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ZAP-70

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https://www.readbyqxmd.com/read/28216435/morpholino-based-correction-of-hypomorphic-zap70-mutation-in-an-adult-with-combined-immunodeficiency
#1
Christina Gavino, Marija Landekic, Jibin Zeng, Ning Wu, Sungmi Jung, Ming-Chao Zhong, Alexis Cohen-Blanchet, Mélanie Langelier, Odile Neyret, Duncan Lejtenyi, Claudia Rochefort, Judith Cotton-Montpetit, Christine McCusker, Bruce Mazer, André Veillette, Donald C Vinh
An adult with hypomorphic ZAP-70 deficiency due to de novo donor splice site mutation manifested autoimmunity, infections especially with DNA-based viruses and lymphoproliferation. Morpholino interference of mutant splice site increased expression of wild-type protein, significantly improving T cell responses.
February 16, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28209773/mannan-binding-lectin-a-serum-collectin-suppresses-t-cell-proliferation-via-direct-interaction-with-cell-surface-calreticulin-and-inhibition-of-proximal-t-cell-receptor-signaling
#2
Na Zhao, Jie Wu, Simin Xiong, Liyun Zhang, Xiao Lu, Shangliang Chen, Qifeng Wu, Hailan Wang, Ying Liu, Zhengliang Chen, Daming Zuo
Mannan binding lectin (MBL), initially described to activate the complement pathway, is also known to be involved in the pathogenesis of autoimmune diseases. We report a thus far unknown function of MBL as a suppressor of T-cell activation. MBL markedly inhibited T-cell proliferation induced by anti-CD3 and anti-CD28 antibodies. Moreover, the presence of MBL during T-cell priming interfered with proximal T-cell receptor signaling by decreasing phosphorylation of Lck, ZAP-70, and LAT. MBL bound to T cells through interaction between the collagen-like region of MBL and calreticulin (CRT) expressed on the T-cell surface...
February 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28183684/prognosis-biomarkers-evaluation-in-chronic-lymphocytic-leukemia
#3
Lorena Caixeta Gomes, Fernanda Cristina Gontijo Evangelista, Lirlândia Pires de Sousa, Sergio Schusterschitz da Silva Araujo, Maria das Graças Carvalho, Adriano de Paula Sabino
OBJECTIVE/BACKGROUND: From clinical and biological points of view, chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by a progressive accumulation of lymphocytes in the peripheral blood, bone marrow, and lymphoid organs. New prognostic markers in CLL may be useful to clinicians for predicting outcome and in clinical decision-making. The aim of this study was to evaluate the potential prognostic value of the apoptotic/survival-controlling proteins and protein tyrosine kinase ZAP-70 gene expression in CLL patients and control individuals, correlating such findings with patients' clinical data...
February 1, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/28164634/cd38-expression-and-variation-as-a-prognostic-factor-chronic-lymphocytic-leukemia
#4
Mesude Falay, Funda Ceran, Ahmet K Gunes, Simten Dagdas, Meltem Ayli, Gulsum Ozet
BACKGROUND: In this study, we aimed to determine a cutoff level for CD38 that would aid us in identifying chronic lymphocytic leukemia patients in need of early therapy and predicting patients at sufficiently low risk who would likely exhibit a rapid improvement; we also aimed to find out if CD38 expression would show variability during disease course and determine the extent of CD38 expression. METHODS: 124 patients were diagnosed with CLL. CD38 and ZAP-70 expression levels were measured with four color flowcytometry...
July 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28100106/systemic-lupus-erythematosus-in-the-light-of-the-regulatory-effects-of-galectin-1-on-t-cell-function
#5
Á Hornung, É Monostori, L Kovács
Galectin-1 is an endogenous immunoregulatory lectin-type protein. Its most important effects are the inhibition of the differentiation and cytokine production of Th1 and Th17 cells, and the induction of apoptosis of activated T-cells. Galectin-1 has been identified as a key molecule in antitumor immune surveillance, and data are accumulating about the pathogenic role of its deficiency, and the beneficial effects of its administration in various autoimmune disease models. Initial animal and human studies strongly suggest deficiencies in both galectin-1 production and responsiveness in systemic lupus erythematosus (SLE) T-cells...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28046066/htlv-1-bzip-factor-enhances-t-cell-proliferation-by-impeding-the-suppressive-signaling-of-co-inhibitory-receptors
#6
Haruka Kinosada, Jun-Ichirou Yasunaga, Kazuya Shimura, Paola Miyazato, Chiho Onishi, Tomonori Iyoda, Kayo Inaba, Masao Matsuoka
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28011996/the-kinase-inhibitors-r406-and-gs-9973-impair-t-cell-functions-and-macrophage-mediated-anti-tumor-activity-of-rituximab-in-chronic-lymphocytic-leukemia-patients
#7
Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Carmen Stanganelli, Esteban Enrique Elías, Patricia Dos Santos, Irma Slavutsky, Horacio Fernández Grecco, María Cabrejo, Raimundo Fernando Bezares, Mirta Giordano, Romina Gamberale, Mercedes Borge
Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients...
April 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27965016/cross-reactivity-of-monoclonal-antibodies-against-cd4-1-and-cd8%C3%AE-of-ginbuna-crucian-carp-with-lymphocytes-of-zebrafish-and-other-cyprinid-species
#8
Ryuichiro Miyazawa, Yuta Matsuura, Yasuhiro Shibasaki, Shintaro Imamura, Teruyuki Nakanishi
We have monoclonal antibodies (mAbs) against CD4-1 (6D1) and CD8α (2C3) in ginbuna crucian carp Carassius auratus langsdorfii. In our previous studies we showed that 2C3 mAb positive cells are the primary cell type showing specific cytotoxicity against allogeneic targets, suggesting that CD8α(+) lymphocytes in ginbuna are equivalent to cytotoxic T lymphocytes (CTLs) in mammals. We further demonstrated the helper T cell function of 6D1 mAb positive cells by studying mixed leukocyte culture (MLC) and hapten/carrier effects...
December 11, 2016: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/27941787/recruitment-of-calcineurin-to-the-tcr-positively-regulates-t-cell-activation
#9
Debjani Dutta, Valarie A Barr, Itoro Akpan, Paul R Mittelstadt, Laishram I Singha, Lawrence E Samelson, Jonathan D Ashwell
Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (Lck(S59)). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70(Y493)), as well as some downstream pathways in a manner consistent with signaling in cells expressing Lck(S59A) (Lck that cannot be phosphorylated) or Lck(S59E) (a phosphomimetic mutant)...
February 2017: Nature Immunology
https://www.readbyqxmd.com/read/27932698/identification-of-inhibitors-of-the-association-of-zap-70-with-the-t-cell-receptor-by-high-throughput-screen
#10
Patrick R Visperas, Christopher G Wilson, Jonathan A Winger, Qingrong Yan, Kevin Lin, Michelle R Arkin, Arthur Weiss, John Kuriyan
ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular ζ-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor...
March 2017: SLAS Discov
https://www.readbyqxmd.com/read/27888629/inhibition-of-bcr-signaling-using-the-syk-inhibitor-tak-659-prevents-stroma-mediated-signaling-in-chronic-lymphocytic-leukemia-cells
#11
Noelia Purroy, Júlia Carabia, Pau Abrisqueta, Leire Egia, Meritxell Aguiló, Cecilia Carpio, Carles Palacio, Marta Crespo, Francesc Bosch
Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27759478/novel-mutation-of-zap-70-related-combined-immunodeficiency-first-case-from-the-national-iranian-registry-and-review-of-the-literature
#12
REVIEW
Afshin Shirkani, Mohammad Shahrooei, Gholamreza Azizi, Hassan Rokni-Zadeh, Hassan Abolhassani, Shokrollah Farrokhi, Glynis Frans, Xavier Bossuyt, Asghar Aghamohammadi
ZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response...
January 2017: Immunological Investigations
https://www.readbyqxmd.com/read/27742074/biomarkers-in-chronic-lymphocytic-leukemia-clinical-applications-and-prognostic-markers
#13
REVIEW
Carlos I Amaya-Chanaga, Laura Z Rassenti
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The Rai and Binet staging systems are often used to predict survival. However, they do not take into account other biological characteristics of CLL cells that may influence the disease course and response to treatment. Prognostic factors such as chromosome abnormalities (trisomy 12, 11q deletions and 17p deletions), β2 microglobulin, thymidine kinase, CD38 and ZAP-70 expression, IGHV mutation status, and mutations in genes such as NOTCH1, MYD88, SF3B1, and ATM are also predictors of prognosis...
March 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27718514/elevated-il-17a-and-il-22-regulate-expression-of-inducible-cd38-and-zap-70-in-chronic-lymphocytic-leukemia
#14
Samaneh Kouzegaran, Soheila Siroosbakht, Bahram Fariborz Farsad, Bijan Rezakhaniha, Banafshe Dormanesh, Vahid Behnod, Amir Saber Tanha
BACKGROUND: In this study, we investigated the role and expression of interleukin (IL)-17A and IL-22 in chronic lymphocytic leukemia Methods: We evaluated the expression of markers above on CLL by ELISA, qRT-PCR, flow cytometric analysis and nonparametric Kruskal-Wallis test. RESULTS: Quantitative RT-PCR revealed that the mRNA levels of IL-17A and IL-22 in PBMCs of CLL patients were upregulated compared with those from healthy subjects (mean ± SD: 1.96 ± 0...
October 8, 2016: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/27700984/an-electrostatic-selection-mechanism-controls-sequential-kinase-signaling-downstream-of-the-t-cell-receptor
#15
Neel H Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A Kadlecek, Ian R Fallahee, William P Russ, Rama Ranganathan, Arthur Weiss, John Kuriyan
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues...
October 4, 2016: ELife
https://www.readbyqxmd.com/read/27686375/the-role-of-zap70-kinase-in-acute-lymphoblastic-leukemia-infiltration-into-the-central-nervous-system
#16
Ameera Alsadeq, Henning Fedders, Christian Vokuhl, Nele M Belau, Martin Zimmermann, Tim Wirbelauer, Steffi Spielberg, Michaela Vossen-Gajcy, Gunnar Cario, Martin Schrappe, Denis M Schewe
Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases...
February 2017: Haematologica
https://www.readbyqxmd.com/read/27662631/differences-in-activation-of-hiv-1-replication-by-superinfection-with-hiv-1-and-hiv-2-in-u1-cells
#17
Xue Wang, Bing Sun, Christelle Mbondji, Santanu Biswas, Jiangqin Zhao, Indira Hewlett
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir that serve as a viral source for the infection of CD4 T cells. The relationship between HIV-1 latent infection and superinfection in macrophages has not been well studied. Using susceptible U1 cells chronically infected with HIV-1, we studied the effects of HIV superinfection on latency and differences in superinfection with HIV-1 and HIV-2 in macrophages. We found that HIV-1 (MN) superinfection displayed increased HIV-1 replication in a time-dependent manner; while cells infected with HIV-2 (Rod) initially showed increased HIV-1 replication, followed by a decrease in HIV-1 RNA production...
September 23, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27584054/increased-il-10-il-17-ratio-is-aggravated-along-with-the-prognosis-of-patients-with-chronic-lymphocytic-leukemia
#18
Nannan Pang, Rui Zhang, Jinhua Li, Zhenghao Zhang, Hailong Yuan, Gang Chen, Fang Zhao, Lei Wang, Haizhou Cao, Jianhua Qu, Jianbing Ding
OBJECTIVE: This study is to investigate the association between the Treg/Th17 cells and prognosis of chronic lymphocytic leukemia (CLL). METHODS: Totally 50 CLL patients and 20 Health controls were included in this study. Regulatory T (Treg) cells and the cell subset secreting IL-17 (Th17) in peripheral blood were detected with flow cytometry. Serum levels of IL-10 and IL-17 were determined with ELISA, and expression of Foxp3 and RORγt was assessed with quantitative real-time PCR...
November 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27443285/slp76-integrates-into-the-b-cell-receptor-signaling-cascade-in-chronic-lymphocytic-leukemia-cells-and-is-associated-with-an-aggressive-disease-course
#19
Nili Dezorella, Ben-Zion Katz, Mika Shapiro, Aaron Polliack, Chava Perry, Yair Herishanu
I In the last decade, the B-cell receptor has emerged as a pivotal stimulus in the pathogenesis of chronic lymphocytic leukemia, and a very feasible therapeutic target in this disease. B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene status and ZAP-70 expression...
December 2016: Haematologica
https://www.readbyqxmd.com/read/27384937/imaging-spatiotemporal-activities-of-zap-70-in-live-t-cells-using-a-fret-based-biosensor
#20
Kaitao Li, Xue Xiang, Jie Sun, Hai-Tao He, Jianhua Wu, Yingxiao Wang, Cheng Zhu
The zeta-chain-associated protein kinase 70 kDa (ZAP-70), a member of the spleen tyrosine kinase (Syk) family, plays an essential role in early T cell receptor (TCR) signaling. Defects in ZAP-70 lead to impaired thymocyte development and peripheral T cell activation. To better understand its activation dynamics and regulation, we visualized ZAP-70 activities in single live T cells with a Förster resonance energy transfer (FRET)-based biosensor, which was designed for probing kinase activities of the Syk family...
December 2016: Annals of Biomedical Engineering
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