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1.
Nat Metab ; 2(10): 1021-1024, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32879473

RESUMO

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l-1, blood glucose concentration of 30.6 mmol l-1 (552 mg dl-1) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic ß-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on ß-cells.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Betacoronavirus/imunologia , Biomarcadores , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-D/genética , Antígenos HLA-D/imunologia , Humanos , Imunoglobulina M/imunologia , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/imunologia , Masculino , Pandemias , Pneumonia Viral/imunologia , Adulto Jovem
2.
Nat Med ; 26(8): 1247-1255, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770166

RESUMO

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Cetose/sangue , Medição de Risco , Autoanticorpos/imunologia , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Insulina/deficiência , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Cetose/imunologia , Masculino , Triagem Neonatal , Fatores de Risco
3.
Nat Commun ; 11(1): 2475, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424134

RESUMO

Autoimmune ß-cell destruction leads to type 1 diabetes, but the pathophysiological mechanisms remain unclear. To help address this void, we created an open-access online repository, unprecedented in its size, composed of large-scale electron microscopy images ('nanotomy') of human pancreas tissue obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD; www.nanotomy.org). Nanotomy allows analyses of complete donor islets with up to macromolecular resolution. Anomalies we found in type 1 diabetes included (i) an increase of 'intermediate cells' containing granules resembling those of exocrine zymogen and endocrine hormone secreting cells; and (ii) elevated presence of innate immune cells. These are our first results of mining the database and support recent findings that suggest that type 1 diabetes includes abnormalities in the exocrine pancreas that may induce endocrine cellular stress as a trigger for autoimmunity.


Assuntos
Bases de Dados como Assunto , Diabetes Mellitus Tipo 1/patologia , Ilhotas Pancreáticas/ultraestrutura , Microscopia Eletrônica , Autoanticorpos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Granulócitos/imunologia , Humanos , Imunidade Inata , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doadores de Tecidos
4.
Arch Immunol Ther Exp (Warsz) ; 68(2): 13, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32297019

RESUMO

Interactions between the immune system and the pancreas are pivotal in understanding how and why ß cells' damage causes problems with pancreas functioning. Pancreatic islets are crucial in maintaining glucose homeostasis in organs, tissue and cells. Autoimmune aggression towards pancreatic islets, mainly ß cells, leads to type 1 diabetes-one of the most prevalent autoimmune disease in the world, being a worldwide risk to health of many people. In this review, we highlight the role of immune cells and its influence in the development of autoimmunity in Langerhans islets. Moreover, we discuss the impact of the immunological factors on future understanding possible recurrence of autoimmunity on 3D-bioprinted bionic pancreas.


Assuntos
Bioimpressão/tendências , Diabetes Mellitus Tipo 1/terapia , Sistema Imunitário/citologia , Pâncreas/imunologia , Células-Tronco/citologia , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Humanos , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas , Pâncreas/patologia
5.
J Immunol ; 204(7): 1787-1797, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32111734

RESUMO

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4+ mimotope (BDC2.5mim) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3+ and Foxp3- PD1+ CD73+ ICOS+ IL-10+ peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5mim/calcitriol liposome administration, adoptive transfer of CD4+ T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5mim/calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8+ T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4+ peptide, BDC2.5mim, and calcitriol induce ChgA-specific CD4+ T cells that regulate CD4+ and CD8+ self-antigen specificities and autoimmune diabetes in NOD mice.


Assuntos
Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Lipossomos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/terapia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Diabetes Mellitus Tipo 1/terapia , Feminino , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Peptídeos/imunologia
6.
JAMA ; 323(4): 339-351, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31990315

RESUMO

Importance: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. Objective: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. Design, Setting, and Participants: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. Exposures: Measurement of islet autoantibodies. Main Outcomes and Measures: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). Results: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001). Conclusions and Relevance: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Ilhotas Pancreáticas/imunologia , Programas de Rastreamento , Doenças Assintomáticas/epidemiologia , Doenças Assintomáticas/psicologia , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/psicologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pais , Inquéritos e Questionários
7.
Nat Rev Endocrinol ; 16(2): 81-90, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836875

RESUMO

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to ß-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive ß-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of ß-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the ß-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on ß-cell function and glycaemia.


Assuntos
Células Secretoras de Insulina/metabolismo , Macrófagos/fisiologia , Obesidade/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Obesidade/imunologia
8.
Dis Markers ; 2019: 9786078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827651

RESUMO

The incidence rate of type 1 diabetes in Kuwait had been increasing exponentially and has doubled in children ≤ 14 years old within almost two decades. Therefore, there is a dire need for a careful systematic familial cohort study. Several immunogenetic factors affect the pathogenesis of the disease. The human leukocyte antigen (HLA) accounts for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by type 1 destruction of pancreatic ß-cells. Both HLA and anti-islet antibodies can be used to characterize, predict susceptibility to the disease, innovate, or delay the ß-cell destruction. Evidence from prospective longitudinal studies suggested that the underlying disease process represents a continuum that begins before the symptoms are clinically evident. Autoimmunity of the functional pancreatic ß-cells results in symptomatic type 1 diabetes and lifelong insulin dependence. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for type 1 diabetes in both children and adults. Although Kuwait is the second among the top 10 countries with a high incidence rate of type 1 diabetes, there have been no proper diagnostic and prediction tools as per the World Health Organization. The Kuwaiti Type 1 Diabetes Study (KADS) was initiated to understand the disease pathogenesis as well as the HLA and anti-islet autoantibody profile of type 1 diabetes in Kuwait. Understanding the disease sequela in a homogenous gene pool and highly consanguineous population of Kuwaitis could help solve the challenges and pathogenesis, as well as hasten the prevention, of type 1 diabetes.


Assuntos
Autoanticorpos/sangue , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA/imunologia , Ilhotas Pancreáticas/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Humanos , Kuweit/epidemiologia , Prognóstico
9.
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
10.
Nat Commun ; 10(1): 5697, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836704

RESUMO

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.


Assuntos
Autoimunidade/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 1/imunologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas/genética , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Epigênese Genética/imunologia , Regulação da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Ilhotas Pancreáticas/imunologia , Masculino , Camundongos Knockout , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Cultura Primária de Células
11.
Islets ; 11(6): 141-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743072

RESUMO

Background & objectives: Islet of Langerhans, the endocrine pancreas plays a significant role in glucose metabolism. Obesity and insulin resistance are the major factors responsible for beta cell dysfunction. Asian Indian population has increased susceptibility to diabetes in spite of having lower BMI. The morphology of islets plays a significant role in beta cell function. The present study was designed for better understanding the morphology, composition and distribution of islets in different parts of the pancreas and its impact on beta cell proportion. Methods: We observed islet morphology and beta cell area proportion by Large-scale computer-assisted analysis in 20 adult human pancreases in non-diabetic Indian population. Immunohistochemical staining with anti-synaptophysin and anti-insulin antibody was used to detect islet and beta cells respectively. Whole slide images were analyzed using ImageJ software. Results: Endocrine proportion were heterogeneously increasing from head to tail with maximum islet and beta cell distribution in the tail region. Larger islets were predominately confined to the tail region. The islets in Indian population were relatively smaller in size, but they have more beta cells (20%) when compared to American population. Interpretation & conclusions: The beta cells of larger islets are functionally more active than the smaller islets via paracrine effect. Thus, reduction in the number of larger islets may be one of the probable reasons for increased susceptibility of Indians to diabetes even at lower BMI. Knowledge about the regional distribution of islets will help the surgeons to preserve the islet rich regions during surgery.


Assuntos
Anticorpos Anti-Insulina/análise , Células Secretoras de Insulina , Ilhotas Pancreáticas , Pâncreas , Adulto , Anatomia Regional/métodos , Autopsia , Variação Biológica da População , Metodologias Computacionais , Feminino , Humanos , Imuno-Histoquímica , Índia/epidemiologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/diagnóstico por imagem , Ilhotas Pancreáticas/imunologia , Masculino , Pâncreas/citologia , Pâncreas/imunologia
12.
J Diabetes Res ; 2019: 9430473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781669

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic ß cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9-23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Galactosilceramidas/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Ilhotas Pancreáticas/efeitos dos fármacos , Células T Matadoras Naturais/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Transferência Adotiva , Animais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Feminino , Fatores de Transcrição Forkhead/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Lipossomos , Camundongos Endogâmicos NOD , Camundongos SCID , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
13.
Curr Diab Rep ; 19(10): 99, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501992

RESUMO

PURPOSE OF REVIEW: Progression rate from islet autoimmunity to clinical diabetes is unpredictable. In this review, we focus on an intriguing group of slow progressors who have high-risk islet autoantibody profiles but some remain diabetes free for decades. RECENT FINDINGS: Birth cohort studies show that islet autoimmunity presents early in life and approximately 70% of individuals with multiple islet autoantibodies develop clinical symptoms of diabetes within 10 years. Some "at risk" individuals however progress very slowly. Recent genetic studies confirm that approximately half of type 1 diabetes (T1D) is diagnosed in adulthood. This creates a conundrum; slow progressors cannot account for the number of cases diagnosed in the adult population. There is a large "gap" in our understanding of the pathogenesis of adult onset T1D and a need for longitudinal studies to determine whether there are "at risk" adults in the general population; some of whom are rapid and some slow adult progressors.


Assuntos
Autoanticorpos/imunologia , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Progressão da Doença , Humanos
14.
Int J Mol Sci ; 20(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561444

RESUMO

Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Senescência Celular/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Animais , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Comunicação Parácrina , Ligação Proteica
15.
Curr Diab Rep ; 19(9): 69, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367976

RESUMO

PURPOSE OF REVIEW: Theories about the pathogenesis of type 1 diabetes (T1D) refer to the potential of primary islet inflammatory signaling as a trigger for the loss of self-tolerance leading to disease onset. Emerging evidence suggests that extracellular vesicles (EV) may represent the missing link between inflammation and autoimmunity. Here, we review the evidence for a role of EV in the pathogenesis of T1D, as well as discuss their potential value in the clinical sphere, as biomarkers and therapeutic agents. RECENT FINDINGS: EV derived from ß cells are enriched in diabetogenic autoantigens and miRNAs that are selectively sorted and packaged. These EV play a pivotal role in antigen presentation and cell to cell communication leading to activation of autoimmune responses. Furthermore, recent evidence suggests the potential of EV as novel tools in clinical diagnostics and therapeutic interventions. In-depth analysis of EV cargo using modern multi-parametric technologies may be useful in enhancing our understanding of EV-mediated immune mechanisms and in identifying robust biomarkers and therapeutic strategies for T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Vesículas Extracelulares/imunologia , Células Secretoras de Insulina/imunologia , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Biomarcadores/análise , Comunicação Celular/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Humanos , Ilhotas Pancreáticas/imunologia , MicroRNAs/imunologia
16.
Nat Commun ; 10(1): 3495, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375697

RESUMO

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica , Transplante das Ilhotas Pancreáticas/efeitos adversos , Linfócitos T Reguladores/transplante , Transferência Adotiva , Aloenxertos/imunologia , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Ilhotas Pancreáticas/imunologia , Macaca mulatta , Masculino , Linfócitos T Reguladores/imunologia , Doadores de Tecidos , Transplante Homólogo/efeitos adversos
17.
Sci Adv ; 5(8): eaaw9336, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31457096

RESUMO

Human leukocyte antigen (HLA)-DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer-restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer-specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell receptor (TCR) contact, stronger disease-associated responses to cross-reactive, immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at the α chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65250-266 peptide and in silico analysis reveal the DQ α52 residue located within the N-terminal edge of the peptide-binding cleft for the enhanced T cell reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide complexes. Accordingly, a structurally promiscuous but nondegenerate TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer-mediated autoimmune diabetes.


Assuntos
Autoantígenos/imunologia , Reações Cruzadas/imunologia , Antígenos HLA-DQ/imunologia , Ilhotas Pancreáticas/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Alelos , Sequência de Aminoácidos , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Epitopos/química , Epitopos/imunologia , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Humanos , Modelos Moleculares , Multimerização Proteica , Relação Estrutura-Atividade , Especificidade do Receptor de Antígeno de Linfócitos T
18.
Pediatr Diabetes ; 20(6): 720-727, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31192505

RESUMO

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevenção & controle , Testes Genéticos , Seleção de Pacientes , Prevenção Primária/métodos , Autoanticorpos/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/diagnóstico , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Masculino , Triagem Neonatal , Polimorfismo de Nucleotídeo Único , Dados Preliminares , Projetos de Pesquisa , Fatores de Risco
19.
Diabetes Care ; 42(8): 1357-1364, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167894

RESUMO

Current efforts to prevent progression from islet autoimmunity to type 1 diabetes largely focus on immunomodulatory approaches. However, emerging data suggest that the development of diabetes in islet autoantibody-positive individuals may also involve factors such as obesity and genetic variants associated with type 2 diabetes, and the influence of these factors increases with age at diagnosis. Although these factors have been linked with metabolic outcomes, particularly through their impact on ß-cell function and insulin sensitivity, growing evidence suggests that they might also interact with the immune system to amplify the autoimmune response. The presence of factors shared by both forms of diabetes contributes to disease heterogeneity and thus has important implications. Characteristics that are typically considered to be nonimmune should be incorporated into predictive algorithms that seek to identify at-risk individuals and into the designs of trials for disease prevention. The heterogeneity of diabetes also poses a challenge in diagnostic classification. Finally, after clinically diagnosing type 1 diabetes, addressing nonimmune elements may help to prevent further deterioration of ß-cell function and thus improve clinical outcomes. This Perspectives in Care article highlights the role of type 2 diabetes-associated genetic factors (e.g., gene variants at transcription factor 7-like 2 [TCF7L2]) and obesity (via insulin resistance, inflammation, ß-cell stress, or all three) in the pathogenesis of type 1 diabetes and their impacts on age at diagnosis. Recognizing that type 1 diabetes might result from the sum of effects from islet autoimmunity and type 2 diabetes-associated factors, their interactions, or both affects disease prediction, prevention, diagnosis, and treatment.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Autoanticorpos/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Progressão da Doença , Humanos , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Obesidade/imunologia , Fatores de Risco , Proteína 2 Semelhante ao Fator 7 de Transcrição/imunologia
20.
Diabetes ; 68(9): 1830-1840, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31175101

RESUMO

We recently established that hybrid insulin peptides (HIPs) are present in human islets and that T cells reactive to HIPs are found in the residual islets of organ donors with type 1 diabetes (T1D). Here, we investigate whether HIP-reactive T cells are indicative of ongoing autoimmunity in patients with T1D. We used interferon-γ enzyme-linked immune absorbent spot analyses on peripheral blood mononuclear cells (PBMCs) to determine whether patients with new-onset T1D or control subjects displayed T-cell reactivity to a panel of 16 HIPs. We observed that nearly one-half of the patients responded to one or more HIPs. Responses to four HIPs were significantly elevated in patients with T1D but not in control subjects. To characterize the T cells reactive to HIPs, we used a carboxyfluorescein succinimidyl ester-based assay to clone T cells from PBMCs. We isolated six nonredundant, antigen-specific T-cell clones, most of which reacting to their target HIPs in the low nanomolar range. One T-cell clone was isolated from the same patient on two different blood draws, indicating persistence of this T-cell clone in the peripheral blood. This work suggests that HIPs are important target antigens in human subjects with T1D and may play a critical role in disease.


Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Insulina/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Autoimunidade/imunologia , Criança , Feminino , Humanos , Ilhotas Pancreáticas/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Adulto Jovem
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