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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...
October 19, 2016: Immunological Investigations
Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
Eun-Kyung Kwon, Chan-Ki Min, Yuri Kim, Jae-Won Lee, Abdimadiyeva Aigerim, Sebastian Schmidt, Hyun-Jun Nam, Seong Kyu Han, Kuglae Kim, Jeong Seok Cha, Hoyoung Kim, Sanguk Kim, Hyun-Soo Cho, Myung-Sik Choi, Nam-Hyuk Cho
Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown...
October 15, 2016: Biochimica et Biophysica Acta
Brij Bharti, Sachin Shukla, Ratnakar Tripathi, Suman Mishra, Mohan Kumar, Manoj Pandey, Rajnikant Mishra
BACKGROUND & OBJECTIVES: The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis...
May 2016: Indian Journal of Medical Research
Wei Zhang, Jie-Fei Bai, Meng-Xuan Zuo, Xin-Xin Cao, Miao Chen, Yan Zhang, Xiao Han, Ding-Rong Zhong, Dao-Bin Zhou
The aim of the study was to investigate the relationship between PD-1 expression on the surface of CD4(+) T cells and prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Sixty patients who were newly diagnosed with DLBCL and 39 healthy controls were enrolled. In CD4(+) T cells of DLBCL patients, the median MFI of PD-1 were 541.5 (range: 348.25-758.75), significantly higher than 250 (range: 211-326) in healthy controls (P < 0.001). The ZAP70, PI3K, and NFAT mRNA expression levels of patients were 0...
October 5, 2016: Cancer Medicine
Matthew D Blunt, Stefan Koehrer, Rachel Dobson, Marta Larrayoz, Sarah Wilmore, Alice Hayman, Jack Parnell, Lindsay D Smith, Andrew Davies, Peter Wm Johnson, Pamela B Conley, Anjali Pandey, Jonathan C Strefford, Freda K Stevenson, Graham Packham, Francesco Forconi, Greg P Coffey, Jan Burger, Andrew J Steele
PURPOSE: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Riccardo V Mancuso, Karl Welzenbach, Peter Steinberger, Stephan Krähenbühl, Gabriele Weitz-Schmidt
The integrin leucocyte function-associated antigen-1 (αLβ2, LFA-1) plays crucial roles in T cell adhesion, migration and immunological synapse (IS) formation. Consequently, αLβ2 is an important therapeutic target in autoimmunity. Three major classes of αLβ2 inhibitors with distinct modes of action have been described to date: Monoclonal antibodies (mAbs), small molecule α/β I allosteric and small molecule α I allosteric inhibitors. The objective of this study was to systematically compare these three modes of αLβ2 inhibition for their αLβ2 inhibitory as well as their potential agonist-like effects...
November 1, 2016: Biochemical Pharmacology
John C Moore, Timothy S Mulligan, Nora Torres Yordán, Daniel Castranova, Van N Pham, Qin Tang, Riadh Lobbardi, Anthony Anselmo, Robert S Liwski, Jason N Berman, Ruslan I Sadreyev, Brant M Weinstein, David M Langenau
The zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) is required for T-cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immunodeficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70(y442)) that was created using TALENs. In contrast to what has been reported in morphant zebrafish, zap70(y442) homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae...
September 6, 2016: Molecular and Cellular Biology
Akihisa Mino, Anja Troeger, Christian Brendel, Alan Cantor, Chad Harris, Marioara F Ciuculescu, David A Williams
RhoH is a haematopoietic -specific, GTPase-deficient Rho GTPase that plays an essential role in T lymphocyte development and haematopoietic cell migration. RhoH is known to interact with ZAP70 in T cell receptor (TCR) signaling and antagonize Rac GTPase activity. To further elucidate the molecular mechanisms of RhoH in T cell function, we carried out in vivo biotinylation and mass spectrometry analysis to identify new RhoH-interacting proteins in Jurkat T cells. We indentified Kaiso by streptavidin capture and confirmed the interaction with RhoH by co-immunoprecipitation...
August 30, 2016: Small GTPases
Kristina J H Kleinwort, Barbara Amann, Stefanie M Hauck, Regina Feederle, Walter Sekundo, Cornelia A Deeg
PURPOSE: Recently, formation of tertiary lymphoid structures was demonstrated and further characterized in the R161H mouse model of spontaneous autoimmune uveitis. In the horse model of spontaneous recurrent uveitis, intraocular lymphoid follicle formation is highly characteristic, and found in all stages and scores of disease, but in depth analyses of immunologic features of these structures are lacking to date. METHODS: Paraffin-embedded eye sections of cases with equine spontaneous recurrent uveitis (ERU) were characterized with immunohistochemistry to gain insight into the distribution, localization, and signaling of immune cells in intraocular tertiary lymphoid tissues...
August 1, 2016: Investigative Ophthalmology & Visual Science
B K Binukumar, Steven L Pelech, Catherine Sutter, Varsha Shukla, Niranjana D Amin, Philip Grant, Manju Bhaskar, Suzanne Skuntz, Joseph Steiner, Harish C Pant
Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer's disease (AD) phenotypes in AD model mice...
September 6, 2016: Journal of Alzheimer's Disease: JAD
Shimona Starling, Clare Jolly
: HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined...
November 1, 2016: Journal of Virology
Nisar Amin, Sriram Balasubramanian, Kamlai Saiya-Cork, Kerby Shedden, Nan Hu, Sami Malek
PURPOSE: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed CLL and CLL with del17p. Mechanistically, ibrutinib interferes with BCR signaling as well as multiple CLL cell to microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. EXPERIMENTAL DESIGN: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole exome sequencing and SNP 6...
August 17, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R Spellman, Sarah Cooley, Michael R Verneris, Bruce R Blazar, Jeffrey S Miller
Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome...
October 1, 2016: Cancer Research
M L Schroeder, B Triggs-Raine, T Zelinski
BACKGROUND: Primary immunodeficiency is a life-threatening genetic disease that appeared to have an increased incidence in Manitoba Mennonites. Determining the genetic basis of this immunodeficiency was an essential step for providing early and appropriate medical intervention. METHODS: Initially, DNA from probands affected with primary immunodeficiency and their family members was assessed for linkage to genes previously associated with immunodeficiency. Candidate genes were sequenced to identify the causative mutation...
2016: BMC Medical Genetics
Geoffrey D E Cuvelier, Tamar S Rubin, Donna A Wall, Marlis L Schroeder
ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive...
October 2016: Journal of Clinical Immunology
Simon Guerard, Rikard Holmdahl, Kajsa Wing
Polysaccharides from Saccharomyces cerevisiae can induce arthritis, ileitis, and interstitial pneumonitis in BALB/c ZAP70 (W163C)-mutant (SKG) mice via T helper 17-cell-dependent pathways. However, little is known regarding the factors influencing disease severity. We investigated mannan-induced arthritis in SKG mice and how NADPH oxidase 2-derived reactive oxygen species (ROS) regulate disease. SKG mice were highly susceptible to both IL-17-mediated T-cell-driven arthritis and T-cell-independent acute psoriasis-like dermatitis...
September 2016: American Journal of Pathology
Peter A Thill, Arthur Weiss, Arup K Chakraborty
The initiation of signaling in T lymphocytes in response to the binding of the T cell receptor (TCR) to cognate ligands is a key step in the emergence of adaptive immune responses. Conventional models posit that TCR signaling is initiated by the phosphorylation of receptor-associated immune receptor activation motifs (ITAMs). The cytoplasmic tyrosine kinase Zap70 binds to phosphorylated ITAMs, is subsequently activated, and then propagates downstream signaling. While evidence for such models is provided by experiments with cell lines, in vivo, Zap70 is bound to phosphorylated ITAMs in resting T cells...
September 15, 2016: Molecular and Cellular Biology
Federica Frezzato, Benedetta Accordi, Valentina Trimarco, Cristina Gattazzo, Veronica Martini, Gloria Milani, Silvia Bresolin, Filippo Severin, Andrea Visentin, Giuseppe Basso, Gianpietro Semenzato, Livio Trentin
B cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B lymphocytes from proliferative activity and apoptosis resistance. The increased awareness of the importance of B cell receptor signaling in CLL has raised new opportunities for targeted intervention. Herein, we describe a study performed with the high-throughput RPPA (reverse phase protein array) technique, which allowed us to simultaneously study different molecules in a large series of patients. We analyzed B lymphocytes from 57 patients with CLL and 11 healthy subjects...
June 16, 2016: Journal of Leukocyte Biology
Wenqiang Cao, Jing Guo, Xiaofeng Wen, Li Miao, Feng Lin, Guanxin Xu, Ruoyu Ma, Shengxia Yin, Zhaoyuan Hui, Tingting Chen, Shixin Guo, Wei Chen, Yingying Huang, Yizhi Liu, Jianli Wang, Lai Wei, Lie Wang
T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1-binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes...
2016: Nature Communications
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