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[PMID]:28467202
[Au] Autor:Shen L; Lu S; Huang D; Li G; Liu K; Cao R; Zong L; Jin L; Wu J
[Ad] Endereço:1 Minigene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
[Ti] Título:A rationally designed peptide IA-2-P2 against type 1 diabetes in streptozotocin-induced diabetic mice.
[So] Source:Diab Vasc Dis Res;14(3):184-190, 2017 May.
[Is] ISSN:1752-8984
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent studies have investigated the potential of type 1 diabetes mellitus-related autoantigens, such as heat shock protein 60, to induce immunological tolerance or to suppress the immune response. A functional 24-residue peptide derived from heat shock protein 60 (P277) has shown anti-type 1 diabetes mellitus potential in experimental animals and in clinical studies, but it also carries a potential atherogenic effect. In this study, we have modified P277 to retain an anti-type 1 diabetes mellitus effect and minimize the atherogenic potential by replacing the P277 B epitope with another diabetes-associated autoantigen, insulinoma antigen-2 (IA-2), to create the fusion peptide IA-2-P2. In streptozotocin-induced diabetic C57BL/6J mice, the IA-2-P2 peptide displayed similar anti-diabetic effects to the control P277 peptide. Also, the IA-2-P2 peptide did not show atherogenic activity in a rabbit model. Our findings indicate the potential of IA-2-P2 as a promising vaccine against type 1 diabetes mellitus.
[Mh] Termos MeSH primário: Chaperonina 60/farmacologia
Diabetes Mellitus Experimental/tratamento farmacológico
Diabetes Mellitus Tipo 1/tratamento farmacológico
Desenho de Drogas
Hipoglicemiantes/farmacologia
Fragmentos de Peptídeos/farmacologia
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/farmacologia
Proteínas Recombinantes de Fusão/farmacologia
Vacinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Aterosclerose/induzido quimicamente
Glicemia/efeitos dos fármacos
Glicemia/metabolismo
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Chaperonina 60/administração & dosagem
Chaperonina 60/toxicidade
Citocinas/metabolismo
Diabetes Mellitus Experimental/sangue
Diabetes Mellitus Experimental/induzido quimicamente
Diabetes Mellitus Experimental/imunologia
Diabetes Mellitus Tipo 1/sangue
Diabetes Mellitus Tipo 1/induzido quimicamente
Diabetes Mellitus Tipo 1/imunologia
Hipoglicemiantes/administração & dosagem
Hipoglicemiantes/toxicidade
Imunização
Ativação Linfocitária/efeitos dos fármacos
Masculino
Camundongos Endogâmicos C57BL
Fragmentos de Peptídeos/administração & dosagem
Fragmentos de Peptídeos/toxicidade
Coelhos
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/administração & dosagem
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/toxicidade
Proteínas Recombinantes de Fusão/administração & dosagem
Proteínas Recombinantes de Fusão/toxicidade
Estreptozocina
Linfócitos T/efeitos dos fármacos
Linfócitos T/imunologia
Linfócitos T/metabolismo
Fatores de Tempo
Vacinas/administração & dosagem
Vacinas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Chaperonin 60); 0 (Cytokines); 0 (Hypoglycemic Agents); 0 (IA-2-P2 peptide); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (Vaccines); 0 (peptide 277, heat shock protein 60); 5W494URQ81 (Streptozocin); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1177/1479164116664189


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[PMID]:28531305
[Au] Autor:Bosi E; Boulware DC; Becker DJ; Buckner JH; Geyer S; Gottlieb PA; Henderson C; Kinderman A; Sosenko JM; Steck AK; Bingley PJ; Type 1 Diabetes TrialNet Study Group
[Ad] Endereço:Diabetes Research Institute, San Raffaele Hospital and San Raffaele Vita Salute University, Milan 20132, Italy.
[Ti] Título:Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives.
[So] Source:J Clin Endocrinol Metab;102(8):2881-2886, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease. Objective: To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. Research Design and Methods: We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated antigen 2, and zinc transporter 8 and islet cell antibodies were tested every 6 to 12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8 years, 8 to 11 years, 12 to 17 years, and ≥18 years, and optimal age breakpoints were identified by recursive partitioning analysis. Results: After median follow-up of 2 years, 141 relatives had developed at least one additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: Relatives with GADA showed a gradual decrease in risk over the four age groups, whereas relatives with IAA showed a sharp decrease above age 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA. Conclusions: In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, whereas immune responses initially directed at glutamic acid decarboxylase can mature over a longer period. These differences have important implications for monitoring these patients and for designing prevention trials.
[Mh] Termos MeSH primário: Autoanticorpos/imunologia
Proteínas de Transporte de Cátions/imunologia
Diabetes Mellitus Tipo 1/imunologia
Família
Glutamato Descarboxilase/imunologia
Insulina/imunologia
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Fatores Etários
Criança
Progressão da Doença
Feminino
Seguimentos
Teste de Tolerância a Glucose
Seres Humanos
Masculino
Radioimunoensaio
Adulto Jovem
Transportador 8 de Zinco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Cation Transport Proteins); 0 (Insulin); 0 (SLC30A8 protein, human); 0 (Zinc Transporter 8); 0 (islet cell antibody); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00569


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[PMID]:28520980
[Au] Autor:Steck AK; Xu P; Geyer S; Redondo MJ; Antinozzi P; Wentworth JM; Sosenko J; Onengut-Gumuscu S; Chen WM; Rich SS; Pugliese A; Type 1 Diabetes TrialNet Study Group
[Ad] Endereço:Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
[Ti] Título:Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?
[So] Source:J Clin Endocrinol Metab;102(8):2873-2880, 2017 Aug 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci. Objective: The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. Design and Setting: The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D. Participants: Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1016 Ab-positive, at-risk non-Hispanic white relatives. Main Outcome Measure: Effect of SNPs on the development of multiple Abs and T1D. Results: Cox proportional analyses included all substantial non-HLA SNPs, HLA genotypes, relationship to proband, sex, age at initial screening, initial Ab type, and number. Factors involved in progression from single to multiple Abs included age at screening, relationship to proband, HLA genotypes, and rs3087243 (cytotoxic T lymphocyte antigen-4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 [GLIS family zinc finger 3 (GLIS3)], and rs3184504 [SH2B adaptor protein 3 (SH2B3)]. When glucose area under the curve (AUC) was included, factors involved in disease progression included glucose AUC, age at screening, Ab number, relationship to proband, HLA genotypes, rs6476839 (GLIS3), and rs7221109 (CCR7). In stratified analyses by age, glucose AUC, age at screening, sibling, HLA genotypes, rs6476839 (GLIS3), and rs4900384 (C14orf64) were significantly associated with progression to diabetes in participants <12 years old, whereas glucose AUC, sibling, rs3184504 (SH2B3), and rs4900384 (C14orf64) were significant in those ≥12. Conclusions: In conclusion, we identified five non-HLA SNPs associated with increased risk of progression from Ab positivity to disease that may improve risk stratification for prevention trials.
[Mh] Termos MeSH primário: Autoanticorpos/imunologia
Diabetes Mellitus Tipo 1/genética
Família
[Mh] Termos MeSH secundário: Adolescente
Adulto
Fatores Etários
Área Sob a Curva
Glicemia/metabolismo
Antígeno CTLA-4/genética
Proteínas de Transporte de Cátions/imunologia
Criança
Diabetes Mellitus Tipo 1/imunologia
Progressão da Doença
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Predisposição Genética para Doença
Genótipo
Teste de Tolerância a Glucose
Glutamato Descarboxilase/imunologia
Cadeias alfa de HLA-DQ/genética
Cadeias beta de HLA-DQ/genética
Cadeias HLA-DRB1/genética
Seres Humanos
Insulina/imunologia
Masculino
Polimorfismo de Nucleotídeo Único
Proteínas/genética
RNA Longo não Codificante/genética
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
Receptores CCR7/genética
Risco
Medição de Risco
Fatores de Transcrição/genética
Adulto Jovem
Transportador 8 de Zinco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Blood Glucose); 0 (CCR7 protein, human); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (Cation Transport Proteins); 0 (GLIS3 protein, human); 0 (HLA-DQ alpha-Chains); 0 (HLA-DQ beta-Chains); 0 (HLA-DQA1 antigen); 0 (HLA-DQB1 antigen); 0 (HLA-DRB1 Chains); 0 (Insulin); 0 (LNK protein, human); 0 (Proteins); 0 (RNA, Long Noncoding); 0 (Receptors, CCR7); 0 (SLC30A8 protein, human); 0 (Transcription Factors); 0 (Zinc Transporter 8); 0 (islet cell antibody); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-4003


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[PMID]:28481342
[Au] Autor:Feigin ME; Garvin T; Bailey P; Waddell N; Chang DK; Kelley DR; Shuai S; Gallinger S; McPherson JD; Grimmond SM; Khurana E; Stein LD; Biankin AV; Schatz MC; Tuveson DA
[Ad] Endereço:Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
[Ti] Título:Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma.
[So] Source:Nat Genet;49(6):825-833, 2017 Jun.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Carcinoma Ductal Pancreático/genética
Regulação Neoplásica da Expressão Gênica
Mutação
Neoplasias Pancreáticas/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/mortalidade
Carcinoma Ductal Pancreático/mortalidade
Seres Humanos
Neoplasias Pancreáticas/mortalidade
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética
Simportadores de Cloreto de Sódio-Potássio/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SLC12A8 protein, human); 0 (Sodium-Potassium-Chloride Symporters); EC 3.1.3.48 (PTPRN2 protein, human); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3861


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[PMID]:28174261
[Au] Autor:Acevedo-Calado M; James EA; Morran MP; Pietropaolo SL; Ouyang Q; Arribas-Layton D; Songini M; Liguori M; Casu A; Auchus RJ; Huang S; Yu L; Michels A; Gianani R; Pietropaolo M
[Ad] Endereço:Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
[Ti] Título:Identification of Unique Antigenic Determinants in the Amino Terminus of IA-2 (ICA512) in Childhood and Adult Autoimmune Diabetes: New Biomarker Development.
[So] Source:Diabetes Care;40(4):561-568, 2017 Apr.
[Is] ISSN:1935-5548
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes. RESEARCH DESIGN AND METHODS: Clinically diagnosed patients with type 2 diabetes ( = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes ( = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed. RESULTS: IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4 T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes ( = 18) and HLA-matched healthy subjects ( = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec. CONCLUSIONS: We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 1/imunologia
Epitopos/imunologia
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Autoanticorpos/imunologia
Autoantígenos/imunologia
Biomarcadores/análise
Criança
Pré-Escolar
Diabetes Mellitus Tipo 2/imunologia
Feminino
Glutamato Descarboxilase/imunologia
Seres Humanos
Leucócitos Mononucleares/imunologia
Masculino
Meia-Idade
Linfócitos T/imunologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Autoantigens); 0 (Biomarkers); 0 (Epitopes); EC 3.1.3.48 (PTPRN protein, human); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.2337/dc16-1527


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[PMID]:27872147
[Au] Autor:Cianciaruso C; Phelps EA; Pasquier M; Hamelin R; Demurtas D; Alibashe Ahmed M; Piemonti L; Hirosue S; Swartz MA; De Palma M; Hubbell JA; Baekkeskov S
[Ad] Endereço:Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
[Ti] Título:Primary Human and Rat ß-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity.
[So] Source:Diabetes;66(2):460-473, 2017 Feb.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The target autoantigens in several organ-specific autoimmune diseases, including type 1 diabetes (T1D), are intracellular membrane proteins, whose initial encounter with the immune system is poorly understood. Here we propose a new model for how these proteins can initiate autoimmunity. We found that rat and human pancreatic islets release the intracellular ß-cell autoantigens in human T1D, GAD65, IA-2, and proinsulin in exosomes, which are taken up by and activate dendritic cells. Accordingly, the anchoring of GAD65 to exosome-mimetic liposomes strongly boosted antigen presentation and T-cell activation in the context of the human T1D susceptibility haplotype HLA-DR4. Cytokine-induced endoplasmic reticulum stress enhanced exosome secretion by ß-cells; induced exosomal release of the immunostimulatory chaperones calreticulin, Gp96, and ORP150; and increased exosomal stimulation of antigen-presenting cells. We propose that stress-induced exosomal release of intracellular autoantigens and immunostimulatory chaperones may play a role in the initiation of autoimmune responses in T1D.
[Mh] Termos MeSH primário: Autoantígenos/imunologia
Autoimunidade/imunologia
Exossomos/metabolismo
Glutamato Descarboxilase/imunologia
Células Secretoras de Insulina/metabolismo
Proinsulina/imunologia
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
[Mh] Termos MeSH secundário: Animais
Calreticulina/imunologia
Linhagem Celular
Células Cultivadas
Células Dendríticas/imunologia
Diabetes Mellitus Tipo 1/imunologia
Estresse do Retículo Endoplasmático/imunologia
Ensaio de Imunoadsorção Enzimática
Exossomos/imunologia
Exossomos/ultraestrutura
Imunofluorescência
Predisposição Genética para Doença
Antígeno HLA-DR4/genética
Proteínas de Choque Térmico HSP70/imunologia
Haplótipos
Seres Humanos
Ilhotas Pancreáticas/metabolismo
Lipossomos/metabolismo
Lipossomos/ultraestrutura
Glicoproteínas de Membrana/imunologia
Camundongos Endogâmicos NOD
Microscopia Eletrônica de Transmissão
Técnicas de Cultura de Órgãos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (Calreticulin); 0 (HLA-DR4 Antigen); 0 (HSP70 Heat-Shock Proteins); 0 (Liposomes); 0 (Membrane Glycoproteins); 0 (endoplasmin); 0 (oxygen-regulated proteins); 9035-68-1 (Proinsulin); EC 3.1.3.48 (PTPRN protein, human); EC 3.1.3.48 (Ptprn protein, mouse); EC 3.1.3.48 (Ptprn protein, rat); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase); EC 4.1.1.15 (glutamate decarboxylase 2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE
[do] DOI:10.2337/db16-0671


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[PMID]:27690455
[Au] Autor:Bian X; Wasserfall C; Wallstrom G; Wang J; Wang H; Barker K; Schatz D; Atkinson M; Qiu J; LaBaer J
[Ad] Endereço:The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
[Ti] Título:Tracking the Antibody Immunome in Type 1 Diabetes Using Protein Arrays.
[So] Source:J Proteome Res;16(1):195-203, 2017 Jan 06.
[Is] ISSN:1535-3907
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We performed an unbiased proteome-scale profiling of humoral autoimmunity in recent-onset type 1 diabetes (T1D) patients and nondiabetic controls against ∼10 000 human proteins using a Nucleic Acid Programmable Protein Array (NAPPA) platform, complemented by a knowledge-based selection of proteins from genes enriched in human pancreas. Although the global response was similar between cases and controls, we identified and then validated six specific novel T1D-associated autoantibodies (AAbs) with sensitivities that ranged from 16 to 27% at 95% specificity. These included AAbs against PTPRN2, MLH1, MTIF3, PPIL2, NUP50 (from NAPPA screening), and QRFPR (by targeted ELISA). Immunohistochemistry demonstrated that NUP50 protein behaved differently in islet cells, where it stained both nucleus and cytoplasm, compared with only nuclear staining in exocrine pancreas. Conversely, PPIL2 staining was absent in islet cells, despite its presence in exocrine cells. The combination of anti-PTPRN2, -MLH1, -PPIL2, and -QRFPR had an AUC of 0.74 and 37.5% sensitivity at 95% specificity. These data indicate that these markers behave independently and support the use of unbiased screening to find biomarkers because the majority was not predicted based on predicted abundance. Our study enriches the knowledge of the "autoantibody-ome" in unprecedented breadth and width.
[Mh] Termos MeSH primário: Autoanticorpos/genética
Ciclofilinas/imunologia
Diabetes Mellitus Tipo 1/imunologia
Proteína 1 Homóloga a MutL/imunologia
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
Receptores Acoplados a Proteínas-G/imunologia
[Mh] Termos MeSH secundário: Adolescente
Especificidade de Anticorpos
Autoanticorpos/biossíntese
Autoimunidade/genética
Biomarcadores/análise
Estudos de Casos e Controles
Criança
Ciclofilinas/genética
Diabetes Mellitus Tipo 1/diagnóstico
Diabetes Mellitus Tipo 1/genética
Diabetes Mellitus Tipo 1/patologia
Feminino
Seres Humanos
Imunidade Humoral/genética
Masculino
Proteína 1 Homóloga a MutL/genética
Pâncreas/imunologia
Pâncreas/patologia
Análise Serial de Proteínas
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética
Receptores Acoplados a Proteínas-G/genética
Sensibilidade e Especificidade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Biomarkers); 0 (MLH1 protein, human); 0 (QRFPR protein, human); 0 (Receptors, G-Protein-Coupled); EC 3.1.3.48 (PTPRN2 protein, human); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 3.6.1.3 (MutL Protein Homolog 1); EC 5.2.1.- (Cyclophilins); EC 5.2.1.8 (PPIL2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161004
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jproteome.6b00354


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[PMID]:27283793
[Au] Autor:Warvsten A; Björnfors M; Arvidsson M; Vaziri-Sani F; Jönsson I; Olsson GE; Ahlm C; Larsson HE; Lernmark Å; Nilsson AL
[Ad] Endereço:Department of Clinical Sciences, Skåne University Hospital SUS, Lund University/CRC, Malmö, Sweden.
[Ti] Título:Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden.
[So] Source:J Med Virol;89(1):24-31, 2017 Jan.
[Is] ISSN:1096-9071
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA), or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radio binding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA, and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615), and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (P = 0.007) and GADA (P < 0.001), but not with IA-2A (P = 0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (P = 0.002) and GADA (P < 0.001), but not of IA-2A (P = 0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer. In conclusion, LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild. J. Med. Virol. 89:24-31, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Autoanticorpos/sangue
Glutamato Descarboxilase/imunologia
Insulina/imunologia
Parechovirus/isolamento & purificação
Infecções por Picornaviridae/veterinária
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
Doenças dos Roedores/patologia
[Mh] Termos MeSH secundário: Animais
Arvicolinae
Feminino
Masculino
Infecções por Picornaviridae/imunologia
Infecções por Picornaviridae/virologia
Doenças dos Roedores/imunologia
Doenças dos Roedores/virologia
Suécia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Insulin); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase); EC 4.1.1.15 (glutamate decarboxylase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160611
[St] Status:MEDLINE
[do] DOI:10.1002/jmv.24597


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[PMID]:26802570
[Au] Autor:Bansal N; Hampe CS; Rodriguez L; O'Brian Smith E; Kushner J; Balasubramanyam A; Redondo MJ
[Ad] Endereço:Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
[Ti] Título:DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes.
[So] Source:Diabet Med;34(5):641-646, 2017 May.
[Is] ISSN:1464-5491
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: To study whether DPD epitope-specific glutamate decarboxylase autoantibodies are found more frequently in children with milder forms of Type 1 diabetes. METHODS: We prospectively evaluated 75 children with new-onset autoimmune Type 1 diabetes, in whom we collected demographic, anthropometric and clinical data and measured islet autoantibodies. Glutamate decarboxylase 65 autoantibody-positive samples were analysed for epitope specificities using recombinant Fab against the DPD-defined epitope of glutamate decarboxylase 65. RESULTS: After adjustment for age, positive DPD epitope recognition was significantly associated with higher C-peptide levels at onset (P = 0.02, r =0.21, n = 35), and high DPD recognition in the highest quartile tended to be associated with HbA ≤ 53 mmol/mol (7%) at the last follow-up [mean (sd) follow-up 1.3 (0.4) years; P = 0.07; for the model, P = 0.044, n = 30)]. Age- and sex-adjusted BMI percentile was significantly correlated with recognition of the DPD-defined epitope (P < 0.03, r =0.14, n = 34), but this correlation was driven by the older age group (age ≥ 10 years; P = 0.016, r =0.27, n = 21) and was not significant in younger children (P = 0.93, n = 13). There were no independent associations with sex, race/ethnicity, diabetic ketoacidosis, HbA , HLA DR3-DQ2/DR4-DQ8 or autoantibody number. CONCLUSIONS: Our findings suggest that recognition of the DPD-defined glutamate decarboxylase 65 autoantibody epitope at Type 1 diabetes onset is directly associated with ß-cell function, BMI and age, which supports the hypothesis that immunological factors contribute to the clinical heterogeneity of Type 1 diabetes. Larger studies relating epitope-specific glutamate decarboxylase 65 autoantibody to clinical phenotype in children with Type 1 diabetes are warranted.
[Mh] Termos MeSH primário: Autoanticorpos/sangue
Diabetes Mellitus Tipo 1/sangue
Glutamato Descarboxilase/imunologia
[Mh] Termos MeSH secundário: Adolescente
Especificidade de Anticorpos
Autoanticorpos/química
Peptídeo C/sangue
Proteínas de Transporte de Cátions/imunologia
Criança
Pré-Escolar
Diabetes Mellitus Tipo 1/imunologia
Epitopos/imunologia
Feminino
Glutamato Descarboxilase/química
Seres Humanos
Lactente
Masculino
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
Transportador 8 de Zinco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (C-Peptide); 0 (Cation Transport Proteins); 0 (Epitopes); 0 (SLC30A8 protein, human); 0 (Zinc Transporter 8); EC 3.1.3.48 (PTPRN2 protein, human); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8); EC 4.1.1.15 (Glutamate Decarboxylase); EC 4.1.1.15 (glutamate decarboxylase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160124
[St] Status:MEDLINE
[do] DOI:10.1111/dme.13077


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[PMID]:27881117
[Au] Autor:Guerra LL; Faccinetti NI; Trabucchi A; Rovitto BD; Sabljic AV; Poskus E; Iacono RF; Valdez SN
[Ad] Endereço:Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Estudios de la Inmunidad Humoral "Prof. Ricardo A. Margni" (IDEHU), Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
[Ti] Título:Novel prokaryotic expression of thioredoxin-fused insulinoma associated protein tyrosine phosphatase 2 (IA-2), its characterization and immunodiagnostic application.
[So] Source:BMC Biotechnol;16(1):84, 2016 Nov 24.
[Is] ISSN:1472-6750
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The insulinoma associated protein tyrosine phosphatase 2 (IA-2) is one of the immunodominant autoantigens involved in the autoimmune attack to the beta-cell in Type 1 Diabetes Mellitus. In this work we have developed a complete and original process for the production and recovery of the properly folded intracellular domain of IA-2 fused to thioredoxin (TrxIA-2 ) in Escherichia coli GI698 and GI724 strains. We have also carried out the biochemical and immunochemical characterization of TrxIA-2 and design variants of non-radiometric immunoassays for the efficient detection of IA-2 autoantibodies (IA-2A). RESULTS: The main findings can be summarized in the following statements: i) TrxIA-2 expression after 3 h of induction on GI724 strain yielded ≈ 10 mg of highly pure TrxIA-2 /L of culture medium by a single step purification by affinity chromatography, ii) the molecular weight of TrxIA-2 (55,358 Da) could be estimated by SDS-PAGE, size exclusion chromatography and mass spectrometry, iii) TrxIA-2 was properly identified by western blot and mass spectrometric analysis of proteolytic digestions (63.25 % total coverage), iv) excellent immunochemical behavior of properly folded full TrxIA-2 was legitimized by inhibition or displacement of [ S]IA-2 binding from IA-2A present in Argentinian Type 1 Diabetic patients, v) great stability over time was found under proper storage conditions and vi) low cost and environmentally harmless ELISA methods for IA-2A assessment were developed, with colorimetric or chemiluminescent detection. CONCLUSIONS: E. coli GI724 strain emerged as a handy source of recombinant IA-2 , achieving high levels of expression as a thioredoxin fusion protein, adequately validated and applicable to the development of innovative and cost-effective immunoassays for IA-2A detection in most laboratories.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 1/diagnóstico
Diabetes Mellitus Tipo 1/imunologia
Escherichia coli/metabolismo
Engenharia de Proteínas/métodos
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia
Tiorredoxinas/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores/sangue
Diabetes Mellitus Tipo 1/sangue
Escherichia coli/genética
Feminino
Seres Humanos
Testes Imunológicos/métodos
Masculino
Meia-Idade
Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/imunologia
Tiorredoxinas/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Recombinant Fusion Proteins); 52500-60-4 (Thioredoxins); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161125
[St] Status:MEDLINE



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