norwegian Surveillance System for Communicable Diseases. Pandemic influenza was defined as either a clinical influenza diagnosis during the main pandemic period or a laboratory-confirmed test. Seasonal influenza was defined by a clinical diagnosis of influenza between 2006 and 2014. We used Cox regression to estimate HRs for new-onset type 1 diabetes after an influenza infection, adjusted for year of birth, sex, place of birth and education. RESULTS: The adjusted HR for type 1 diabetes after pandemic influenza infection was 1.19 (95% CI 0.97, 1.46). In the subgroup with laboratory-confirmed influenza A (H1N1), influenza was associated with a twofold higher risk of subsequent type 1 diabetes before age 30 years (adjusted HR: 2.26, 95% CI 1.51, 3.38). CONCLUSIONS/INTERPRETATION: Overall, we could not demonstrate a clear association between clinically reported pandemic influenza infection and incident type 1 diabetes. However, we found a twofold excess of incident diabetes in the subgroup with laboratory-confirmed pandemic influenza A (H1N1).


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Influenza Humana/epidemiologia , Adolescente , Adulto , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Incidência , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/complicações , Masculino , Sistema de Registros , Adulto Jovem
13.
J Endocrinol ; 238(1): 61-75, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29743341

RESUMO

The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas ß cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering ß cell autoimmunity.


Assuntos
Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Diabetes Mellitus Tipo 1/virologia , Inflamação/complicações , Paniculite/complicações , Parvovirus/fisiologia , Tecido Adiposo/imunologia , Tecido Adiposo/virologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Imunidade Inata/fisiologia , Inflamação/patologia , Inflamação/virologia , Macrófagos/fisiologia , Masculino , Paniculite/imunologia , Paniculite/patologia , Paniculite/virologia , Parvovirus/imunologia , Ratos , Transdução de Sinais/imunologia
14.
Diabetes Obes Metab ; 20(9): 2075-2084, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29749030

RESUMO

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV-W-Env). HERV-W-Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human ß-islet cells. In vivo HERV-W-Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV-W-Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV-W-Env and to neutralize the effect of HERV-W-Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW-T1D study, which is a randomized placebo-controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6-month open-label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV-W-Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non-immunomodulatory disease-modifying treatment for T1D.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Retrovirus Endógenos/efeitos dos fármacos , Produtos do Gene env/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Diabetes Mellitus Tipo 1/virologia , Retrovirus Endógenos/imunologia , Produtos do Gene env/sangue , Produtos do Gene env/imunologia , Humanos
15.
Xenotransplantation ; 25(6): e12409, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29782054

RESUMO

BACKGROUND: Subcutaneous implantation of a macroencapsulated patch containing human allogenic islets has been successfully used to alleviate type 1 diabetes mellitus (T1DM) in a human recipient without the need for immunosuppression. The use of encapsulated porcine islets to treat T1DM has also been reported. Although no evidence of pathogen transfer using this technology has been reported to date, we deemed it appropriate to determine if the encapsulation technology would prevent the release of virus, in particular, the porcine endogenous retrovirus (PERV). METHODS: HEK293 (human epithelial kidney) and swine testis (ST) cells were co-cultured with macroencapsulated pig islets embedded in an alginate patch, macroencapsulated PK15 (swine kidney epithelial) cells embedded in an alginate patch and free PK15 cells. Cells and supernatant were harvested at weekly time points from the cultures for up to 60 days and screened for evidence of PERV release using qRT-PCR to detect PERV RNA and SG-PERT to detect reverse transcriptase (RT). RESULTS: No PERV virus, or evidence of PERV replication, was detected in the culture medium of HEK293 or pig cells cultured with encapsulated porcine islets. Increased PERV activity relative to the background was not detected in ST cells cultured with encapsulated PK15 cells. However, PERV was detected in 1 of the 3 experimental replicates of HEK293 cells cultured with encapsulated PK15 cells. Both HEK293 and ST cells cultured with free PK15 cells showed an increase in RT detection. CONCLUSIONS: With the exception of 1 replicate, there does not appear to be evidence of transmission of replication competent PERV from the encapsulated islet cells or the positive control PK15 cells across the alginate barrier. The detection of PERV would suggest the alginate barrier of this replicate may have become compromised, emphasizing the importance of quality control when producing encapsulated islet patches.


Assuntos
Alginatos/metabolismo , Retrovirus Endógenos/patogenicidade , Ilhotas Pancreáticas/virologia , Infecções por Retroviridae/transmissão , Animais , Diabetes Mellitus Tipo 1/virologia , Células HEK293 , Humanos , Ilhotas Pancreáticas/citologia , Transplante das Ilhotas Pancreáticas/métodos , Suínos , Transplante Heterólogo/métodos , Zoonoses/virologia
16.
Kaohsiung J Med Sci ; 34(5): 274-280, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29699634

RESUMO

Type 1 diabetes is a multi-factorial disease that can develop due to the combination of genetic and environmental factors. Viruses, particularly enteroviruses, are major environmental candidates in the pathogenesis of type 1 diabetes, even though the mechanisms of pathogenicity of these viruses and their effects on the immune system have not been understood very well yet. Previous studies show that any imbalance in the population of different lymphocyte subsets could develop autoimmune diseases. Our theory is that enteroviral infection causes an impairment in the distribution of lymphocyte subtypes and consequently results in the diabetes onset in some individuals. Therefore, in this project, we evaluated the distribution of T CD8+ lymphocytes and their subsets in type 1 diabetes patients. This study was conducted to investigate the relationship between enteroviral infection and type 1 diabetes mellitus in an Iranian population, and suggestion a predicting approach for susceptible subjects.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Infecções por Enterovirus/imunologia , Enterovirus/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Antígenos CD/sangue , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/patologia , Proteínas do Capsídeo/sangue , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/virologia , Enterovirus/patogenicidade , Infecções por Enterovirus/complicações , Infecções por Enterovirus/genética , Infecções por Enterovirus/virologia , Feminino , Expressão Gênica , Glutamato Descarboxilase/sangue , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Humanos , Imunofenotipagem , Irã (Geográfico) , Contagem de Linfócitos , Masculino , Subpopulações de Linfócitos T/patologia
17.
PLoS One ; 13(4): e0193992, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29664909

RESUMO

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Enterovirus Humano B/isolamento & purificação , Infecções por Enterovirus/virologia , Higiene , Adulto , Austrália , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Incidência , Masculino , Comportamento de Redução do Risco
18.
DNA Cell Biol ; 37(5): 422-425, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29638163

RESUMO

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing pancreatic beta cells. Although environmental factors interplay with genetic susceptibility to promote immune dysregulation and disease, it remains unclear as to which potential environmental factors are causative and not simply correlative. Despite many hints that the microbiome can have a profound effect on T1D, significant changes in bacterial gut flora and diversity appear to emerge only after the detection of early signs of T1D. Surprisingly, we recently found significant differences in the gut virome preceding the initial signs of T1D, raising the tantalizing possibility that the state of the virome may influence or predict whether susceptible individuals progress on the path to disease. The challenge will be to discern whether there is likely a causative relationship between detected virome differences and T1D.


Assuntos
Diabetes Mellitus Tipo 1/virologia , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/virologia , Vírus/isolamento & purificação , Animais , Enterovirus/genética , Enterovirus/imunologia , Enterovirus/isolamento & purificação , Humanos , Imunidade Inata/fisiologia , Fenômenos Fisiológicos Virais , Vírus/genética , Vírus/imunologia
19.
Pediatr Diabetes ; 19(5): 923-929, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29569355

RESUMO

At the time of the clinical onset of type 1 diabetes (T1D), we investigated 82 pediatric cases in parallel with 117 non-diabetic controls matched by age, geographic area, and time of collection. The occurrence of an enteroviral infection was evaluated in peripheral blood using a sensitive method capable of detecting virtually all human enterovirus (EV) types. While non-diabetic controls were consistently EV-negative, 65% of T1D cases carried EVs in blood. The vitamin D status was assessed by measuring the concentration of 25-hydroxyvitamin D [25(OH)D] in serum. Levels of 25(OH)D were interpreted as deficiency (≤50 nmol/L), insufficiency (52.5-72.5 nmol/L), and sufficiency (75-250 nmol/L). In T1D cases, the median serum concentration of 25(OH)D was 54.4 ± 27.3 nmol/L vs 74.1 ± 28.5 nmol/L in controls (P = .0001). Diabetic children/adolescents showed deficient levels of vitamin D 25(OH)D (ie, 72.5 nmol/L) in 48.8% cases vs 17.9% in non-diabetic controls (P = .0001). Unexpectedly, the median vitamin D concentration was significantly reduced in virus-positive vs virus-negative diabetics (48.2 ± 22.5 vs 61.8 ± 31.2 nmol/L; P = .015), with deficient levels in 58.5% vs 31.0%, respectively. Thus, at the time of clinical onset, EV-positive cases had reduced vitamin D levels compared with EV-negative cases. This could indicate either that the virus-negative children/adolescents had been hit by a non-infectious T1D-triggering event, or that children/adolescents with proper levels of vitamin D had been able to rapidly clear the virus. Thus, it would be important to assess whether adequate vitamin D supplementation before or during the prediabetic phase of T1D may counteract the diabetogenic potential of infectious pathogens.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Infecções por Enterovirus/complicações , Deficiência de Vitamina D/complicações , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Itália/epidemiologia , Masculino
20.
JCI Insight ; 3(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415896

RESUMO

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic ß cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than ß cell death, suggesting loss of ß cell identity. We undertook this study to examine whether viral infection could induce human ß cell dedifferentiation. Using the functional human ß cell line EndoC-ßH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in ß cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human ß cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human ß cell dedifferentiation.


Assuntos
Desdiferenciação Celular/imunologia , Diabetes Mellitus Tipo 1/imunologia , Infecções por Enterovirus/imunologia , Células Secretoras de Insulina/fisiologia , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Tipo 1/virologia , Enterovirus/imunologia , Infecções por Enterovirus/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Indutores de Interferon/farmacologia , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , NF-kappa B/metabolismo , Poli I-C/farmacologia , Cultura Primária de Células , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
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