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1.
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
2.
Mol Immunol ; 43(12): 1965-71, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16423395

RESUMO

Bcl-6, a major regulator of B lymphocyte function that contributes to neoplastic transformation of B cells, is expressed in activated germinal center (GC) B cells and down-regulated during terminal differentiation to plasma cells. Regulation of Bcl-6 expression is incompletely characterized. Terminal B cell differentiation is associated with down-regulation of Bcl-6, activation of Blimp-1, modulation of Myc, and specifically with the up-regulation of the Mad1 and Mad4 transcription factors, which play a critical role in cell differentiation and cell cycle regulation. Because the Mad E-box consensus binding site is present in the upstream promoter of Bcl-6, we investigated whether Bcl-6 may be under control of the Mad1 transcription factor. Anti-sense Mad1 oligonucleotides abrogated the down-regulation of Bcl-6 expression that occurred during in vitro differentiation of mouse splenic B cells induced by dextran-conjugated anti-IgD Ab and IL-5. Transduction of the WEHI 231 B cell line with retroviruses expressing Mad1 down-regulated Bcl-6 expression. Expression of the 5' upstream promoter region of Bcl-6 was down-regulated by co-expression of Mad1. Last, chromatin immunoprecipitation assays with anti-Mad1 Ab demonstrated in vivo interaction of Mad1 with the Bcl-6 promoter region. The findings suggest that Mad1 is a transcriptional repressor of Bcl-6.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Repressoras/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Sítios de Ligação , Diferenciação Celular/imunologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oligonucleotídeos Antissenso/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/metabolismo , Baço/citologia , Baço/imunologia
3.
Diabetes ; 66(2): 241-255, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27980006

RESUMO

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, "The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.


Assuntos
Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Complicações do Diabetes/genética , Complicações do Diabetes/fisiopatologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Genótipo , Humanos , Hipoglicemiantes/uso terapêutico , Fenótipo , Medicina de Precisão , Prognóstico , Fatores de Risco
4.
Mol Immunol ; 39(15): 923-32, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12695118

RESUMO

A role for histone acetylation, which can alter the accessibility of DNA to transcriptional regulatory proteins and contribute to gene expression, in regulating terminal B cell differentiation was investigated in the mature B lymphoma L10A and mouse splenic B cells. Incubation of the L10A cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and butyrate increased expression of Blimp-1, J chain, and mad genes, decreased expression of c-myc and BSAP/Pax-5 genes, increased the expression of surface CD43 and Syndecan-1, and decreased surface IgM. Incubation of splenic B cells with TSA and dextran conjugated anti-IgD Ab increased Blimp-1 gene and Syndecan-1 surface expression. The alteration in gene expression and cell surface markers was consistent with induction of the onset of terminal B cell differentiation. Co-incubation of L10A cells with TSA and cycloheximide (CHX) abrogated the up-regulation of Blimp-1 expression, indicating that TSA-activated Blimp-1 expression required synthesis of a transcriptional activator. In contrast, mad expression was increased in L10A cells cultured with TSA and cycloheximide or cycloheximide alone, suggesting mad expression may occur independent of Blimp-1 expression and is regulated by a labile, HDAC associated transcriptional repressor. The results demonstrate that histone acetylation regulates transcription of genes controlling terminal B cell differentiation.


Assuntos
Antígenos CD , Linfócitos B/enzimologia , Inibidores de Histona Desacetilases , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Ácidos Hidroxâmicos/farmacologia , Imunoglobulina M/metabolismo , Leucossialina , Glicoproteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Biossíntese de Proteínas , Proteoglicanas/biossíntese , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Sialoglicoproteínas/biossíntese , Baço/imunologia , Sindecana-1 , Sindecanas , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Células Tumorais Cultivadas
5.
Curr Opin Endocrinol Diabetes Obes ; 22(4): 270-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26087338

RESUMO

PURPOSE OF REVIEW: The purpose of this review was to describe the potential for general childhood population-based screening of risk of symptomatic type 1 diabetes (T1D) RECENT FINDINGS: The earliest stages of T1D can be identified and risk and rate of progression to symptomatic disease can be estimated by the presence of multiple islet autoantibodies and glucose intolerance (dysglycemia) in individuals screened for risk. Screening for human leukocyte antigen risk genotypes in neonates with follow-up detection of islet autoantibodies in childhood has been explored. An alternative approach of general childhood population-based detection of autoantibodies at well child visits provides an approach to detect a high proportion of children who will develop T1D. The Fr1da study was launched in Bavaria in 2015 to explore this concept. SUMMARY: General childhood population-based screening for risk of T1D will allow detection of an at-risk population that can participate in natural history studies to better understand disease pathogenesis and intervention trials to prevent symptomatic disease and will provide a framework for public health-based prevention of childhood-onset T1D.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diagnóstico Precoce , Programas de Rastreamento/normas , Criança , Humanos , Risco
6.
Diabetes ; 64(12): 3967-77, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26420863

RESUMO

From 27-29 October 2014, more than 100 people gathered in Chicago, IL, to participate in a research symposium titled "Diabetes and the Microbiome," jointly sponsored by the American Diabetes Association and JDRF. The conference brought together international scholars and trainees from multiple disciplines, including microbiology, bioinformatics, endocrinology, metabolism, and immunology, to share the current understanding of host-microbe interactions and their influences on diabetes and metabolism. Notably, this gathering was the first to assemble specialists with distinct expertise in type 1 diabetes, type 2 diabetes, immunology, and microbiology with the goal of discussing and defining potential pathophysiologies linking the microbiome and diabetes. In addition to reviewing existing evidence in the field, speakers presented their own original research to provide a comprehensive view of the current understanding of the topics under discussion.Presentations and discussions throughout the conference reflected a number of important concepts. The microbiota in any host represent a complex ecosystem with a high degree of interindividual variability. Different microbial communities, comprising bacteria, archaea, viruses, and fungi, occupy separate niches in and on the human body. Individually and collectively, these microbes provide benefits to the host-including nutrient harvest from food and protection against pathogens. They are dynamically regulated by both host genes and the environment, and they critically influence both physiology and lifelong health. The objective of the symposium was to discuss the relationship between the host and the microbiome-the combination of microbiota and their biomolecular environment and ecology-specifically with regard to metabolic and immunological systems and to define the critical research needed to understand and potentially target the microbiome in the prevention and treatment of diabetes. In this report, we present meeting highlights in the following areas: 1) relationships between diabetes and the microbiome, 2) bioinformatic tools, resources, and study design considerations, 3) microbial programming of the immune system, 4) the microbiome and energy balance, 5) interventions, and 6) limitations, unanswered questions, and resource and policy needs.


Assuntos
Pesquisa Biomédica , Diabetes Mellitus Tipo 1/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Medicina Baseada em Evidências , Microbioma Gastrointestinal , Modelos Biológicos , Medicina de Precisão , Animais , Pesquisa Biomédica/tendências , Terapia Combinada , Biologia Computacional/tendências , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico
7.
Diabetes Care ; 38(10): 1964-74, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26404926

RESUMO

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of ß-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of ß-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Autoanticorpos/imunologia , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Diagnóstico Precoce , Predisposição Genética para Doença , Humanos , Células Secretoras de Insulina/imunologia , Estado Pré-Diabético/classificação , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/imunologia , Estudos Prospectivos , Sociedades Médicas , Estados Unidos
8.
Diabetes Technol Ther ; 15 Suppl 2: S2-4-S2-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23786297

RESUMO

George Eisenbarth's pioneering and visionary research has provided a critical foundation that will be built on in the years ahead as we progress toward prevention of type 1 diabetes. His almost 30-year old model that type 1 diabetes was a chronic and predictable autoimmune disease with multiple identifiable progressive stages with a potential for interventions to prevent progression to symptomatic diabetes has stood the test of time. To deliver on the Eisenbarth vision and his "unfinished journey," the field needs: (1) to improve detection of risk of type 1 diabetes, (2) to improve staging and prediction of progression, (3) to perform smaller, shorter, practical, and an increased number of prevention clinical trials, and (4) to increase awareness of the potential for risk detection, staging, and prevention of type 1 diabetes and benefit/risk of prevention.


Assuntos
Doenças Autoimunes/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Doenças Autoimunes/história , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Análise Custo-Benefício , Diabetes Mellitus Tipo 1/história , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Suscetibilidade a Doenças/imunologia , Diagnóstico Precoce , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Modelos Imunológicos
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