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https://www.readbyqxmd.com/read/29146547/a-gene-module-associated-with-dysregulated-tcr-signaling-pathways-in-cd4-t-cell-subsets-in-rheumatoid-arthritis
#1
Shuji Sumitomo, Yasuo Nagafuchi, Yumi Tsuchida, Haruka Tsuchiya, Mineto Ota, Kazuyoshi Ishigaki, Shinichiro Nakachi, Rika Kato, Keiichi Sakurai, Norio Hanata, Shoko Tateishi, Hiroko Kanda, Akari Suzuki, Yuta Kochi, Keishi Fujio, Kazuhiko Yamamoto
We analyzed the transcriptome of detailed CD4(+) T cell subsets including them after abatacept treatment, and examined the difference among CD4(+) T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4(+) T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500...
November 13, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29125235/comparison-of-the-mrna-expression-profile-of-b-cell-receptor-components-in-normal-cd5-high-b-lymphocytes-and-chronic-lymphocytic-leukemia-a-key-role-of-zap70
#2
Aleena A Gladkikh, Daria M Potashnikova, Victor Tatarskiy, Margarita Yastrebova, Alvina Khamidullina, Natasha Barteneva, Ivan Vorobjev
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils...
November 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29105157/reduced-numbers-of-mature-medullary-thymic-epithelial-cells-in-skg-mice
#3
Robby Engelmann, Andra Biemelt, Anja Johl, Daniela Kuthning, Brigitte Müller-Hilke
Attenuated T cell receptor (TCR) signaling contributes to the susceptibility for autoimmunity as shown via mutants of PTPN22 and Zap70 genes. We here set out to investigate the effect of an attenuated TCR signal on the composition of the thymic epithelial cell (TEC) compartment. To that extent, we combined flow cytometry and histology and compared the TEC subpopulations of Zap70 wild type with SKG mutant mice. We found an increased cortical TEC compartment in SKG thymi at the expense of reduced numbers of mature medullary TECs and a 4...
November 3, 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29075057/evaluation-of-interleukin-9-expression-as-a-potential-therapeutic-target-in-chronic-lymphocytic-leukemia-in-a-cohort-of-egyptian-patients
#4
Hadeer A Abbassy, Reham A Aboelwafa, Omar M Ghallab
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that has a highly variable clinical course. Genomic features as zeta-chain-associated protein kinase 70 (ZAP70) expression and CD38 expression provide further differentiation of disease prognosis. Extensive studies have confirmed the oncogenic activities of IL-9 in lymphoma. The aim of the current study was to investigate the contribution of IL-9 expression to the pathogenesis of CLL and its correlation to other prognostic parameters. This study was conducted on 80 patients at diagnosis with CLL and 80 healthy controls...
December 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28965845/the-immune-signaling-adaptor-lat-contributes-to-the-neuroanatomical-phenotype-of-16p11-2-bp2-bp3-cnvs
#5
Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C Collins, Konstantin Popadin, Camille S Bonnet, Giuliana Giannuzzi, Anne M Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond
Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28930697/overexpression-of-muc1-and-genomic-alterations-in-its-network-associate-with-prostate-cancer-progression
#6
Xiaozeng Lin, Yan Gu, Anil Kapoor, Fengxiang Wei, Tariq Aziz, Diane Ojo, Yanzhi Jiang, Michael Bonert, Bobby Shayegan, Huixiang Yang, Khalid Al-Nedawi, Pierre Major, Damu Tang
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN(-/-) mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort...
November 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28912049/two-novel-mutations-in-zap70-gene-that-result-in-human-immunodeficiency
#7
Beatriz Adriana Llamas-Guillén, Nina Pastor, Gabriela López-Herrera, Maria Edith González-Serrano, Lucero Valenzuela-Vázquez, Maria Elena Bravo-Adame, Tania Maria Villanueva-Cabello, Paul Gaytán, Jorge Yañez, Ivan Martinez-Duncker, Miguel Ruiz-Fernández, André Veillette, Sara Elva Espinosa-Padilla, Mario Ernesto Cruz-Munoz
No abstract text is available yet for this article.
September 11, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28846922/interaction-of-zap70-and-cxcr4-receptor-at-lamellipodia-that-determines-the-directionality-during-jurkat-t-cells-chemotaxis
#8
Chia-Yun Wu, Yi-Ying Tsai, Sheng-Yi Chen, Yu-Ping Lin, Jyh-Wei Shin, Chia-Ching Wu, Bei-Chang Yang
Directional migration of T-lymphocytes is a key process during immune activation and is tightly regulated both temporally and spatially. The initial cell membrane protrusion at a particular site is critical for determining the direction of cell migration. In this study, we found that ZAP-70 protein appeared not only at the margin of the spreading areas of polarized Jurkat T cells but also formed clusters near the center of the cell body on a fibronectin plate. Specifically, some pZAP-70 was located at the lamellipodia/filopodia and was closely associated with the most extended membrane contact...
October 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28835371/b-cell-receptor-signaling-regulates-metabolism-in-chronic-lymphocytic-leukemia
#9
Hima Vangapandu, Ondrej Havranek, Mary Ayres, Benny A Kaipparettu, Kumudha Balakrishnan, William Wierda, Michael J Keating, R Eric Davis, Christine M Stellrecht, Varsha Gandhi
Chronic lymphocytic leukemia (CLL) cells are quiescent but have active transcription and translation processes, suggesting that these lymphocytes are metabolically active. Based on this premise, the metabolic phenotype of CLL lymphocytes was investigated by evaluating the two intracellular ATP generating pathways. Metabolic flux was assessed by measuring glycolysis as extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation as oxygen consumption rate (OCR) and then correlated with prognostic factors...
August 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28833060/tcr-signalling-network-organization-at-the-immunological-synapses-of-murine-regulatory-t-cells
#10
Marco van Ham, René Teich, Lars Philipsen, Jana Niemz, Nicole Amsberg, Josef Wissing, Manfred Nimtz, Lothar Gröbe, Stefanie Kliche, Nadine Thiel, Frank Klawonn, Mario Hubo, Helmut Jonuleit, Peter Reichardt, Andreas J Müller, Jochen Huehn, Lothar Jänsch
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells...
August 17, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28814981/cpg-location-and-methylation-level-are-crucial-factors-for-the-early-detection-of-oral-squamous-cell-carcinoma-in-brushing-samples-using-bisulfite-sequencing-of-a-13-gene-panel
#11
Luca Morandi, Davide Gissi, Achille Tarsitano, Sofia Asioli, Andrea Gabusi, Claudio Marchetti, Lucio Montebugnoli, Maria Pia Foschini
BACKGROUND: Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28745977/zap70-and-downstream-ranbp2-are-required-for-the-exact-timing-of-the-meiotic-cell-cycle-in-oocytes
#12
Hyun-Jung Kim, Su-Yeon Lee, Hyun-Seo Lee, Eun-Young Kim, Jung-Jae Ko, Kyung-Ah Lee
In previous studies, we observed that Zeta-chain-associated protein kinase 70 (Zap70) regulates spindle assembly and chromosome alignment in mouse oocyte and that Ran binding protein 2 (RanBP2) is a highly associated gene with Zap70 based on a microarray analysis. Because RanBP2 is related to nuclear envelope breakdown (NEBD) during mitosis, the aim of the present study was to elucidate the molecular mechanism of Zap70 with respect to RanBP2 in the germinal vesicle breakdown (GVBD) of oocytes. Results indicated that RanBP2 expression was regulated by Zap70 and that depletion of RanBP2 using RanBP2 RNAi manifested comparable phenotypes to those observed in Zap70 RNAi-treated oocytes, which presented faster processing of GVBD...
August 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28736554/differential-requirements-for-src-family-kinases-in-syk-or-zap70-mediated-slp-76-phosphorylation-in-lymphocytes
#13
Frank Fasbender, Maren Claus, Sabine Wingert, Mina Sandusky, Carsten Watzl
In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28735895/a-phosphosite-within-the-sh2-domain-of-lck-regulates-its-activation-by-cd45
#14
Adam H Courtney, Jeanine F Amacher, Theresa A Kadlecek, Marianne N Mollenauer, Byron B Au-Yeung, John Kuriyan, Arthur Weiss
The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck...
August 3, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28708231/ibrutinib-treatment-of-a-patient-with-relapsing-chronic-lymphocytic-leukemia-and-sustained-remission-of-richter-syndrome
#15
Elisa Albi, Stefano Baldoni, Patrizia Aureli, Erica Dorillo, Beatrice Del Papa, Stefano Ascani, Mauro Di Ianni, Franca Falzetti, Paolo Sportoletti
PURPOSE: Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS. METHODS: The patient was diagnosed with CLL in 2003. Biological findings at onset included absent ZAP70 expression, mutated IGVH, and NOTCH1 mutation...
July 5, 2017: Tumori
https://www.readbyqxmd.com/read/28672038/t-cell-activation-and-differentiation-is-modulated-by-a-cd6-domain-1-antibody-itolizumab
#16
Usha Bughani, Arindam Saha, Anshu Kuriakose, Reshmi Nair, Ravindra B Sadashivarao, Rasika Venkataraman, Swati Patel, Anuja Tushar Deshchougule, Satish Kumar S, Enrique Montero, Harish V Pai, Dinesh V Palanivelu, Ramakrishnan Melarkode, Pradip Nair
CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis...
2017: PloS One
https://www.readbyqxmd.com/read/28603521/novel-combined-immune-deficiency-and-radiation-sensitivity-blended-phenotype-in-an-adult-with-biallelic-variations-in-zap70-and-rnf168
#17
Ivan K Chinn, Robert P Sanders, Asbjørg Stray-Pedersen, Zeynep H Coban-Akdemir, Vy Hong-Diep Kim, Harjit Dadi, Chaim M Roifman, Troy Quigg, James R Lupski, Jordan S Orange, I Celine Hanson
With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28526413/tcr-crosslinking-promotes-crk-adaptor-protein-binding-to-tyrosine-phosphorylated-cd3%C3%AE-chain
#18
Guangyu Dong, Rachel Kalifa, Pulak Ranjan Nath, Sigal Gelkop, Noah Isakov
T cell antigen receptor (TCR) binding of a peptide antigen presented by antigen-presenting cells (APCs) in the context of surface MHC molecules initiates signaling events that regulate T cell activation, proliferation and differentiation. A key event in the activation process is the phosphorylation of the conserved tyrosine residues within the CD3 chain immunoreceptor tyrosine-based activation motifs (ITAMs), which operate as docking sites for SH2 domain-containing effector proteins. Phosphorylation of the CD3ζ ITAMs renders the CD3 chain capable of binding the ζ-chain associated protein 70 kDa (ZAP70), a protein tyrosine kinase that is essential for T cell activation...
July 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28517553/ifi16-reduced-expression-is-correlated-with-unfavorable-outcome-in-chronic-lymphocytic-leukemia
#19
Pier Paolo Piccaluga, Claudio Agostinelli, Simona Righi, Maria Ciccone, Maria Carla Re, Giuseppina Musumeci, Erica Diani, Caterina Signoretto, Isabella Bon, Ottavio Piccin, Antonio Cuneo, Claudio Tripodo, Cristina Ponti, Donato Zipeto, Santo Landolfo, Davide Gibellini
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Its clinical course is typically indolent; however, based on a series of pathobiological, clinical, genetic, and phenotypic parameters, patient survival varies from less than 5 to more than 20 years. In this paper, we show for the first time that the expression of the interferon-inducible DNA sensor IFI16, a member of the PYHIN protein family involved in proliferation inhibition and apoptosis regulation, is associated with the clinical outcome in CLL...
June 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28465009/crk-adaptor-proteins-regulate-cd3%C3%AE-chain-phosphorylation-and-tcr-cd3-down-modulation-in-activated-t-cells
#20
Guangyu Dong, Rachel Kalifa, Pulak Ranjan Nath, Yael Babichev, Sigal Gelkop, Noah Isakov
T cell receptor (TCR) recognition of a peptide antigen in the context of MHC molecules initiates positive and negative cascades that regulate T cell activation, proliferation and differentiation, and culminate in the acquisition of effector T cell functions. These processes are a prerequisite for the induction of specific T cell-mediated adaptive immune responses. A key event in the activation of TCR-coupled signaling pathways is the phosphorylation of tyrosine residues within the cytoplasmic tails of the CD3 subunits, predominantly CD3ζ...
April 29, 2017: Cellular Signalling
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