المؤلفون: Martin Haupt-Jorgensen, Karsten Buschard, Flemming Pociot, Kristina Pedersen, Knut Dahl-Jørgensen, Ivan C. Gerling, Simranjeet Kaur, Lars Krogvold

المصدر: Diabetologia
Pedersen, K, Haupt-Jorgensen, M, Krogvold, L, Kaur, S, Gerling, I C, Pociot, F, Dahl-Jørgensen, K & Buschard, K 2021, ' Genetic predisposition in the 2′-5′A pathway in the development of type 1 diabetes : potential contribution to dysregulation of innate antiviral immunity ', Diabetologia, vol. 64, no. 8, pp. 1805-1815 . https://doi.org/10.1007/s00125-021-05469-5Test

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Ribonuclease L, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Disease, Type 2 diabetes, Biology, Interferon α, RNase L, Type 1 interferon, Antiviral Agents, Polymorphism, Single Nucleotide, Article, Virus, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal Medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Gene, Type 1 diabetes, Oligoribonucleotides, Adenine Nucleotides, RNA-Binding Proteins, medicine.disease, Immunity, Innate, Toll-like receptor 7, Diabetes Mellitus, Type 1, 030104 developmental biology, Gene Expression Regulation, Virus Diseases, Immunology, 2′-5′A pathway, 2′-5′ Oligoadenylate synthetase, Female, Genome-Wide Association Study

الوصف: Aims/hypothesis The incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift. Viruses may play an important role in the disease, as they seem to activate the 2′-5′-linked oligoadenylate (2′-5′A) pathway of the innate antiviral immune system. Our aim was to investigate this possibility. Methods Innate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data. SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined. These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD). Results We found 27 novel SNPs in genes nominally associated with type 1 diabetes. Three of those SNPs were located upstream of the 2′-5′A pathway, namely SNP rs4767000 (p = 1.03 × 10−9, OR 1.123), rs1034687 (p = 2.16 × 10−7, OR 0.869) and rs739744 (p = 1.03 × 10−9, OR 1.123). We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel. The most aberrant genes were a group of IFN-stimulated genes. Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10−4, 95% CI −0.43, −0.15); MX1 increased by 142% (p < 1.00 × 10−4, 95% CI −0.52, −0.22); and ISG15 increased by 197% (p = 2.00 × 10−4, 95% CI −0.68, −0.18). Conclusions/interpretation We identified a genetic predisposition in the 2′-5′A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes. This study describes a potential role for the 2′-5′A pathway and other components of the innate antiviral immune system in beta cell autoimmunity. Graphical abstract

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc7c11e2de9bab5e6655271157f4e1c3Test
https://doi.org/10.1007/s00125-021-05469-5Test

المؤلفون: Carmella Evans-Molina, Clive Wasserfall, Megan T Legge, Eleni Beli, Craig A. Beam, Ryan Silk, Kieran M. Mcgrail, Linda A. DiMeglio, Mark A. Atkinson, Stephanie Woerner, Maria B. Grant

المصدر: Diabetologia
Beam, C A, Beli, E, Wasserfall, C H, Woerner, S E, Legge, M T, Evans-Molina, C, McGrail, K M, Silk, R, Grant, M B, Atkinson, M A & DiMeglio, L A 2021, ' Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes ', Diabetologia . https://doi.org/10.1007/s00125-021-05468-6Test

مصطلحات موضوعية: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, type 1 diabetes, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Circadian clock, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, Cytotoxic T cell, education.field_of_study, B-Lymphocytes, Immune cells, Flow Cytometry, Circadian Rhythm, Cytokine, Type 1 diabetes, Female, Adult, Adolescent, Period (gene), Population, Biology, Chronobiology Disorders, circadian ryhtms, Article, 03 medical and health sciences, Clinical, Young Adult, Immune system, SDG 3 - Good Health and Well-being, Circadian Clocks, Internal Medicine, medicine, Animals, Humans, Circadian rhythms, Circadian rhythm, Lymphocyte Count, education, Interleukin-6, Dendritic Cells, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 1, Immune System, Immunology, 030217 neurology & neurosurgery

الوصف: Aims/hypothesis The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. Methods Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18–40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. Results Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. Conclusions/interpretation Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation. Graphical abstract

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5304384a2a7eb86434e13bd1acc63ddbTest
http://europepmc.org/articles/PMC8245361Test

المؤلفون: Peter J. Oefner, Damian R. Plichta, Anders Ø. Petersen, Daniel C. Chung, Wolfram Gronwald, Ramnik J. Xavier, Annamari Ranki, Hera Vlamakis, Martta Jokinen, Gerhard Liebisch, Katja Dettmer

المصدر: J Allergy Clin Immunol
Petersen, A, Jokinen, M, Plichta, D R, Liebisch, G, Gronwald, W, Dettmer, K, Oefner, P J, Vlamakis, H, Chung, D C, Ranki, A & Xavier, R J 2021, ' Cytokine-specific autoantibodies shape the gut microbiome in autoimmune polyendocrine syndrome type 1 ', Journal of Allergy and Clinical Immunology, vol. 148, no. 3, pp. 876-888 . https://doi.org/10.1016/j.jaci.2021.03.025Test

مصطلحات موضوعية: Male, 0301 basic medicine, Lactobacillus rhamnosus GG, Autoimmunity, medicine.disease_cause, GABA, Autoantibody, 0302 clinical medicine, Immunology and Allergy, Child, Polyendocrinopathies, Autoimmune, Irritable bowel syndrome, biology, Lacticaseibacillus rhamnosus, Tryptophan, Middle Aged, 3. Good health, Actinobacteria, Diarrhea, Chemokine, Child, Preschool, Cytokines, Female, medicine.symptom, Adult, Adolescent, Immunology, Article, Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Lactobacillus rhamnosus, medicine, APS-1, Humans, Microbiome, Cytokine, Aged, Autoantibodies, Autoimmune disease, Bacteroidetes, business.industry, Probiotics, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, 030104 developmental biology, Autoimmune polyendocrine syndrome type 1, Mutation, business, 030217 neurology & neurosurgery, APECED, Transcription Factors

الوصف: BACKGROUND: Gastrointestinal dysfunction is a frequent and disabling manifestation of autoimmune polyendocrine syndrome type 1 (APS-1), a rare monogenic multi-organ autoimmune disease caused by the loss of central AIRE-controlled immune tolerance. OBJECTIVE: We aimed to understand the role of the gut microbiome in APS-1 symptoms and potentially alleviate common gastrointestinal symptoms by probiotic intervention. METHODS: We characterized the fecal microbiomes of 28 APS-1 patients and searched for associations with gastrointestinal symptoms, circulating anti-cytokine autoantibodies and tryptophan-related metabolites. We additionally administered daily doses of the probiotic Lactobacillus rhamnosus GG for three months. RESULTS: Of 581 metagenomic operational taxonomic units (mOTUs) characterized in total, 14 were significantly associated with APS-1 compared to healthy controls, with six mOTUs depleted and eight enriched in APS-1 patients. Four overabundant mOTUs were significantly associated with severity of constipation. We observed phylogenetically conserved microbial associations with autoantibodies against cytokines. After the three-month intervention with the probiotic L. rhamnosus GG, a subset of gastrointestinal symptoms were alleviated. L. rhamnosus GG abundance was increased post-intervention and corresponded with decreased abundances of Alistipes onderdonkii and Collinsella aerofaciens, two species positively associated with severity of diarrhea in APS-1 patients. CONCLUSION: The APS-1 microbiome correlates with several APS-1 symptoms, some of which are alleviated after a three-month L. rhamnosus GG intervention. Autoantibodies against cytokines appear to shape the gut microbiome by positively correlating with a taxonomically consistent group of bacteria. CLINICAL IMPLICATIONS: Administration of L. rhamnosus GG appears to alleviate certain gastrointestinal symptoms of APS-1.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::808656f1200240d39f165329158bc32eTest
https://doi.org/10.1016/j.jaci.2021.03.025Test

المؤلفون: Rafick-Pierre Sekaly, Elisavet Serti, Shannon K. Boi, Ashley H. Castellaw, Dietmar Zehn, Hai Nguyen, Hazem E. Ghoneim, Caitlin C. Zebley, Michael E. Busch, Mars Stone, Rachel L. Rutishauser, Francesca Alfei, Eddie A. James, Maureen A. McGargill, Cate Speake, Ben Youngblood, Jeremy Chase Crawford, Yiping Fan, Gerald T. Nepom, Steven G. Deeks, Hossam A. Abdelsamed, Susan Pereira Ribeiro, Shanta Alli, Hongjian Jin, Laurence A. Turka

المصدر: Nature immunology
Nature immunology, vol 21, iss 5
Nature Immunology

مصطلحات موضوعية: 0301 basic medicine, Male, Cell Plasticity, CD8-Positive T-Lymphocytes, Regenerative Medicine, Autoantigens, Epigenesis, Genetic, Mice, 0302 clinical medicine, Stem Cell Research - Nonembryonic - Human, Insulin-Secreting Cells, 2.1 Biological and endogenous factors, Immunology and Allergy, Cytotoxic T cell, Aetiology, Cells, Cultured, Cultured, Diabetes, Acquired immune system, Flow Cytometry, Cell biology, medicine.anatomical_structure, Female, Stem cell, Beta cell, Single-Cell Analysis, Type 1, Adult, Pluripotent Stem Cells, Adolescent, Cells, T cell, Immunology, Biology, Autoimmune Disease, Article, 03 medical and health sciences, Young Adult, Genetic, Diabetes Mellitus, Genetics, medicine, Animals, Humans, Epigenetics, Metabolic and endocrine, DNA Methylation, Stem Cell Research, 030104 developmental biology, Diabetes Mellitus, Type 1, T cell differentiation, Immunologic Memory, CD8, Epigenesis, 030215 immunology

الوصف: The pool of beta cell-specific CD8+ T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell 'multipotency index' and found that beta cell-specific CD8+ T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T cells. Assessment of beta cell-specific CD8+ T cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses and document the use of this methylation-based multipotency index for investigating human and mouse CD8+ T cell differentiation.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::89c766e2ff25c8b1dacf4caad1134276Test
http://europepmc.org/articles/PMC7183435Test

المؤلفون: Heikki Hyöty, Santosh Lamichhane, Jorma Ilonen, Partho Sen, Jorma Toppari, Tuomas Lindeman, Matej Orešič, Esko Kemppainen, Riitta Veijola, María Asunción López-Bascón, Tuukka Rönkkö, Mikael Knip, Tuulia Hyötyläinen, Alex M. Dickens

المساهمون: Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, HUS Children and Adolescents, Children's Hospital, Research Programs Unit, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine

المصدر: Diabetologia

مصطلحات موضوعية: Male, 0301 basic medicine, PREDICTION, Endocrinology, Diabetes and Metabolism, CHILDHOOD, Autoimmunity, ACTIVATION, Transcriptome, 0302 clinical medicine, Longitudinal Studies, RISK, Aged, 80 and over, Sisätaudit - Internal medicine, Middle Aged, 3. Good health, Type 1 diabetes, Disease Progression, Female, Birth cohort, Adult, FEASIBILITY, Genotype, 030209 endocrinology & metabolism, Ceramides, Peripheral blood mononuclear cell, Article, Islets of Langerhans, Young Adult, 03 medical and health sciences, Metabolomics, Immune system, INFLAMMATION, Lipidomics, Internal Medicine, medicine, Humans, Aged, Autoantibodies, Sphingolipids, business.industry, Sphingolipid metabolism, Autoantibody, Lipid metabolism, Lipid Metabolism, medicine.disease, MICROBIOME, Diabetes Mellitus, Type 1, 030104 developmental biology, Genome-scale metabolic modelling, Peripheral blood mononuclear cells, ANTIBODIES, Immunology, Leukocytes, Mononuclear, 3111 Biomedicine, ISLET AUTOANTIBODIES, business

الوصف: Aims/hypothesis Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes. Methods In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10). Results During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression. Conclusions/interpretation Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes. Data availability The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolightsTest/), under accession number MTBLS1015.

وصف الملف: application/pdf; fulltext; 1017–1031

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::db8db141e75e5dead62b6ef2f2c63a3dTest
https://doi.org/10.1007/s00125-020-05107-6Test

المؤلفون: Vittorio Krogh, Rudolf Kaaks, Yvonne T. van der Schouw, Gianluca Severi, Eva Ardanaz, Marc J. Gunter, Tilman Kühn, Nicholas J. Wareham, Timothy J. Key, Francesca Mancini, Carlotta Sacerdote, María José Sánchez, Heiner Boeing, Annemieke M.W. Spijkerman, Peter M. Nilsson, Guy Fagherazzi, Miren Dorronsoro, María Dolores Chirlaque, Kay-Tee Khaw, Olov Rolandsson, Stephen J. Sharp, Salvatore Panico, Domenico Palli, Nita G. Forouhi, Christiane S. Hampe, Claudia Langenberg, Kim Overvad, Rosario Tumino, Elio Riboli

المساهمون: Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), LSHM_CT_2006_037197 N∫ 6236 National Institutes of Health, NIH: DK26190 Compagnia di San Paolo Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Medical Research Council, MRC: MC_UU_12015/1, MC_UU_12015/5, MR/N003284/1 Cancer Research UK, CRUK World Cancer Research Fund, WCRF Bundesministerium für Bildung und Forschung, BMBF Västerbotten Läns Landsting Ministerie van Volksgezondheid, Welzijn en Sport, VWS Agentschap NL: IGE05012 Vetenskapsrådet, VR Umeå Universitet Bundesministerium für Forschung und Technologie, BMFT Deutsche Krebshilfe Bundesministerium für Bildung und Frauen, BMBF Stichting Diabetes Onderzoek Nederland NIHR Imperial Biomedical Research Centre, BRC NIHR Cambridge Biomedical Research Centre: IS-BRC-1215-20014, O. Rolandsson: The Västerboten County Council, M. Dorronsoro: We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as to the team of trained nurses who participated in the recruitment, R. Kaaks: German Cancer Aid, German Ministry of Research (BMBF), K. T. Khaw: Medical Research Council UK, Cancer Research UK, T. Kühn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF), S. Panico: Compagnia di San Paolo, A. M. W. Spijkerman: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Statistics Netherlands (the Netherlands), EPIC Ragusa acknowledges for their participation blood donors of AVIS-Ragusa (local blood donors association), Y. T. van der Schouw: EPIC Bilthoven and Utrecht acknowledge the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), Dutch ZON (Zorg Onderzoek Nederland), WCRF, Statistics Netherland, E. Riboli: Imperial College Biomedical Research Centre., Open access funding provided by Umea University. Funding for the InterAct project was provided by the EU FP6 Programme (grant number LSHM_CT_2006_037197). The autoantibody measurement was funded by Västerbotten County Council and Umeå University, Sweden (OR), the National Institutes of Health (DK26190) (CSH) and the Medical Research Council (MC_UU_12015/1) (NJW). OR: the Västerbotten County Council, Umeå University, MDC: Health Research Fund (FIS) of the Spanish Ministry of Health, Murcia Regional Government (N∫ 6236), EA: the Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government, RK: German Cancer Aid, the German Ministry of Research (BMBF), TJK: Cancer Research UK, KTK: the Medical Research Council UK, Cancer Research UK, PMN: the Swedish Research Council, KO: the Danish Cancer Society, SP: Compagnia di San Paolo, AMWS: the Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands, RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government, AMWS: LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), YTvdS: verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht, LK Research Funds, Dutch Prevention Funds, NGF: MRC core support (MC_UU_12015/5), NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Acknowledgements, We thank all EPIC participants and staff for their contribution to this study. We thank N. Kerrison (MRC Epidemiology Unit, Cambridge, UK) for managing the data and the laboratory team at the MRC Epidemiology Unit, Cambridge for managing the blood samples for the EPIC-InterAct project. We thank the participants of the Spanish EPIC cohort for their contribution to the study as well as the team of trained nurses who participated in the recruitment. O. Rolandsson: The V?sterboten County Council, T. K?hn: German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF), E. Riboli: Imperial College Biomedical Research Centre. Some of the data were presented as an abstract at the 54th EASD Annual Meeting in 2018., Rolandsson, Olov [0000-0002-1341-6828], Apollo - University of Cambridge Repository

المصدر: Rolandsson, O, Hampe, C S, Sharp, S J, Ardanaz, E, Boeing, H, Fagherazzi, G, Mancini, F R, Nilsson, P M, Overvad, K, Chirlaque, M-D, Dorronsoro, M, Gunter, M J, Kaaks, R, Key, T J, Khaw, K-T, Krogh, V, Kühn, T, Palli, D, Panico, S, Sacerdote, C, Sánchez, M-J, Severi, G, Spijkerman, A M W, Tumino, R, van der Schouw, Y T, Riboli, E, Forouhi, N G, Langenberg, C & Wareham, N J 2020, ' Autoimmunity plays a role in the onset of diabetes after 40 years of age ', Diabetologia, vol. 63, no. 2, pp. 266-277 . https://doi.org/10.1007/s00125-019-05016-3Test
Diabetologia
Diabetologia, Springer Verlag, 2020, 63 (2), pp.266-277. ⟨10.1007/s00125-019-05016-3⟩
Diabetologia, 63, 266. Springer Verlag

مصطلحات موضوعية: Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Autoimmunity, Type 2 diabetes, medicine.disease_cause, LADA, Endocrinology, Autoantibody, 0302 clinical medicine, POPULATION, RISK, 0303 health sciences, Glutamate Decarboxylase, ANTIBODY POSITIVITY, GAD, Middle Aged, Phenotype, Genetic risk score, Pathophysiology, 3. Good health, Diabetes and Metabolism, Type 1 diabetes, Endokrinologi och diabetes, Female, Life Sciences & Biomedicine, Adult, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Antibodies, Article, 1117 Public Health and Health Services, Endocrinology & Metabolism, 03 medical and health sciences, GLUTAMIC-ACID DECARBOXYLASE, Insulin resistance, Diabetes mellitus, Internal Medicine, medicine, Humans, TYPE-1, Aged, 030304 developmental biology, Science & Technology, business.industry, RECOGNITION, 1103 Clinical Sciences, ADULTS, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Incident diabetes, Case-Control Studies, Immunology, 1114 Paediatrics and Reproductive Medicine, AUTOANTIBODIES, indident diabetes, business

الوصف: Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

وصف الملف: application/pdf; text/xml; image/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::46551c110c8a2c18bb7e24b7c5c12882Test
https://doi.org/10.1007/s00125-019-05016-3Test

المؤلفون: Kevan C, Herold, Brian N, Bundy, S Alice, Long, Jeffrey A, Bluestone, Linda A, DiMeglio, Matthew J, Dufort, Stephen E, Gitelman, Peter A, Gottlieb, Jeffrey P, Krischer, Peter S, Linsley, Jennifer B, Marks, Wayne, Moore, Antoinette, Moran, Henry, Rodriguez, William E, Russell, Desmond, Schatz, Jay S, Skyler, Eva, Tsalikian, Diane K, Wherrett, Anette-Gabriele, Ziegler, Carla J, Greenbaum, Stuart, Weinzimer

المصدر: The New England journal of medicine, vol 381, iss 7

مصطلحات موضوعية: Male, CD3 Complex, T-Lymphocytes, 030204 cardiovascular system & hematology, Medical and Health Sciences, HLA-DR3 Antigen, 0302 clinical medicine, Monoclonal, Medicine, 030212 general & internal medicine, Child, Humanized, Glucose tolerance test, biology, Teplizumab, medicine.diagnostic_test, Anti-CD3 Antibody, Diabetes, General Medicine, Middle Aged, 6.1 Pharmaceuticals, Disease Progression, Female, Antibody, Type 1, medicine.drug, Adult, Adolescent, Clinical Trials and Supportive Activities, Metabolic and Endocrine, Antibodies, Monoclonal, Humanized, Autoimmune Disease, Antibodies, Article, Young Adult, 03 medical and health sciences, Double-Blind Method, Clinical Research, General & Internal Medicine, Lymphopenia, Diabetes mellitus, Diabetes Mellitus, HLA-DR4 Antigen, Humans, Lymphocyte Count, Proportional Hazards Models, Autoimmune disease, Type 1 diabetes, business.industry, Prevention, Type 1 Diabetes TrialNet Study Group, Exanthema, Glucose Tolerance Test, medicine.disease, Diabetes Mellitus, Type 1, Immunology, biology.protein, business

الوصف: BackgroundType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.MethodsWe conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.ResultsA total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.ConclusionsTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::52e74cac9934865ec3bde41d3e5f7293Test
https://doi.org/10.1056/nejmoa1902226Test

المؤلفون: Jonathan Hemler, Xuemei Yu, Sierra Barone, Jonathan M. Irish, Nowrin U. Chowdhury, Valerie A. Gerriets, Jeffrey C. Rathmell, Masha V. Poyurovsky, Xiang Ye, Kellen L. Olszewski, Dawn C. Newcomb, Kirsten Young, Ryszard Dworski, Peter J. Siska, Matthew Z. Madden, Jacqueline Cephus, Diana C. Contreras Healey, Jason W. Locasale, R. Stokes Peebles, Debolanle O. Dahunsi

المصدر: J Immunol

مصطلحات موضوعية: Blood Glucose, Male, Glutamine, medicine.medical_treatment, Dexamethasone, Mice, 0302 clinical medicine, Immunology and Allergy, Lung, Cells, Cultured, Glucose Transporter Type 1, biology, Glutaminase, Pyroglyphidae, Alternaria, Drug Synergism, Middle Aged, Healthy Volunteers, Cytokine, Female, medicine.symptom, Bronchoalveolar Lavage Fluid, Immunosuppressive Agents, Adult, Primary Cell Culture, Immunology, Inflammation, Carbohydrate metabolism, Article, Young Adult, 03 medical and health sciences, Th2 Cells, In vivo, medicine, Animals, Humans, House dust mite, business.industry, Glucose transporter, biology.organism_classification, Asthma, T cell cytokine production, respiratory tract diseases, Disease Models, Animal, Case-Control Studies, Th17 Cells, business, Biomarkers, 030215 immunology

الوصف: T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17–producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4– and IL-17–producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e9867c920583985c42b42f399d45c2eTest
https://doi.org/10.4049/jimmunol.2001029Test

المؤلفون: Christian Boitard, Léo Bertrand, Camille Rousseau, Pauline Soulard, Isabelle Nel, Etienne Larger, Agnès Lehuen, Matthieu Rouland, Lucie Beaudoin, Zouriatou Gouda

المساهمون: Institut Cochin, Inserm, CNRS, Laboratory of Excellence Inflamex, Université de Paris, Paris, France, Diabetology Department, Cochin Hospital, AP-HP Centre - Université de Paris, Paris, France, ROULAND, Matthieu

المصدر: Diabetologia
Diabetologia, Springer Verlag, 2021, 64 (10), pp.2306-2321. ⟨10.1007/s00125-021-05527-y⟩

مصطلحات موضوعية: Antigens, Differentiation, T-Lymphocyte, Male, Granzyme B production, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, Blood Donors, Autoimmunity, medicine.disease_cause, 0302 clinical medicine, Glucose homeostasis, IL-2 receptor, ComputingMilieux_MISCELLANEOUS, Innate immunity, 0303 health sciences, Middle Aged, Flow Cytometry, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Type 1 diabetes, Cytokine, Proto-Oncogene Proteins c-bcl-2, Cytokines, Female, Human, Adult, MAIT cells, Mucosal-Associated Invariant T Cells, Article, Young Adult, 03 medical and health sciences, Antigens, CD, Internal Medicine, medicine, Humans, Lectins, C-Type, Interleukin-7 receptor, Aged, 030304 developmental biology, Granzyme, Autoimmune disease, business.industry, Interleukin-2 Receptor alpha Subunit, medicine.disease, Diabetes Mellitus, Type 1, Immunology, business, Biomarkers, 030215 immunology

الوصف: Aims/hypothesis Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αβ T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes. Methods MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2–14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes. Results MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25+ MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7f472b09f7f8af8edd6dddf782a029eTest
https://hal.archives-ouvertes.fr/hal-03448807Test

المؤلفون: Chengliang Wang, Puja Kumari, Chuan Li, Gabriel A. Rabinovich, Margaret M. Fettis, Sachin D. Deshmukh, Arun Wanchoo, Anthony T. Vella, Shivalee Duduskar, Gregory A. Hudalla, Christoph Sponholz, Beiyan Zhou, Michael Bauer, Ashley J. Russo, Renjie Liu, Vijay A. K. Rathinam, Santiago P. Méndez-Huergo, Jianbin Ruan, Sivapriya Kailasan Vanaja, Juan M. Pérez Sáez, Karthik Chandiran, Swathy O. Vasudevan, Antoine Ménoret

المصدر: Nat Immunol

مصطلحات موضوعية: Lipopolysaccharides, Male, 0301 basic medicine, Galectin 1, Lipopolysaccharide, Mice, chemistry.chemical_compound, 0302 clinical medicine, Alarmins, Immunology and Allergy, Caspase, Aged, 80 and over, Mice, Knockout, biology, Intracellular Signaling Peptides and Proteins, Pyroptosis, Middle Aged, Up-Regulation, Cell biology, Necroptosis, Female, Inflammation Mediators, medicine.symptom, Signal transduction, Intracellular, Signal Transduction, Adult, animal structures, Immunology, Inflammation, PTPRC, Article, 03 medical and health sciences, Sepsis, otorhinolaryngologic diseases, medicine, Animals, Humans, Aged, Macrophages, Phosphate-Binding Proteins, Endotoxemia, Mice, Inbred C57BL, Disease Models, Animal, stomatognathic diseases, RAW 264.7 Cells, 030104 developmental biology, chemistry, Case-Control Studies, biology.protein, Leukocyte Common Antigens, HeLa Cells, 030215 immunology

الوصف: Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fcd368de112bdf46f79b07a7aa7e0a0dTest
https://doi.org/10.1038/s41590-020-00844-7Test