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https://www.readbyqxmd.com/read/29141313/-tocilizumab-for-refractory-systemic-juvenile-idiopathic-arthritis
#1
J M Lai, F Q Wu, Z X Zhou, M Kang, X L Huang, G X Su, S N Li, J Zhu, X N Wang
Objective: To evaluate the efficacy and side effects of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Method: In this prospective self case-control study, the children diagnosed with refractory systemic juvenile idiopathic arthritis admitted to Department of Rheumatism and Immunology of Children's Hospital Affiliated to Capital Institute of Pediatrics from December 2013 to June 2016 were enrolled and information before and after treatment of tocilizumab was analyzed. The tocilizumab was introvenously guttae in a dose of 8-12 mg/kg every 2 weeks...
November 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29127360/a-mouse-model-of-autoimmune-cholangitis-via-syngeneic-bile-duct-protein-immunization
#2
Wen-Tao Ma, Qing-Zhi Liu, Jing-Bo Yang, Yan-Qing Yang, Zhi-Bin Zhao, Hong-Di Ma, M Eric Gershwin, Zhe-Xiong Lian
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29116089/resistance-to-tgf%C3%AE-suppression-and-improved-anti-tumor-responses-in-cd8-t-cells-lacking-ptpn22
#3
Rebecca J Brownlie, Celine Garcia, Mate Ravasz, Dietmar Zehn, Robert J Salmond, Rose Zamoyska
Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8(+) T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 (-/-) T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression...
November 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29113828/downregulation-of-bdh2-modulates-iron-homeostasis-and-promotes-dna-demethylation-in-cd4-t-cells-of-systemic-lupus-erythematosus
#4
Ming Zhao, Meng-Ying Li, Xiao-Fei Gao, Su-Jie Jia, Ke-Qin Gao, Yin Zhou, Hui-Hui Zhang, Yi Huang, Jing Wang, Hai-Jing Wu, Qian-Jin Lu
DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4(+) T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4(+) T cells compared with healthy controls...
November 4, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29106410/generation-of-higher-affinity-t-cell-receptors-by-antigen-driven-differentiation-of-progenitor-t-cells-in-vitro
#5
Thomas M Schmitt, David H Aggen, Kumiko Ishida-Tsubota, Sebastian Ochsenreither, David M Kranz, Philip D Greenberg
Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low-avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs...
November 6, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29102863/negative-selection-epitope-mimicry-and-autoimmunity
#6
REVIEW
Noel R Rose
Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence...
November 2, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29088923/oxidative-modifications-in-tissue-pathology-and-autoimmune-disease
#7
Mei-Ling Yang, Hester Doyle, Steven G Clarke, Kevan Herold, Mark Mamula
SIGNIFICANCE: Various autoimmune syndromes are characterized by abnormalities found at the level of tissues and cells, as well as by microenvironmental influences, such as reactive oxygen species (ROS), that alter intracellular metabolism and protein expression. Moreover, the convergence of genetic, epigenetic, and even environmental influences can result in B and T lymphocyte autoimmunity and tissue pathology. Recent Advances: This review will describe how oxidative stress to cells and tissues may alter posttranslational protein modifications, both directly and indirectly, as well as potentially lead to aberrant gene expression...
October 31, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29078319/ptip-chromatin-regulator-controls-development-and-activation-of-b-cell-subsets-to-license-humoral-immunity-in-mice
#8
Dan Su, Stijn Vanhee, Rebeca Soria, Elin Jaensson Gyllenbäck, Linda M Starnes, Martina Kubec Højfeldt, Gabriel K Pedersen, Joan Yuan, Jeremy A Daniel
B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29062305/morbid-sequences-suggest-molecular-mimicry-between-microbial-peptides-and-self-antigens-a-possibility-of-inciting-autoimmunity
#9
Susanta Pahari, Deepyan Chatterjee, Shikha Negi, Jagdeep Kaur, Balvinder Singh, Javed N Agrewala
Understanding etiology of autoimmune diseases has been a great challenge for designing drugs and vaccines. The pathophysiology of many autoimmune diseases may be attributed to molecular mimicry provoked by microbes. Molecular mimicry hypothesizes that a sequence homology between foreign and self-peptides leads to cross-activation of autoreactive T cells. Different microbial proteins are implicated in various autoimmune diseases, including multiple sclerosis, human type 1 diabetes, primary biliary cirrhosis and rheumatoid arthritis...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29058307/genetic-immunization-with-mouse-thyrotropin-hormone-receptor-plasmid-breaks-self-tolerance-for-a-murine-model-of-autoimmune-thyroid-disease-and-graves-orbitopathy
#10
Anke Schlüter, Mareike Horstmann, Salvador Diaz-Cano, Svenja Plöhn, Kerstin Stähr, Stefan Mattheis, Michael Oeverhaus, Stephan Lang, Ulrich Flögel, Utta Berchner-Pfannschmidt, Anja Eckstein, J Paul Banga
Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A-subunit plasmid. Autoimmune thyroid disease in the self-antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells...
October 23, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28978474/precocious-interleukin-21-expression-in-naive-mice-identifies-a-natural-helper-cell-population-in-autoimmune-disease
#11
Elisabeth A Marnik, Xulong Wang, Thomas J Sproule, Giljun Park, Gregory J Christianson, Sarah Kate Lane-Reticker, Shweta Jain, Theodore Duffy, Hongsheng Wang, Gregory W Carter, Herbert C Morse, Derry C Roopenian
Interleukin 21 (IL-21) plays key roles in humoral immunity and autoimmune diseases. It is known to function in mature CD4(+) T follicular B cell helper (TFH) cells, but its potential involvement in early T cell ontogeny is unclear. Here, we find that a significant population of newly activated thymic and peripheral CD4(+) T cells functionally expresses IL-21 soon after birth. This naturally occurring population, termed natural (n)TH21 cells, exhibits considerable similarity to mature TFH cells. nTH21 cells originating and activated in the thymus are strictly dependent on autoimmune regulator (AIRE) and express high levels of NUR77, consistent with a bias toward self-reactivity...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28978470/ccr7-modulates-the-generation-of-thymic-regulatory-t-cells-by-altering-the-composition-of-the-thymic-dendritic-cell-compartment
#12
Zicheng Hu, Yu Li, Annemarie Van Nieuwenhuijze, Hilary J Selden, Angela M Jarrett, Anna G Sorace, Thomas E Yankeelov, Adrian Liston, Lauren I R Ehrlich
Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here, we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7(-/-) mice have increased Treg cellularity because of a hematopoietic but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DCs) promotes survival of mature Sirpα(-) DCs. Thus, CCR7 deficiency results in apoptosis of Sirpα(-) DCs, which is counterbalanced by expansion of immature Sirpα(+) DCs that efficiently induce Treg generation...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28947542/nur77-regulates-nondeletional-mechanisms-of-tolerance-in-t-cells
#13
Qian Nancy Hu, Alexander Y W Suen, Laura M Henao Caviedes, Troy A Baldwin
Negative selection against highly self-reactive thymocytes is critical for preventing autoimmunity. Thymocyte deletion, anergy induction, and agonist selection are all forms of negative selection that can occur following a high-affinity TCR signal. Of Bim and Nur77, two TCR-induced proteins with proapoptotic function, Bim has been shown to be important for clonal deletion in several model systems, whereas Nur77 was often dispensable. However, Nur77 has been reported to influence other aspects of T cell development by mechanisms that may not be related to its proapoptotic function...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28945568/-thymic-b-cells-not-simple-bystanders-of-t-cell-lymphopoiesis
#14
Vincent Gies, Aurélien Guffroy, Anne-Sophie Korganow
The thymus is the central site for the differentiation and selection of T cells. It has been known for decades that B lymphocytes reside in the thymus, but little attention has been paid to this unique population. Thymic B cells are mainly located in the medulla and at the cortico-medullary junction. They develop intrathymically, do not recirculate and harbor a distinct phenotype in comparison to peripheral B cells. Furthermore, because of their activated phenotype and their precise histological localization, they have been suspected to play a role in the selection of self-reactive T cells...
August 2017: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/28931755/combination-central-tolerance-and-peripheral-checkpoint-blockade-unleashes-antimelanoma-immunity
#15
Pearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K Hong, Imran Khan, Maria Mouchess, Ajay S Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M Kirkwood, Stergios Moschos, Lawrence Fong, Mark S Anderson, Maureen A Su
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28906131/effects-of-immunomodulators-on-the-response-induced-by-vaccines-against-autoimmune-diseases
#16
Dante J Marciani
A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self-antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity...
November 2017: Autoimmunity
https://www.readbyqxmd.com/read/28900679/ctla-4-an-essential-immune-checkpoint-for-t-cell-activation
#17
Shunsuke Chikuma
The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28892471/dynamic-regulation-of-t-follicular-regulatory-cell-responses-by-interleukin-2-during-influenza-infection
#18
Davide Botta, Michael J Fuller, Tatiana T Marquez-Lago, Holly Bachus, John E Bradley, Amy S Weinmann, Allan J Zajac, Troy D Randall, Frances E Lund, Beatriz León, André Ballesteros-Tato
Interleukin 2 (IL-2) promotes Foxp3(+) regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones...
November 2017: Nature Immunology
https://www.readbyqxmd.com/read/28887429/nfm-cross-reactivity-to-mog-does-not-expand-a-critical-threshold-level-of-high-affinity-t-cells-necessary-for-onset-of-demyelinating-disease
#19
Lori Blanchfield, Joseph J Sabatino, Laurel Lawrence, Brian D Evavold
Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4(+) T cells due to cross-recognition of multiple self-epitopes such as has been suggested for myelin oligodendrocyte glycoprotein epitope 35-55 (MOG35-55) and neurofilament medium protein epitope 15-35 (NFM15-35). NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic Ag...
October 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28878770/changes-in-reactivity-in-vitro-of-cd4-cd25-and-cd4-cd25-t-cell-subsets-in-transplant-tolerance
#20
Bruce M Hall, Catherine M Robinson, Karren M Plain, Nirupama D Verma, Giang T Tran, Masaru Nomura, Nicole Carter, Rochelle Boyd, Suzanne J Hodgkinson
Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4(+)CD25(+) T cells, yet in many models, proliferation of CD4(+) T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4(+), CD4(+)CD25(+), and CD4(+)CD25(-) T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4(+) T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells...
2017: Frontiers in Immunology
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