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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
Omer Nuri Pamuk, Hakan Gurkan, Gulsum Emel Pamuk, Hilmi Tozkır, Julide Duymaz, Metin Yazar
We aimed to evaluate the relationship between some important genetic variations and expressions of these genes in our SLE population. We also determined their association with clinical parameters. Eighty-four SLE patients (79 F, 5 M) and 105 healthy controls (98 F, 7 M) were included in the study. rs13277113, rs2736340, rs7829816, rs6983130, rs2613310, and rs704853 polymorphisms, gene expressions of Src family kinases (Blk, Hck, Lck, and Lyn), and Syk kinases (Syk, ZAP70) were studied by real-time PCR. The heterozygous genotypic pattern (GA) for rs13277113 polymorphism was more frequent in patients with SLE when compared to that in controls (48...
November 18, 2016: Clinical Rheumatology
S Iwata, Y Tanaka
B cells play a pivotal role in the pathogenesis of autoimmune diseases. In patients with systemic lupus erythematosus (SLE), the percentages of plasmablasts and IgD(-)CD27(-) double-negative memory B cells in peripheral blood are significantly increased, while IgD(+)CD27(+) IgM memory B cells are significantly decreased compared to healthy donors. The phenotypic change is significantly associated with disease activity and concentration of autoantibodies. Treatment of B-cell depletion using rituximab results in the reconstitution of peripheral B cells in SLE patients with subsequent improvement in disease activity...
July 2016: Lupus
Guo-Min Deng, George C Tsokos
No abstract text is available yet for this article.
September 2016: Experimental Dermatology
Sarah J Fleischer, Capucine Daridon, Vanessa Fleischer, Peter E Lipsky, Thomas Dörner
OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with hyperactivity of B cells and abnormalities of B cell receptor (BCR) signaling. To address the linkage between dysregulated BCR signaling and increased B cell function, we assessed immediate phosphorylation events in lupus B cells. METHODS: B cells from SLE patients and healthy donors were analyzed by flow cytometry to assess phosphorylated CD22, Syk, and Akt as well as the basal expression of the BCR coreceptors CD22 and CD19...
May 2016: Arthritis & Rheumatology
Nils Rother, Johan van der Vlag
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that autoimmunity in SLE depends on autoreactive T cells. In this review, we summarize the literature that addresses the roles of T cell signaling, and Th17 and regulatory T cells (Tregs) in the development of SLE. T cell receptor (TCR) signaling appears to be aberrant in T cells of patients with SLE...
2015: Frontiers in Immunology
Anil K Chauhan, Terry L Moore, Ye Bi, Chen Chen
CD4(+) T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor γ-chain FcRγ-Syk. A role for FcγRIIIa activation from immune complex (IC) ligation and sublytic terminal complement complex (C5b-9) in CD4(+) T-cell responses is not investigated. In this study, we show that the ICs present in SLE patients by ligating to FcγRIIIa on CD4(+) T-cells phosphorylate Syk and provide a co-stimulatory signal to CD4(+) T-cells in the absence of CD28 signal...
January 15, 2016: Journal of Biological Chemistry
Y Yu, C D Koehn, Y Yue, S Li, G M Thiele, M P Hearth-Holmes, T R Mikuls, J R O'Dell, L W Klassen, Z Zhang, K Su
Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0...
2015: Current Molecular Medicine
Nan-Hua Chang, Timothy T Li, Julie J Kim, Carolina Landolt-Marticorena, Paul R Fortin, Dafna D Gladman, Murray B Urowitz, Joan E Wither
Previous studies suggest that the B cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has been unclear whether this is the result of altered B cell signaling or differences in various B cell subpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of cell signaling in distinct B cell subpopulations stratified based upon developmental stage and cell surface IgM levels, which we use to show that the naïve B cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation...
April 2015: Journal of Autoimmunity
S Iwata, K Yamaoka, H Niiro, S Jabbarzadeh-Tabrizi, S-P Wang, M Kondo, M Yoshikawa, K Akashi, Y Tanaka
OBJECTIVE: Activation of B cells is a hallmark of systemic lupus erythematosus (SLE). Syk and TRAF6 are key signaling molecules in B-cell activation through BCR and CD40/TLR, respectively. Nevertheless, whether expression of Syk and TRAF6 is altered in SLE B cells remains unknown. METHODS: Phosphorylation and/or expression of Syk and TRAF6 were analyzed by flow cytometry in peripheral blood mononuclear cells isolated from SLE patients. RESULTS: Pronounced phosphorylation and expression of Syk were noted in B cells from SLE patients compared with healthy donors...
June 2015: Lupus
Ana Barrera-Vargas, Diana Gómez-Martín, Jorge Alcocer-Varela
There are different abnormalities that lead to the autoreactive phenotype in T cells from systemic lupus erythematosus (SLE) patients. Proximal signaling, involving the T-cell receptor (TCR) and its associated protein tyrosine kinases (PTKs), is significantly affected in SLE. This ultimately leads to aberrant responses, which include enhanced tyrosine phosphorylation and calcium release, as well as decreased IL-2 secretion. Lck, ZAP70 and Syk, which are PTKs with a major role in proximal signaling, all present abnormal functioning that contributes to an altered T cell response in these patients...
September 2014: Human Immunology
Sarah J Fleischer, Claudia Giesecke, Henrik E Mei, Peter E Lipsky, Capucine Daridon, Thomas Dörner
OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and autoantibody production. As spleen tyrosine kinase (Syk) is pivotal in B cell activation, these experiments aimed to examine the extent to which Syk was abnormally expressed in SLE B cells and the nature of the B cell subset that differently expressed Syk. METHODS: B cells from healthy donors and SLE patients were analyzed by flow cytometry to assess basal expression of Syk and phosphorylated Syk...
December 2014: Arthritis & Rheumatology
Alexandros P Grammatikos, Debjani Ghosh, Amy Devlin, Vasileios C Kyttaris, George C Tsokos
Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules...
2013: PloS One
Matthew C Lucas, David M Goldstein, Johannes C Hermann, Andreas Kuglstatter, Wenjian Liu, Kin Chun Luk, Fernando Padilla, Michelle Slade, Armando G Villaseñor, Jutta Wanner, Wenwei Xie, Xiaohu Zhang, Cheng Liao
A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases...
December 13, 2012: Journal of Medicinal Chemistry
Wang-Dong Xu, Yu-Jing Zhang, Wei Wang, Rui Li, Hai-Feng Pan, Dong-Qing Ye
Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Immune complex, autoantibodies and autoreactive lymphocytes are involved in manifestations of SLE. Recently, investigations have indicated that expression of the transcription factor cAMP responsive element modulator (CREM) is abnormal in T cells and might play an important role in the pathogenesis of SLE. CREM has much influence on the promoters, such as IL-2, c-fos, TCR ζ, and SYK. Moreover, activity of CREM itself has been demonstrated, particularly with an auto-regulatory feedback mechanism...
March 2012: Cellular Immunology
Shigeru Iwata, Kunihiro Yamaoka, Hiroaki Niiro, Kazuhisa Nakano, Sheau-Pey Wang, Kazuyoshi Saito, Koichi Akashi, Yoshiya Tanaka
Biological products have proven its high efficacy on autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Meanwhile, small molecular drugs have attracted attention over the years because of its availability of oral administration and cost effectiveness. Spleen tyrosine kinase (Syk) is a 72 kDa protein tyrosine kinase widely expressed on cells that are involved in the immune system and inflammation such as B cells, T cells, macrophages and synovial fibroblast. Syk is involved in intracellular signaling of the multi-chain immune receptors, including B cell receptor (BCR), ζchain of T-cell receptor (TCR), FcR and integrins, which contains the immune-receptor tyrosine-based activation motif (ITAM)...
2012: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
Debjani Ghosh, George C Tsokos, Vasileios C Kyttaris
Effector T cells and T cells from patients with systemic lupus erythematosus (SLE) express increased levels of the spleen tyrosine kinase (Syk). Syk binds to the T cell receptor (TCR)-CD3 complex and transduces the TCR-mediated signal in the cell more efficiently than the canonical CD3ζ chain. The reasons for the increased expression of Syk are unclear. In the present study, we found that Syk is regulated by the transcription factor c-Jun in cooperation with Ets2. c-Jun and Ets2 bound to the SYK promoter in close proximity and increased the promoter activity in a specific manner...
April 6, 2012: Journal of Biological Chemistry
A K Chauhan, T L Moore
In systemic lupus erythematosus (SLE), the autoantibodies that form immune complexes (ICs) trigger activation of the complement system. This results in the formation of membrane attack complex (MAC) on cell membrane and the soluble terminal complement complex (TCC). Hyperactive T cell responses are hallmark of SLE pathogenesis. How complement activation influences the T cell responses in SLE is not fully understood. We observed that aggregated human γ-globulin (AHG) bound to a subset of CD4(+) T cells in peripheral blood mononuclear cells and this population increased in the SLE patients...
February 2012: Clinical and Experimental Immunology
Debjani Ghosh, Katalin Kis-Toth, Yuang-Taung Juang, George C Tsokos
OBJECTIVE: T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (Syk), which is involved in the aberrant CD3/T cell receptor-mediated signaling process, and increased amounts of CREMα, which suppresses the production of interleukin-2. Syk expression can be suppressed by CREMα. This study was undertaken to investigate why CREMα fails to suppress Syk expression in SLE T cells. METHODS: CREMα was overexpressed in healthy T cells by transfection with CREMα expression vector, and Syk expression and phosphorylation were measured...
March 2012: Arthritis and Rheumatism
Vasileios C Kyttaris, George C Tsokos
PURPOSE OF REVIEW: Over the past year several key pathways in systemic lupus erythematosus (SLE) lymphocyte signaling have been identified. Pathways that can be exploited for therapy are discussed in this review. RECENT FINDINGS: Inhibition of SLE T cell activation by blocking spleen tyrosine kinase (Syk) and SLE T cell migration by blocking CD44 or CXCR4 lead to amelioration of lupus in lupus-prone mice. Similar results can be achieved by boosting CD8+ Treg numbers...
September 2011: Current Opinion in Rheumatology
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