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Alexander Puck, Stefan Hopf, Madhura Modak, Otto Majdic, Petra Cejka, Stephan Blüml, Klaus Schmetterer, Catharina Arnold-Schrauf, Jens G Gerwien, Klaus S Frederiksen, Elisabeth Thell, Judith Leitner, Peter Steinberger, Regina Aigner, Maria Seyerl-Jiresch, Gerhard J Zlabinger, Johannes Stöckl
The cytoplasmic tail of CD45 (ct-CD45) is proteolytically cleaved and released upon activation of human phagocytes. It acts on T cells as an inhibitory, cytokine-like factor in vitro. Here we show, that ct-CD45 is abundant in human peripheral blood plasma from healthy adults compared with plasma derived from umbilical cord blood and plasma from patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Plasma depleted of ct-CD45 enhanced T-cell proliferation, while addition of exogenous ct-CD45 protein inhibited proliferation and reduced cytokine production of human T lymphocytes in response to TCR signaling...
October 8, 2016: European Journal of Immunology
Hui Chen, Hongqin You, Lifang Wang, Xuan Zhang, Jianmin Zhang, Wei He
Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors...
September 16, 2016: Journal of Biological Chemistry
Maria P Karampetsou, Denis Comte, Katalin Kis-Toth, Cox Terhorst, Vasileios C Kyttaris, George C Tsokos
T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Huai-Chia Chuang, Xiaohong Wang, Tse-Hua Tan
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been reported to induce JNK activation through activating the MAP3K-MAP2K cascade. The physiological roles of MAP4Ks in immunity and inflammation are largely unknown until recent studies using biochemical approaches and knockout mice. Surprisingly, JNK is not the major target of MAP4Ks in immune cells; MAP4Ks regulate immune responses through novel targets...
2016: Advances in Immunology
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
Kirsty E Waddington, Elizabeth C Jury
Plasma membrane lipid rafts are heterogeneous cholesterol and glycosphingolipid (GSL)-enriched microdomains, within which the tight packing of cholesterol with the saturated-acyl chains of GSLs creates a region of liquid-order relative to the surrounding disordered membrane. Thus lipid rafts govern the lateral mobility and interaction of membrane proteins and regulate a plethora of signal transduction events, including T-cell antigen receptor (TCR) signalling. The pathways regulating homoeostasis of membrane cholesterol and GSLs are tightly controlled and alteration of these metabolic processes coincides with immune cell dysfunction as is evident in atherosclerosis, cancer and autoimmunity...
August 2015: Biochemical Society Transactions
Shanshan Yin, Yujia Mao, Xuemei Li, Cai Yue, Chen Zhou, Linfang Huang, Wenxiu Mo, Di Liang, Jianmin Zhang, Wei He, Xuan Zhang
In this study, we measured the proportion of peripheral Vδ2 T cells as well as the status and chemokine receptor expression profiles in SLE patients and healthy control (HC). In addition, Vδ2 T cell infiltration in the kidneys of patients with lupus nephritis was examined. The results showed that the percentage of peripheral Vδ2 T cells in new-onset SLE was decreased, and negatively correlated with the SLE Disease Activity Index score and the severity of proteinuria. These cells had a decreased apoptosis but an increased proliferation, and they showed increased accumulation in SLE kidneys...
2015: Scientific Reports
Weiguo Sui, Xianliang Hou, Guimian Zou, Wenti Che, Ming Yang, Can Zheng, Fuhua Liu, Peng Chen, Xiaolian Wei, Liusheng Lai, Yong Dai
The ability of T lymphocytes to mount an immune response against a diverse array of pathogens is primarily conveyed by the amino acid (aa) sequence of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (TCR). In this study, we used a combination of multiplex-PCR, Illumina sequencing and IMGT/HighV-QUEST for a standardized analysis of the characteristics and polymorphisms of the T-cell receptor BV complementarity-determining region 3 (TCR BV CDR3) gene in peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy donors (NC)...
October 2015: Molecular Immunology
Zhentao Guo, Yingge Wang, Rongqian Li, Haifeng Huang, Rong Wang
OBJECTIVE: To clarify the role of T cells in kidney pathology of three widely used murine lupus models. MATERIAL AND METHODS: Cells infiltrating the glomeruli and perivascular areas in MRL/lpr (n = 10 female), NZB× NZW F1 (B/W F1) (n = 9 female), and BXSB (n = 10 male) mice were captured by laser microdissection (LMD). Samples were subjected to nested reverse transcription polymerase chain reaction (RT-PCR) with primers specific to β-actin, T-cell receptor β chain (TCR-Cβ), interleukin (IL)-10, IL-13, IL-17, and interferon-g (IFN-γ)...
2014: Central-European Journal of Immunology
Vaishali R Moulton, Andrew R Gillooly, Marcel A Perl, Anastasia Markopoulou, George C Tsokos
T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3' untranslated region (UTR) of CD3ζ mRNA...
2015: PloS One
Dharma R Thapa, Raffi Tonikian, Chao Sun, Mei Liu, Andrea Dearth, Michelle Petri, Francois Pepin, Ryan O Emerson, Ann Ranger
INTRODUCTION: T cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity...
2015: Arthritis Research & Therapy
Christian J Maine, Kristi Marquardt, John C Scatizzi, K Michael Pollard, Dwight H Kono, Linda A Sherman
A single nucleotide polymorphism in PTPN22 is linked to increased disease susceptibility in a range of autoimmune diseases including systemic lupus erythematosus (SLE). PTPN22 encodes the Lyp phosphatase that dampens TCR signaling and is necessary for signaling downstream of toll-like receptors in myeloid cells. To understand these dual functions in disease, we examined the impact of deficiency in PTPN22 on a spontaneous murine model of SLE. Male PTPN22 KO mice carrying BXSB chromosome 1 and the Yaa disease accelerating factor developed disease at a similar rate and severity as PTPN22 WT...
January 2015: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Maria Carmen Cenit, Mario Martínez-Florensa, Marta Consuegra, Lizette Bonet, Elena Carnero-Montoro, Noelia Armiger, Miguel Caballero-Baños, Maria Teresa Arias, Daniel Benitez, Norberto Ortego-Centeno, Enrique de Ramón, José Mario Sabio, Francisco J García-Hernández, Carles Tolosa, Ana Suárez, Miguel A González-Gay, Elena Bosch, Javier Martín, Francisco Lozano
OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis...
2014: PloS One
Lei Shen, Hong Zhang, Maria Caimol, Claudia J Benike, Eliza F Chakravarty, Samuel Strober, Edgar G Engleman
IgG autoantibodies, including antibodies to double-stranded DNA (dsDNA), are pathogenic in systemic lupus erythematosus (SLE), but the mechanisms controlling their production are not understood. To assess the role of invariant natural killer T (iNKT) cells in this process, we studied 44 lupus patients. We took advantage of the propensity of PBMCs from patients with active disease to spontaneously secrete IgG in vitro. Despite the rarity of iNKT cells in lupus blood (0.002-0.05% of CD3-positive T cells), antibody blockade of the conserved iNKT TCR or its ligand, CD1d, or selective depletion of iNKT cells, inhibited spontaneous secretion of total IgG and anti-dsDNA IgG by lupus PBMCs...
February 2015: European Journal of Immunology
Zhou Li, Ma Long, Liu ChunMei, Shi Bin, Yu Jiang, Ma Rui, Ma Qingqing, Yao XinSheng
T cells play an important role in the onset and progression of systemic lupus erythematosus (SLE), and the biases in T cell receptor beta variable (TRBV) region families and complementarity determining region three (CDR3) composition in SLE patients and mouse models have been widely reported. However, the relationship between the composition and variation in the TCR β-chain CDR3 repertoire and SLE has not been established. Here, we compared and analyzed the thymic and splenic TCR β-chain CDR3 mRNA sequences by Roche 454 high-throughput sequencing from MRL/lpr mice at different ages...
January 2015: Immunogenetics
Parisa Sinai, Igor M Dozmorov, Ran Song, Pamela L Schwartzberg, Edward K Wakeland, Christoph Wülfing
Changes in immune function during the course of systemic lupus erythematosus (SLE) are well characterized. Class-switched antinuclear antibodies are the hallmark of SLE, and T/B-cell interactions are thus critical. However, changes in immune function contributing to disease susceptibility are unknown. Here, we have analyzed primary T and B cells from a mouse model of SLE prior to the onset of disease. To allow cognate T-cell activation with low affinity, we have developed a lower potency peptide ligand for the OTII TCR...
December 2014: European Journal of Immunology
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
James A Tarbox, Molly P Keppel, Nermina Topcagic, Charles Mackin, Miriam Ben Abdallah, Kevin W Baszis, Andrew J White, Anthony R French, Megan A Cooper
PURPOSE: Autoimmune diseases are thought to be caused by a loss of self-tolerance of the immune system. One candidate marker of immune dysregulation in autoimmune disease is the presence of increased double negative T cells (DNTs) in the periphery. DNTs are characteristically elevated in autoimmune lymphoproliferative syndrome, a systemic autoimmune disease caused by defective lymphocyte apoptosis due to Fas pathway defects. DNTs have also been found in the peripheral blood of adult patients with systemic lupus erythematosus (SLE), where they may be pathogenic...
July 2014: Journal of Clinical Immunology
H-X Wang, S Chu, J Li, W-N Lai, H-X Wang, X-J Wu, X Kang, Y-R Qiu
BACKGROUND: Increased numbers of TCRαβ(+)CD4(-)CD8(-) T cells in the peripheral blood of systemic lupus erythematosus (SLE) patients in the United States and United Kingdom have been reported. However, the proportions of TCRαβ(+)CD4(-)CD8(-) T cells and their involvement in the pathogenesis of SLE in Chinese populations are yet to be determined. METHODS: A total of 120 SLE patients, 38 rheumatoid arthritis (RA) patients and 43 normal control subjects were examined...
June 2014: Lupus
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