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https://www.readbyqxmd.com/read/29233566/activation-of-thyroid-antigen-reactive-b-cells-in-recent-onset-autoimmune-thyroid-disease-patients
#1
Mia J Smith, Marynette Rihanek, Brianne M Coleman, Peter A Gottlieb, Virginia D Sarapura, John C Cambier
Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand the underlying pathogenesis of AITD that ultimately leads to production of autoantibodies and loss of thyroid function...
December 9, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29221580/mechanisms-of-allergen-immunotherapy-for-inhaled-allergens-and-predictive-biomarkers
#2
REVIEW
Mohamed H Shamji, Stephen R Durham
Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells...
December 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29203543/a-novel-mechanism-behind-the-immunopathogenesis-of-vulvovaginal-candidiasis-neutrophil-anergy
#3
Junko Yano, Brian M Peters, Mairi C Noverr, Paul L Fidel
For over three decades, investigators have studied the pathogenesis of vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) through clinical studies and animal models. While there was considerable consensus that susceptibility was not associated with any apparent deficiencies in adaptive immunity, protective immune mechanisms and the role of innate immunity remained elusive. It was not until an innovative live challenge design was conducted in women that a fuller understanding of the natural history of infection/disease was achieved...
December 4, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/29194071/revisiting-the-phenotypic-and-genetic-profiling-of-anergic-t-cells-mediating-long-term-transplant-tolerance
#4
Sylvaine You, Lucienne Chatenoud
PURPOSE OF REVIEW: Herein our focus will be to revisit peripheral tolerance mechanisms and in particular 'active' or 'dominant' tolerance as originally defined and mediated by regulatory CD4FoxP3 T lymphocytes (Treg) and also T-cell anergy that appears as a major mainstay to support long-term allograft survival. RECENT FINDINGS: It is at the same time interesting and rewarding that the tool that recently guided our efforts along this path is the in-vivo use of CD3 antibody, the first monoclonal introduced in the clinic (Orthoclone OKT3) about 35 years ago to treat and prevent rejection of renal allografts...
November 30, 2017: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/29177124/harnessing-apoptotic-cells-for-transplantation-tolerance-current-status-and-future-perspectives
#5
Anil Dangi, Xunrong Luo
Purpose of review: The use of donor apoptotic cells is an emerging therapy for inducing transplantation tolerance. In this review, we will discuss current understanding of mechanisms of this approach, as well as crucial aspects necessary for successful translation of this approach to clinical transplantation. Recent findings: Transplantation tolerance by donor apoptotic cells is mediated by their homeostatic interaction with recipient phagocytes, and subsequent expansion of suppressor cell populations as well as inhibition of effector T cells via deletion and anergy...
December 2017: Current Transplantation Reports
https://www.readbyqxmd.com/read/29170668/epitope-specific-tolerance-modes-differentially-specify-susceptibility-to-proteolipid-protein-induced-experimental-autoimmune-encephalomyelitis
#6
Lei Wang, Julia Winnewisser, Christine Federle, Gregor Jessberger, Klaus-Armin Nave, Hauke B Werner, Bruno Kyewski, Ludger Klein, Maria Hinterberger
Immunization with myelin components can elicit experimental autoimmune encephalomyelitis (EAE). EAE susceptibility varies between mouse strains, depending on the antigen employed. BL/6 mice are largely resistant to EAE induction with proteolipid protein (PLP), probably a reflection of antigen-specific tolerance. However, the extent and mechanism(s) of tolerance to PLP remain unclear. Here, we identified three PLP epitopes in PLP-deficient BL/6 mice. PLP-sufficient mice did not respond against two of these, whereas tolerance was "leaky" for an epitope with weak predicted MHCII binding, and only this epitope was encephalitogenic...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29170366/initiation-of-hiv-neutralizing-b-cell-lineages-with-sequential-envelope-immunizations
#7
Wilton B Williams, Jinsong Zhang, Chuancang Jiang, Nathan I Nicely, Daniela Fera, Kan Luo, M Anthony Moody, Hua-Xin Liao, S Munir Alam, Thomas B Kepler, Akshaya Ramesh, Kevin Wiehe, James A Holland, Todd Bradley, Nathan Vandergrift, Kevin O Saunders, Robert Parks, Andrew Foulger, Shi-Mao Xia, Mattia Bonsignori, David C Montefiori, Mark Louder, Amanda Eaton, Sampa Santra, Richard Scearce, Laura Sutherland, Amanda Newman, Hilary Bouton-Verville, Cindy Bowman, Howard Bomze, Feng Gao, Dawn J Marshall, John F Whitesides, Xiaoyan Nie, Garnett Kelsoe, Steven G Reed, Christopher B Fox, Kim Clary, Marguerite Koutsoukos, David Franco, John R Mascola, Stephen C Harrison, Barton F Haynes, Laurent Verkoczy
A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing...
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29163518/mixed-signals-co-stimulation-in-invariant-natural-killer-t-cell-mediated-cancer-immunotherapy
#8
REVIEW
Susannah C Shissler, Michael S Lee, Tonya J Webb
Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29163472/the-kynurenine-pathway-as-a-novel-link-between-allergy-and-the-gut-microbiome
#9
REVIEW
Aaron P Van der Leek, Yarden Yanishevsky, Anita L Kozyrskyj
In the past few decades, the indoleamine 2,3 dioxygenase (IDO) subset of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism has been the subject of much research in the area of immune tolerance. In this review, we aim to incorporate new findings on this pathway in relation to allergy and the gut microbiome, while providing a comprehensive overview of the pathway itself. Stimulated by interferon gamma, IDO acts as a tolerogenic, immunosuppressive enzyme to attenuate allergic responses by the induction of the KYN-IDO pathway, resultant depletion of TRP, and elevation in KYN metabolites...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29140996/childhood-tuberculosis-is-associated-with-decreased-abundance-of-t-cell-gene-transcripts-and-impaired-t-cell-function
#10
Cheryl Hemingway, Maurice Berk, Suzanne T Anderson, Victoria J Wright, Shea Hamilton, Hariklia Eleftherohorinou, Myrsini Kaforou, Greg M Goldgof, Katy Hickman, Beate Kampmann, Johan Schoeman, Brian Eley, David Beatty, Sandra Pienaar, Mark P Nicol, Michael J Griffiths, Simon J Waddell, Sandra M Newton, Lachlan J Coin, David A Relman, Giovanni Montana, Michael Levin
The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB...
2017: PloS One
https://www.readbyqxmd.com/read/29128997/pd-1-pd-l1-immune-checkpoint-blockade-in-malignant-lymphomas
#11
REVIEW
Yi Wang, Ling Wu, Chen Tian, Yizhuo Zhang
Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas...
November 11, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29122838/soluble-cd80-protein-delays-tumor-growth-and-promotes-tumor-infiltrating-lymphocytes
#12
Lucas A Horn, Tiha M Long, Ryan Atkinson, Virginia Clements, Suzanne Ostrand-Rosenberg
Tumor cells employ various immune suppressive strategies to overcome antitumor immunity. One such method is tumor expression of programmed death ligand-1 (PD-L1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD-1) on T cells. Our previous in vitro cellular studies with human and mouse PD-L1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1-mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1...
November 9, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29111717/discovery-of-a-novel-and-selective-indoleamine-2-3-dioxygenase-ido-1-inhibitor-3-5-fluoro-1h-indol-3-yl-pyrrolidine-2-5-dione-eos200271-pf-06840003-and-its-characterization-as-a-potential-clinical-candidate
#13
Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Marie Cordonnier, Deepak Dalvie, Frederik Deroose, Jun Li Feng, Bruno Gomes, Samantha Greasley, Stephen E Kaiser, Manfred Kraus, Michel Négrerie, Karen A Maegley, Nichol Miller, Brion W Murray, Manfred Schneider, James Solowiej, Albert E Stewart, Joseph Tumang, Vince R Torti, Benoit Van den Eynde, Martin Wythes
Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. SAR around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode...
November 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29111199/density-dependent-re-tuning-of-autoreactive-t-cells-alleviates-their-pathogenicity-in-a-lymphopenic-environment
#14
Eleanore Chuang, Marilyn Augustine, Matthew Jung, Ronald H Schwartz, Nevil J Singh
Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells...
December 2017: Immunology Letters
https://www.readbyqxmd.com/read/29093272/t-cells-presenting-viral-antigens-or-autoantigens-induce-cytotoxic-t-cell-anergy
#15
Nathalie E Blachère, Dana E Orange, Emily C Gantman, Bianca D Santomasso, Graeme C Couture, Teresa Ramirez-Montagut, John Fak, Kevin J O'Donovan, Zhong Ru, Salina Parveen, Mayu O Frank, Michael J Moore, Robert B Darnell
In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29078267/gut-dysbiosis-breaks-immunological-tolerance-toward-the-central-nervous-system-during-young-adulthood
#16
Sudhir K Yadav, Sridhar Boppana, Naoko Ito, John E Mindur, Martin T Mathay, Ankoor Patel, Suhayl Dhib-Jalbut, Kouichi Ito
Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS self-antigens has been suggested to initiate CNS autoimmunity. Age and microbial infection are well-known factors involved in the development of autoimmune diseases, including MS. Recent studies have suggested that alterations in the gut microbiota, referred to as dysbiosis, are associated with MS. However, it is still largely unknown how gut dysbiosis affects the onset and progression of CNS autoimmunity...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29074182/t-cell-ignorance-is-bliss-t-cells-are-not-tolerized-by-langerhans-cells-presenting-human-papillomavirus-antigens-in-the-absence-of-costimulation
#17
Andrew W Woodham, Lisa Yan, Joseph G Skeate, Daniel van der Veen, Heike E Brand, Michael K Wong, Diane M Da Silva, W Martin Kast
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs...
December 2016: Papillomavirus Research
https://www.readbyqxmd.com/read/29045749/immune-checkpoint-inhibitor-related-myocarditis
#18
Kazuko Tajiri, Kazutaka Aonuma, Ikuo Sekine
Immune checkpoint inhibitors have demonstrated significant clinical benefit in many cancers. The clinical benefit afforded by these treatments can be accompanied by a unique and distinct spectrum of adverse events. Recently, several fatal cases of immune checkpoint inhibitor-related myocarditis were reported. Although its frequency is comparatively lower than that of other immune-related adverse events, myocarditis can lead to circulatory collapse and lethal ventricular arrhythmia. Immune checkpoints, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), play important roles in establishing peripheral tolerance to the heart...
October 17, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29020680/hepatic-t-cell-tolerance-induction-in-an-inflammatory-environment
#19
Janine Dywicki, Fatih Noyan, Ana Clara Misslitz, Martin Hapke, Melanie Galla, Jerome Schlue, Roland S Liblau, Richard Taubert, Michael P Manns, Elmar Jaeckel, Matthias Hardtke-Wolenski
For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre)...
October 12, 2017: Digestive Diseases
https://www.readbyqxmd.com/read/28968466/changes-in-the-cellular-microrna-profile-by-the-intracellular-expression-of-hiv-1-tat-regulator-a-potential-mechanism-for-resistance-to-apoptosis-and-impaired-proliferation-in-hiv-1-infected-cd4-t-cells
#20
María Sánchez-Del Cojo, María Rosa López-Huertas, Francisco Díez-Fuertes, Sara Rodríguez-Mora, Mercedes Bermejo, Guillermo López-Campos, Elena Mateos, Laura Jiménez-Tormo, Francisco Gómez-Esquer, Gema Díaz-Gil, José Alcamí, Mayte Coiras
HIV-1 induces changes in the miRNA expression profile of infected CD4+ T cells that could improve viral replication. HIV-1 regulator Tat modifies the cellular gene expression and has been appointed as an RNA silencing suppressor. Tat is a 101-residue protein codified by two exons that regulates the elongation of viral transcripts. The first exon of Tat (amino acids 1-72) forms the transcriptionally active protein Tat72, but the presence of the second exon (amino acids 73-101) results in a more competent regulatory protein (Tat101) with additional functions...
2017: PloS One
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