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https://www.readbyqxmd.com/read/28317311/novel-pathogenic-variants-in-foxp3-in-fetuses-with-echogenic-bowel-and-skin-desquamation-identified-by-ultrasound
#1
Raymond J Louie, Queenie K-G Tan, Jennifer B Gilner, R Curtis Rogers, Noelle Younge, Stephanie B Wechsler, Marie T McDonald, Barbara Gordon, Christopher A Saski, Julie R Jones, Shelley J Chapman, Roger E Stevenson, John W Sleasman, Michael J Friez
Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy...
March 20, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28289675/humoral-immunodeficiency-with-hypotonia-feeding-difficulties-enteropathy-and-mild-eczema-caused-by-a-classical-foxp3-mutation
#2
Paul Tuijnenburg, Eloy Cuadrado, Annet M Bosch, Angelika Kindermann, Machiel H Jansen, Marielle Alders, Ester M M van Leeuwen, Taco W Kuijpers
We describe here the case of a boy who presented with pulmonary infections, feeding difficulties due to velopharyngeal insufficiency and gastroesophageal reflux, myopathy, and hypotonia soon after birth. Later, he was also found to have an elevated immunoglobulin (Ig) E and mild eczema and was diagnosed with inflammatory bowel disease. Further immunological screening at the age of 7 years showed low B and NK cell numbers but normal CD4(+) and CD8(+) T cells and notably, normal numbers of CD4(+) regulatory T (Treg) cells...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/28275376/immunological-balance-is-associated-with-clinical-outcome-after-autologous-hematopoietic-stem-cell-transplantation-in-type-1-diabetes
#3
Kelen C R Malmegrim, Júlia T C de Azevedo, Lucas C M Arruda, Joana R F Abreu, Carlos E B Couri, Gislane L V de Oliveira, Patricia V B Palma, Gabriela T Scortegagna, Ana B P L Stracieri, Daniela A Moraes, Juliana B E Dias, Fabiano Pieroni, Renato Cunha, Luiza Guilherme, Nathália M Santos, Milton C Foss, Dimas T Covas, Richard K Burt, Belinda P Simões, Júlio C Voltarelli, Bart O Roep, Maria C Oliveira
Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8(+) T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28248954/pathogenic-implications-for-autoimmune-mechanisms-derived-by-comparative-eqtl-analysis-of-cd4-versus-cd8-t-cells
#4
Silva Kasela, Kai Kisand, Liina Tserel, Epp Kaleviste, Anu Remm, Krista Fischer, Tõnu Esko, Harm-Jan Westra, Benjamin P Fairfax, Seiko Makino, Julian C Knight, Lude Franke, Andres Metspalu, Pärt Peterson, Lili Milani
Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28222218/reduced-inflammatory-responses-of-follicular-helper-t-cell-promote-the-development-of-regulatory-b-cells-after-roux-en-y-gastric-bypass
#5
Junfang Zhan, Liyu Huang, Haiyong Ma, Huan Chen, Yuan Yang, Sheng Tan, Wendy Song, Weiguo Zhao, Xiaojiang Dai
Bariatric surgery is currently the most effective strategy in treating severe obesity and its comorbidities, such as type 2 diabetes (T2D). However, the mechanism through which bariatric surgery mediates its benefits is not completely understood. Since obesity and T2D represent yet another inflammatory disease, and follicular helper T (Tfh) cells play important roles in inflammatory disorders, we investigated whether the Tfh activity was altered after Roux-en-Y gastric bypass (RYGB), one of the most common bariatric surgery procedures...
February 21, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28205558/plant-based-vaccines-for-oral-delivery-of-type-1-diabetes-related-autoantigens-evaluating-oral-tolerance-mechanisms-and-disease-prevention-in-nod-mice
#6
Amanda L Posgai, Clive H Wasserfall, Kwang-Chul Kwon, Henry Daniell, Desmond A Schatz, Mark A Atkinson
Autoantigen-specific immunological tolerance represents a central objective for prevention of type 1 diabetes (T1D). Previous studies demonstrated mucosal antigen administration results in expansion of Foxp3(+) and LAP(+) regulatory T cells (Tregs), suggesting oral delivery of self-antigens might represent an effective means for modulating autoimmune disease. Early preclinical experiments using the non-obese diabetic (NOD) mouse model reported mucosal administration of T1D-related autoantigens [proinsulin or glutamic acid decarboxylase 65 (GAD)] delayed T1D onset, but published data are conflicting regarding dose, treatment duration, requirement for combinatorial agents, and extent of efficacy...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28201972/cell-based-tolerogenic-therapy-experience-from-animal-models-of-multiple-sclerosis-type-1-diabetes-and-rheumatoid-arthritis
#7
Ivana Stojanović, Mirjana Dimitrijević, Marta Vives-Pi, Maria Jose Mansilla, Irma Pujol-Autonell, Silvia Rodríguez-Fernandez, Lenka Palová-Jelínková, David P Funda, Alisa Gruden-Movsesijan, Ljiljana Sofronić-Milosavljević, Catharien M U Hilkens, Eva Martínez-Cáceres, Djordje Miljković
Cell-based tolerogenic therapy is a promising approach for the treatment of autoimmune diseases and transplant rejection. Regulatory T cells and tolerogenic dendritic cells have been particularly explored in the treatment of various autoimmune disorders in experimental models of disease. Although some of these cells have already been tested in a limited number of clinical trials, there is still a need for preclinical research on tolerogenic cells in animal models of autoimmunity. This review will focus on the relevance of data obtained from studies in experimental animal models for the use of tolerogenic cell-based therapy in humans...
February 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28152213/melatonin-signaling-in-t-cells-functions-and-applications
#8
REVIEW
Wenkai Ren, Gang Liu, Shuai Chen, Jie Yin, Jing Wang, Bie Tan, Guoyao Wu, Fuller W Bazer, Yuanyi Peng, Tiejun Li, Russel J Reiter, Yulong Yin
Melatonin affects a variety of physiological processes including circadian rhythms, cellular redox status, and immune function. Importantly, melatonin significantly influences T-cell-mediated immune responses, which are crucial to protect mammals against cancers and infections, but are associated with pathogenesis of many autoimmune diseases. This review focuses on our current understanding of the significance of melatonin in T-cell biology and the beneficial effects of melatonin in T-cell response-based diseases...
February 2, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28134752/mechanisms-by-which-b-cells-and-regulatory-t-cells-influence-development-of-murine-organ-specific-autoimmune-diseases
#9
REVIEW
Jason S Ellis, Helen Braley-Mullen
Experiments with B cell-deficient (B-/-) mice indicate that a number of autoimmune diseases require B cells in addition to T cells for their development. Using B-/- Non-obese diabetic (NOD) and NOD.H-2h4 mice, we demonstrated that development of spontaneous autoimmune thyroiditis (SAT), Sjogren's syndrome and diabetes do not develop in B-/- mice, whereas all three diseases develop in B cell-positive wild-type (WT) mice. B cells are required early in life, since reconstitution of adult mice with B cells or autoantibodies did not restore their ability to develop disease...
January 26, 2017: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/28127155/the-histone-modification-code-in-the-pathogenesis-of-autoimmune-diseases
#10
REVIEW
Yasuto Araki, Toshihide Mimura
Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28126203/skin-derived-tslp-systemically-expands-regulatory-t-cells
#11
Theresa M Leichner, Atsushi Satake, Victor Sanoe Harrison, Yukinori Tanaka, Angela S Archambault, Brian S Kim, Mark C Siracusa, Warren J Leonard, Ali Naji, Gregory F Wu, David Artis, Taku Kambayashi
Regulatory T cells (Tregs) are a subset of CD4(+) T cells with suppressive function and are critical for limiting inappropriate activation of T cells. Hence, the expansion of Tregs is an attractive strategy for the treatment of autoimmune diseases. Here, we demonstrate that the skin possesses the remarkable capacity to systemically expand Treg numbers by producing thymic stromal lymphopoietin (TSLP) in response to vitamin D receptor stimulation. An ∼2-fold increase in the proportion and absolute number of Tregs was observed in mice treated topically but not systemically with the Vitamin D3 analog MC903...
January 23, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28125840/association-of-high-mobility-group-box-1-with-th-cell-related-cytokines-in-the-vitreous-of-ocular-sarcoidosis-patients
#12
Masaru Takeuchi, Manzo Taguchi, Tomohito Sato, Kyoko Karasawa, Yutaka Sakurai, Kohzou Harimoto, Masataka Ito
Purpose: High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein released from necrotic cells, which is also secreted by activated leukocytes and acts as a primary proinflammatory cytokine. In this study, we compared vitreous HMGB1 levels in ocular sarcoidosis with those in noninflammatory vitreoretinal diseases and evaluated its association with Th cell-related and proinflammatory cytokines. Methods: The study group consisted of 24 patients with ocular sarcoidosis...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28117148/generation-of-human-islet-specific-regulatory-t-cells-by-tcr-gene-transfer
#13
Caroline M Hull, Lauren E Nickolay, Megan Estorninho, Max W Richardson, James L Riley, Mark Peakman, John Maher, Timothy I M Tree
Based on the success in animal models of type 1 diabetes (T1D), clinical trials of adoptive regulatory T cell (Treg) therapy are underway using ex vivo expanded polyclonal Tregs. However, pre-clinical data also demonstrate that islet-specific Tregs are more potent than polyclonal Tregs at reversing T1D. Translation of this approach into man will require methods to generate large populations of islet-specific Tregs which, to date, has proved to be a major hurdle. Here we demonstrate the feasibility of lentiviral-mediated T cell receptor (TCR) gene transfer to confer antigen specificity on polyclonal human Tregs...
January 20, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28116870/multicomponent-injectable-hydrogels-for-antigen-specific-tolerogenic-immune-modulation
#14
Catia S Verbeke, Susana Gordo, David A Schubert, Sarah A Lewin, Rajiv M Desai, Jessica Dobbins, Kai W Wucherpfennig, David J Mooney
Biomaterial scaffolds that enrich and modulate immune cells in situ can form the basis for potent immunotherapies to elicit immunity or reëstablish tolerance. Here, the authors explore the potential of an injectable, porous hydrogel to induce a regulatory T cell (Treg) response by delivering a peptide antigen to dendritic cells in a noninflammatory context. Two methods are described for delivering the BDC peptide from pore-forming alginate gels in the nonobese diabetic mouse model of type 1 diabetes: encapsulation in poly(lactide-co-glycolide) (PLG) microparticles, or direct conjugation to the alginate polymer...
January 24, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28108611/reversal-of-diabetes-in-nod-mice-by-clinical-grade-proinsulin-and-il-10-secreting-lactococcus-lactis-in-combination-with-low-dose-anti-cd3-depends-on-the-induction-of-foxp3-positive-t-cells
#15
Tatiana Takiishi, Dana Paulina Cook, Hannelie Korf, Guido Sebastiani, Francesca Mancarella, João Paulo Monteiro Carvalho Mori Cunha, Clive Wasserfall, Noelia Casares, Juan José Lasarte, Lothar Steidler, Pieter Rottiers, Francesco Dotta, Conny Gysemans, Chantal Mathieu
The introduction of β-cell autoantigens via the gut through Lactococcus lactis (L. lactis) has been demonstrated to be a promising approach for diabetes reversal in NOD mice. Here we show that a combination therapy of low-dose anti-CD3 with a clinical-grade self-containing L. lactis, appropriate for human application, secreting human proinsulin and interleukin-10, cured 66% of mice with new-onset diabetes, which is comparable to therapy results with plasmid-driven L. lactis Initial blood glucose concentrations (<350 mg/dL) and insulin autoantibody positivity were predictors of the stable reversal of hyperglycemia, and decline in insulin autoantibody positivity was an immune biomarker of therapeutic outcome...
February 2017: Diabetes
https://www.readbyqxmd.com/read/28081217/collective-genetic-interaction-effects-and-the-role-of-antigen-presenting-cells-in-autoimmune-diseases
#16
Hyung Jun Woo, Chenggang Yu, Jaques Reifman
Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body's own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects...
2017: PloS One
https://www.readbyqxmd.com/read/28081180/pi3k%C3%AE-deficient-nod-mice-are-protected-from-diabetes-by-restoring-the-balance-of-regulatory-to-effector-t-cells
#17
Jamil Azzi, Lindsay Thueson, Robert Moore, Rozita Abdoli, Helena Reijonen, Reza Abdi
With a steady increase in its incidence and lack of curative treatment, type 1 diabetes (T1D) has emerged as a major health problem worldwide. To design novel effective therapies, there is a pressing need to identify regulatory targets controlling the balance of autoreactive to regulatory-T-cells (Tregs). We previously showed that the inhibition of the γ-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3Kγ-inhibition, we developed a new NOD mouse model of T1D lacking the γ-subunit of PI3K...
2017: PloS One
https://www.readbyqxmd.com/read/28074676/potential-route-of-th17-treg-cell-dynamics-in-targeting-type-1-diabetes-and-rheumatoid-arthritis-an-autoimmune-disorder-perspective
#18
Suresh Kumar Karri, A Sheela
Cytokines, small secreted proteins, have a specific effect on the interactions and communications between cells. They play a pivotal role in the pathogenesis of autoimmune diseases. Factors in the breakdown of self-tolerance and the subsequent events leading to the induction of pathogenic responses remain unclear for most of the autoimmune diseases. Large numbers of studies have revealed a general scheme in which pro-inflammatory cytokines contribute to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate the regression of inflammation and thereby recovery from the disease...
January 11, 2017: British Journal of Biomedical Science
https://www.readbyqxmd.com/read/28065853/sitagliptin-inhibit-human-lymphocytes-proliferation-and-th1-th17-differentiation-in-vitro
#19
Marcelo Maia Pinheiro, Caroline Lais Stoppa, Claudete Justina Valduga, Cristina Eunice Okuyama, Renata Gorjão, Regina Mara Silva Pereira, Susana Nogueira Diniz
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein, CD26, and plays an important role in T-cell immunity. Recent studies suggest that DPP-4 inhibitors improve beta-cell function and attenuate autoimmunity in type 1 diabetic mouse models. To investigate the direct effect of DPP4 in immune response, human peripheral blood mononuclear cells (PBMC) from healthy volunteers were obtained by Ficoll gradient and cultivated in the absence (control) or presence of phytohemagglutinin (PHA), or stimulated with PHA and treated with sitagliptin...
March 30, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28062695/the-clonal-invariant-nkt-cell-repertoire-in-people-with-type-1-diabetes-is-characterized-by-a-loss-of-clones-expressing-high-affinity-tcrs
#20
Anna S Tocheva, Salah Mansour, Tristan G H Holt, Samuel Jones, Andrew Chancellor, Joseph P Sanderson, Efrem Eren, Tim J Elliott, Richard I G Holt, Stephan D Gadola
Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production...
January 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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