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Follicular T helper

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https://www.readbyqxmd.com/read/28916523/cutting-edge-a-critical-role-of-lesional-t-follicular-helper-cells-in-the-pathogenesis-of-igg4-related-disease
#1
Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Akinori Sato, Noriko Ogasawara, Chieko Tsubomatsu, Hiroki Takahashi, Hiroshi Nakase, Tetsuo Himi, Shingo Ichimiya
IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells...
September 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28916434/effects-of-icos-t-cell-depletion-via-afucosylated-monoclonal-antibody-medi-570-on-pregnant-cynomolgus-monkeys-and-the-developing-offspring
#2
Simone M Nicholson, Gianluca Carlesso, Lily I Cheng, Halie Cook, Karma DaCosta, Joel Leininger, Kathleen McKeever, Stephen Weasel Scott, Devon Taylor, Katie Streicher, Steve Eck, Molly Reed, Raffaella Faggioni, Ronald Herbst, Rakesh Dixit, Patricia C Ryan
MEDI-570 is a fully human afucosylated monoclonal antibody (MAb) against Inducible T-cell costimulator (ICOS), highly expressed on CD4+ T follicular helper (TFH) cells. Effects of MEDI-570 were evaluated in an enhanced pre-postnatal development toxicity (ePPND) study in cynomolgus monkeys. Administration to pregnant monkeys did cause any abortifacient effects. Changes in hematology and peripheral blood T lymphocyte subsets in maternal animals and infants and the attenuated infant IgG immune response to keyhole limpet hemocyanin (KLH) were attributed to MEDI-570 pharmacology...
September 12, 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/28899868/b-cell-derived-il-6-initiates-spontaneous-germinal-center-formation-during-systemic-autoimmunity
#3
Tanvi Arkatkar, Samuel W Du, Holly M Jacobs, Elizabeth M Dam, Baidong Hou, Jane H Buckner, David J Rawlings, Shaun W Jackson
Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral autoimmunity, whether B cell-derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed...
September 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28892471/dynamic-regulation-of-t-follicular-regulatory-cell-responses-by-interleukin-2-during-influenza-infection
#4
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...
September 11, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28892065/regulatory-t-cells-impede-acute-and-long-term-immunity-to-blood-stage-malaria-through-ctla-4
#5
Samarchith P Kurup, Nyamekye Obeng-Adjei, Scott M Anthony, Boubacar Traore, Ogobara K Doumbo, Noah S Butler, Peter D Crompton, John T Harty
Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)(+)CD4(+) regulatory T (Treg) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that Treg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (TFH)-B cell interactions in germinal centers...
September 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28888925/follicular-helper-t-cells-are-essential-for-the-elimination-of-plasmodium-infection
#6
Damián Pérez-Mazliah, Minh Phuong Nguyen, Caroline Hosking, Sarah McLaughlin, Matthew D Lewis, Irene Tumwine, Prisca Levy, Jean Langhorne
CD4(+) follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P...
September 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28888664/regulatory-t-cells-and-tlr9-activation-shape-antibody-formation-to-a-secreted-transgene-product-in-aav-muscle-gene-transfer
#7
Roland W Herzog, Mario Cooper, George Q Perrin, Moanaro Biswas, Ashley T Martino, Laurence Morel, Cox Terhorst, Brad E Hoffman
Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response...
August 1, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28887367/tfr-cells-lack-il-2r%C3%AE-but-express-decoy-il-1r2-and-il-1ra-and-suppress-the-il-1-dependent-activation-of-tfh-cells
#8
Paul-Gydeon G Ritvo, Guillame Churlaud, Valentin Quiniou, Laura Florez, Faustine Brimaud, Gwladys Fourcade, Encarnita Mariotti-Ferrandiz, David Klatzmann
Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25(+) cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25(-), in mice and humans...
September 8, 2017: Science Immunology
https://www.readbyqxmd.com/read/28885497/influence-of-the-novel-atp-competitive-dual-mtorc1-2-inhibitor-azd2014-on-immune-cell-populations-and-heart-allograft-rejection
#9
Daniel Fantus, Helong Dai, Yoshihiro Ono, Alicia Watson, Shinichiro Yokota, Kanishka Mohib, Osamu Yoshida, Mark A Ross, Simon C Watkins, Bala Ramaswami, Anna Valusjkikh, David M Rothstein, Angus W Thomson
BACKGROUND: Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. METHODS: mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts...
September 6, 2017: Transplantation
https://www.readbyqxmd.com/read/28881401/generation-of-t-follicular-helper-cells-in-vitro-requirement-for-bcr-cross-linking-and-cognate-b-and-t-cell-interaction
#10
Anne Kolenbrander, Bastian Grewe, David Nemazee, Klaus Überla, Vladimir Temchura
The minimal requirements for in vitro modeling of the natural CD4(+) T-cell differentiation into T follicular helper (TFH) cells are still under investigation. We co-cultured wild type and TCR-transgenic CD4(+) T-cells from naïve mice with dendritic cells and BCR-transgenic B-cells in the presence of HIV-derived virus-like particles containing matched B- and T-cell epitopes. This co-culturing induced co-expression of TFH-master regulator transcription factor BCL-6 and CXCR5 in up to 10% of the wild type and up to 40% of the TCR-transgenic CD4(+) T-cells...
September 7, 2017: Immunology
https://www.readbyqxmd.com/read/28879521/fcrla-a-resident-endoplasmic-reticulum-protein-that-associates-with-multiple-immunoglobulin-isotypes-in-b-lineage-cells
#11
Tessa E Blackburn, Teresa Santiago, Peter D Burrows
FCRLA is homologous to receptors for the Fc portion of IgG (FcγR) and is located in the same region of human chromosome one, but has several unusual and unique features. It is a soluble resident ER protein retained in this organelle by unknown mechanisms involving the N-terminal domain, a disordered domain with three Cys residues in close proximity in the human protein. Unlike the FcγRs, FCRLA is not glycosylated and has no transmembrane region. FCRLA is included in this CTMI volume on IgM-binding proteins because it binds IgM in the ER, but quite surprisingly, given the isotype-restricted ligand specificity of the other FcRs, it also binds all other Ig isotypes so far tested, IgG and IgA...
September 7, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28878083/how-germinal-centers-evolve-broadly-neutralizing-antibodies-the-breadth-of-the-follicular-helper-t-cell-response
#12
Rob J De Boer, Alan S Perelson
Many HIV-1 infected patients evolve broadly neutralizing antibodies (bnAbs). This evolutionary process typically takes several years, and is poorly understood as selection taking place in germinal centers occurs on the basis of antibody affinity. B cells with the highest affinity receptors tend to acquire the most antigen from the FDC network, and present the highest density of cognate peptides to follicular helper T cells (Tfh), which provide survival signals to the B cell. BnAbs are therefore only expected to evolve when the B cell lineage evolving breadth is consistently capturing and presenting more peptides to Tfh cells than other lineages of more specific B cells...
September 6, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28876451/selective-hdac6-inhibition-decreases-early-stage-of-lupus-nephritis-by-downregulating-both-innate-and-adaptive-immune-responses
#13
Jingjing Ren, Xiaofeng Liao, Miranda D Vieson, Miao Chen, Reilly Scott, Jillian Kazmierczak, Xin M Luo, Christopher M Reilly
We have previously demonstrated that HDAC6 expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) NZB/W F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for five weeks...
September 6, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28875978/il4-and-il21-cooperate-to-induce-the-high-bcl6-protein-level-required-for-germinal-center-formation
#14
Stéphane Chevrier, Tobias Kratina, Dianne Emslie, David M Tarlinton, Lynn M Corcoran
Bcl6 is a transcriptional repressor and critical mediator of the germinal center reaction during a T cell dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B cell receptor causes rapid proteasomal degradation of Bcl6...
September 6, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28864814/rituximab-based-first-line-treatment-for-chronic-gvhd-after-allogeneic-sct-results-of-a-phase-2-study
#15
Florent Malard, Myriam Labopin, Ibrahim Yakoub-Agha, Sylvain Chantepie, Thierry Guillaume, Didier Blaise, Reza Tabrizi, Leonardo Magro, Bernard Vanhove, Gilles Blancho, Philippe Moreau, Béatrice Gaugler, Patrice Chevallier, Mohamad Mohty
Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality and morbidity after allogeneic stem-cell transplantation (allo-SCT). In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the efficacy of addition of rituximab to corticosteroid and cyclosporine A as first line therapy for newly diagnosed cGVHD after allo-SCT. Twenty-four patients (median age, 47 years) with mild (n=2), moderate (n=7) or severe (n=15) cGVHD were included...
September 1, 2017: Blood
https://www.readbyqxmd.com/read/28861081/14%C3%A2-years-after-discovery-clinical-follow-up-on-15-patients-with-inducible-co-stimulator-deficiency
#16
Johanna Schepp, Janet Chou, Andrea Skrabl-Baumgartner, Peter D Arkwright, Karin R Engelhardt, Sophie Hambleton, Tomohiro Morio, Ekkehard Röther, Klaus Warnatz, Raif Geha, Bodo Grimbacher
BACKGROUND: Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes. OBJECTIVE: We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients. METHODS: We describe the clinical and laboratory data of 15 patients with available clinical data...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28859168/p2x7-receptor-drives-th1-cell-differentiation-and-controls-the-follicular-helper-t-cell-population-to-protect-against-plasmodium-chabaudi-malaria
#17
Érika Machado de Salles, Maria Nogueira de Menezes, Renan Siqueira, Henrique Borges da Silva, Eduardo Pinheiro Amaral, Sheyla Inés Castillo-Méndez, Isabela Cunha, Alexandra Dos Anjos Cassado, Flávia Sarmento Vieira, David Nicholas Olivieri, Carlos Eduardo Tadokoro, José Maria Alvarez, Robson Coutinho-Silva, Maria Regina D'Império-Lima
A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28855737/capicua-deficiency-induces-autoimmunity-and-promotes-follicular-helper-t-cell-differentiation-via-derepression-of-etv5
#18
Sungjun Park, Seungwon Lee, Choong-Gu Lee, Guk Yeol Park, Hyebeen Hong, Jeon-Soo Lee, Young Min Kim, Sung Bae Lee, Daehee Hwang, Youn Soo Choi, John D Fryer, Sin-Hyeog Im, Seung-Woo Lee, Yoontae Lee
High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner...
July 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28843293/langerhans-cells-orchestrate-tfh-dependent-humoral-immunity
#19
Trupti Vardam, Niroshana Anandasabapathy
T follicular helper cells contribute to the development of long-lasting humoral immunity by germinal center formation. Somatic hypermutation and affinity maturation take place in germinal centers leading to the generation of memory B cells and plasma cells. As such, T follicular helper cells impact immunodeficiencies, autoimmunity, and cancer. This necessitates further understanding of how T follicular helper cells are regulated in health and disease. The current study by Levin et al. builds on prior work to further substantiate a critical role for skin migratory dendritic cells and in particular Langerhans cells at governing T follicular helper and germinal center formation after intradermal immunization with HIV p24-coated polylactic acid nanoparticles...
September 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28833093/multifaceted-role-of-il-21-in-rheumatoid-arthritis-current-understanding-and-future-perspectives
#20
REVIEW
Palani Dinesh, MahaboobKhan Rasool
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects...
August 18, 2017: Journal of Cellular Physiology
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