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https://www.readbyqxmd.com/read/28626026/protein-kinase-c%C3%AE-activates-fat-mass-and-obesity-associated-protein-by-influencing-its-ubiquitin-proteasome-degradation
#1
Haoran Tai, Xiaobo Wang, Jiao Zhou, Xiaojuan Han, Tingting Fang, Hui Gong, Ning Huang, Honghan Chen, Jianqiong Qin, Ming Yang, Xiawei Wei, Li Yang, Hengyi Xiao
PKCβ is a serine-threonine kinase associated with obesity and diabetic complications; its activation contributes to weight gain, and deletion of its gene results in resistance to genetic- and diet-induced obesity. Fat mass and obesity-associated (FTO) protein is a recently identified RNA demethylase, and its overexpression in mice leads to increased body weight as well as fat mass. Although sharing some features in anabolism regulation, PKCβ and FTO have not been investigated together; therefore, their relationship has not been established...
June 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28620237/lea29y-expression-in-transgenic-neonatal-porcine-islet-like-cluster-promotes-long-lasting-xenograft-survival-in-humanized-mice-without-immunosuppressive-therapy
#2
L Wolf-van Buerck, M Schuster, F S Oduncu, A Baehr, T Mayr, S Guethoff, J Abicht, B Reichart, N Klymiuk, E Wolf, J Seissler
Genetically engineered pigs are a promising source for islet cell transplantation in type 1 diabetes, but the strong human anti-pig immune response prevents its successful clinical application. Here we studied the efficacy of neonatal porcine islet-like cell clusters (NPICCs) overexpressing LEA29Y, a high-affinity variant of the T cell co-stimulation inhibitor CTLA-4Ig, to engraft and restore normoglycemia after transplantation into streptozotocin-diabetic NOD-SCID IL2rγ(-/-) (NSG) mice stably reconstituted with a human immune system...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28620093/increased-interleukin-35-levels-in-patients-with-type-1-diabetes-with-remaining-c-peptide
#3
Daniel Espes, Kailash Singh, Stellan Sandler, Per-Ola Carlsson
OBJECTIVE: Many patients with long-standing type 1 diabetes have remaining functional β-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after ≥10 years duration of disease. RESEARCH DESIGN AND METHODS: Patients (n = 113; ≥18 years of age) with type 1 diabetes and with disease duration of ≥10 years were recruited at Uppsala University Hospital. Residual β-cell function was determined with an ultrasensitive C-peptide ELISA...
June 15, 2017: Diabetes Care
https://www.readbyqxmd.com/read/28611472/cd11a-icam-1-blockade-combined-with-il-2-targeting-therapy-causes-a-paradoxical-acceleration-of-type-1-diabetes
#4
Ekua W Brenu, Timothy J Bartley, Casey M Wright, Emma Hamilton-Williams
Enhancement of regulatory T cell (Treg) function is the goal of many immunotherapies aimed at treating type 1 diabetes (T1D). The use of IL-2 is hindered by its effects on other populations such as effector T cells and NK cells. Combination therapies aimed at suppressing effector T cells while using IL-2 to expand Tregs could be beneficial and have been trialed in T1D patients. We have investigated a combination therapy using IL-2 and αCD11a blocking antibody to simultaneously expand Tregs and suppress the activation and migration of autoreactive T cells...
June 14, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28607385/exogenous-interleukin-37-ameliorates-atherosclerosis-via-inducing-the-treg-response-in-apoe-deficient-mice
#5
Qingwei Ji, Kai Meng, Kunwu Yu, Song Huang, Ying Huang, Xiaohong Min, Yucheng Zhong, Bangwei Wu, Yuzhou Liu, Shaoping Nie, Jianwei Zhang, Yujie Zhou, Qiutang Zeng
Our previous study indicated that interleukin (IL)-37 is involved in atherosclerosis. In the present study, Anterior tibial arteries were collected from diabetes patients and controls. A histopathological analysis showed that IL-37 was over-expressed in human atherosclerotic plaques. Many types of cells including macrophages, vascular smooth muscle cells (VSMCs), endothelial cells and T lymphocyte expressed IL-37 in human atherosclerotic plaques. ApoE-/- mice were divided into a control group and a recombinant human IL-37-treated group...
June 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28593827/liposome-based-immunotherapy-against-autoimmune-diseases-therapeutic-effect-on-multiple-sclerosis
#6
Irma Pujol-Autonell, Maria-Jose Mansilla, Silvia Rodriguez-Fernandez, Mary Cano-Sarabia, Juan Navarro-Barriuso, Rosa-Maria Ampudia, Aleix Rius, Sonia Garcia-Jimeno, David Perna-Barrull, Eva Martinez-Caceres, Daniel Maspoch, Marta Vives-Pi
AIM: Based on the ability of apoptosis to induce immunological tolerance, liposomes were generated mimicking apoptotic cells, and they arrest autoimmunity in Type 1 diabetes. Our aim was to validate the immunotherapy in other autoimmune disease: multiple sclerosis. MATERIALS & METHODS: Phosphatidylserine-rich liposomes were loaded with disease-specific autoantigen. Therapeutic capability of liposomes was assessed in vitro and in vivo. RESULTS: Liposomes induced a tolerogenic phenotype in dendritic cells, and arrested autoimmunity, thus decreasing the incidence, delaying the onset and reducing the severity of experimental disease, correlating with an increase in a probably regulatory CD25(+) FoxP3(-) CD4(+) T-cell subset...
June 2017: Nanomedicine
https://www.readbyqxmd.com/read/28592385/nucleotide-binding-oligomerization-domain-containing-protein-2-nod2-modulates-t1dm-susceptibility-by-gut-microbiota
#7
Yang-Yang Li, James A Pearson, Chen Chao, Jian Peng, Xiaojun Zhang, Zhiguang Zhou, Yu Liu, F Susan Wong, Li Wen
Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) is an innate immune receptor. To investigate the role of Nod2 in susceptibility to the autoimmune disease, type 1 diabetes mellitus (T1DM), we generated Nod2(-/-) non-obese diabetic (NOD) mice. The Nod2(-/-)NOD mice had different composition of the gut microbiota compared to Nod2(+/+)NOD mice and were significantly protected from diabetes, but only when housed separately from Nod2(+/+)NOD mice. This suggested that T1DM susceptibility in Nod2(-/-)NOD mice is dependent on the alteration of gut microbiota, which modulated the frequency and function of IgA-secreting B-cells and IL-10 promoting T-regulatory cells...
June 4, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28587604/kcnj11-abcc8-and-tcf7l2-polymorphisms-and-the-response-to-sulfonylurea-treatment-in-patients-with-type-2-diabetes-a-bioinformatics-assessment
#8
Jingwen Song, Yunzhong Yang, Franck Mauvais-Jarvis, Yu-Ping Wang, Tianhua Niu
BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing...
June 6, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28553653/not-only-glycaemic-but-also-other-metabolic-factors-affect-t-regulatory-cell-counts-and-proinflammatory-cytokine-levels-in-women-with-type-1-diabetes
#9
Katerina Stechova, Jana Sklenarova-Labikova, Tereza Kratzerova, Pavlina Pithova, Dominik Filipp
Type 1 diabetic (T1D) patients suffer from insulinopenia and hyperglycaemia. Studies have shown that if a patient's hyperglycaemic environment is not compensated, it leads to complex immune dysfunctions. Similarly, T1D mothers with poor glycaemic control exert a negative impact on the immune responses of their newborns. However, questions concerning the impact of other metabolic disturbances on the immune system of T1D mothers (and their newborns) have been raised. To address these questions, we examined 28 T1D women in reproductive age for the relationship between various metabolic, clinical, and immune parameters...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28550204/cutting-edge-origins-recruitment-and-regulation-of-cd11c-cells-in-inflamed-islets-of-autoimmune-diabetes-mice
#10
Joanna E Klementowicz, Ashley E Mahne, Allyson Spence, Vinh Nguyen, Ansuman T Satpathy, Kenneth M Murphy, Qizhi Tang
In NOD mice, CD11c(+) cells increase greatly with islet inflammation and contribute to autoimmune destruction of pancreatic β cells. In this study, we investigated their origin and mechanism of recruitment. CD11c(+) cells in inflamed islets resembled classical dendritic cells based on their transcriptional profile. However, the majority of these cells were not from the Zbtb46-dependent dendritic-cell lineage. Instead, monocyte precursors could give rise to CD11c(+) cells in inflamed islets. Chemokines Ccl5 and Ccl8 were persistently elevated in inflamed islets and the influx of CD11c(+) cells was partially dependent on their receptor Ccr5...
May 26, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28546003/thymic-epithelial-cell-specific-deletion-of-jmjd6-reduces-aire-protein-expression-and-exacerbates-disease-development-in-a-mouse-model-of-autoimmune-diabetes
#11
Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui
Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity...
July 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28542921/cd40-mediated-signaling-influences-trafficking-tcr-expression-and-t-cell-pathogenesis-in-the-nod-model-of-type-1-diabetes
#12
Gisela M Vaitaitis, Dan M Waid, Martin G Yussman, David H Wagner
CD40 plays a critical role in the pathogenesis of type 1 diabetes (T1D). The mechanism of action however is undetermined, likely because CD40 expression has been grossly underestimated. CD40 is expressed on numerous cell types that now include T cells and pancreatic β cells. CD40(+) CD4(+) cells (TH40) prove highly pathogenic in NOD mice and in translational human T1D studies. We generated BDC2.5.CD40(-/-) and re-derived NOD.CD154(-/-) mice to better understand CD40 mechanism of action. Fully functional CD40 expression is required not only for T1D development but for insulitis...
May 19, 2017: Immunology
https://www.readbyqxmd.com/read/28539428/cutting-edge-dual-tcr%C3%AE-expression-poses-an-autoimmune-hazard-by-limiting-regulatory-t-cell-generation
#13
Nathaniel J Schuldt, Jennifer L Auger, Justin A Spanier, Tijana Martinov, Elise R Breed, Brian T Fife, Kristin A Hogquist, Bryce A Binstadt
Despite accounting for 10-30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an autoimmune hazard by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes. We bred NOD mice hemizygous at both TCRα and β (TCRα(+/-) β(+/-)) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T cell ratio and protection from diabetes...
May 24, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28536240/reply-to-tolerogenic-insulin-peptide-therapy-precipitates-type-1-diabetes
#14
Carolin Daniel, Benno Weigmann, Harald von Boehmer
In this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3(+) regulatory T cell conversion.
May 23, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28534310/combination-immunotherapy-for-type-1-diabetes
#15
REVIEW
Robert N Bone, Carmella Evans-Molina
PURPOSE OF REVIEW: Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D...
July 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28529840/adoptive-cell-therapy-with-tregs-to-improve-transplant-outcomes-the-promise-and-the-stumbling-blocks
#16
Mohamed B Ezzelarab, Angus W Thomson
The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety...
December 2016: Current Transplantation Reports
https://www.readbyqxmd.com/read/28512194/ancient-antagonism-between-celf-and-rbfox-families-tunes-mrna-splicing-outcomes
#17
Matthew R Gazzara, Michael J Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W Lynch, Yoseph Barash
Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28506774/immunomodulatory-and-protective-effects-of-adipose-tissue-derived-mesenchymal-stem-cells-in-an-allograft-islet-composite-transplantation-for-experimental-autoimmune-type-1-diabetes
#18
Jamal Mohammadi Ayenehdeh, Bahare Niknam, Shima Rasouli, Seyed Mahmoud Hashemi, Hossein Rahavi, Nima Rezaei, Masoud Soleimani, Ali Liaeiha, Mohammad Hossein Niknam, Nader Tajik
BACKGROUND: Allogeneic islet transplantation could be an ideal alternative therapy for Type 1 Diabetes Mellitus (T1DM). Adipose Tissue-derived Mesenchymal Stem Cells (AT-MSCs) characterized by immunomodulatory and protective effects may have the potential to improve the outcome of this highly immunogenic transplant. METHODS: Syngenic AT-MSCs along with allograft islets embedded in hydrogelic composite and transplanted intraperitoneally in Streptozotocin (STZ) induced diabetic C57BL/6 mice...
May 12, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28496193/exendin-4-exhibits-enhanced-anti-tumor-effects-in-diabetic-mice
#19
Lan He, Priscilla T Y Law, Chun Kwok Wong, Juliana C N Chan, Paul K S Chan
Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. The underlying mechanism of this observation might be partly contributed by dysregulated immune response in diabetes. In this study, we hypothesized that the impaired anti-tumor immune response in diabetic status could be modulated by exendin-4, a glucagon-like protein receptor agonist which exhibits anti-diabetic effects...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28467828/dominant-protection-from-hla-linked-autoimmunity-by-antigen-specific-regulatory-t-cells
#20
Joshua D Ooi, Jan Petersen, Yu H Tan, Megan Huynh, Zoe J Willett, Sri H Ramarathinam, Peter J Eggenhuizen, Khai L Loh, Katherine A Watson, Poh Y Gan, Maliha A Alikhan, Nadine L Dudek, Andreas Handel, Billy G Hudson, Lars Fugger, David A Power, Stephen G Holt, P Toby Coates, Jon W Gregersen, Anthony W Purcell, Stephen R Holdsworth, Nicole L La Gruta, Hugh H Reid, Jamie Rossjohn, A Richard Kitching
Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4(+) T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145)...
May 11, 2017: Nature
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