Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic lupus erythematosus (SLE) is an autoimmune disease, which predominantly affects females, and causes multiple organ dysfunctions. Recent studies have revealed the underlying immunological abnormalities, especially in lymphocytes from SLE patients. T lymphocytes from SLE patients present abnormalities in T cell receptor (TCR) signaling, for example, decreased expression of TCR zeta chain, PKC theta, and NF-kB p65, decreased PKC dependent protein phosphorylation, impaired translocation of NF-kB p65, decreased production of IL-2 etc. Recently, it is known that reconstitution of deficient TCR zeta chain in T lymphocytes from SLE patients leads to restoration of impaired IL-2 production upon CD3/CD28 stimulation. This time, analysis of abnormal TCR signaling in SLE patients and attempt to correct the impaired IL-2 production by replenishing missing signaling molecules are to be discussed.
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PMID:Attempt to correct abnormal signal transduction in T lymphocytes from systemic lupus erythematosus patients. 1643 47

Systemic lupus erythematosus (SLE) presents various clinical features; however, underlying mechanisms remain unclear. In the immunity of SLE, impaired T cell receptor (TCR) signaling and altered cytokine production are in the center of pathogenesis, although, little is known about NFAT (nuclear factor of activated T cells) in lupus T lymphocytes. TCR stimulation activates NFAT1 through Ca2+/calcineurin (Cn) pathway, facilitating nuclear translocation of NFAT1 from cytosol. Therefore, we investigated relationship of disease activity/features and intracellular NFAT1 localization in T lymphocytes from active lupus patients by fractionation. Results showed no significant relationship between disease activity and NFAT1 distribution. However, interestingly, we observed skewed NFAT1 distribution in pellet in patients with active lupus nephritis or pleuritis. In vitro cyclosporin A treatment suggested autonomously activated Ca2+/Cn pathway in lupus T lymphocytes. Considering these results, NFAT1 might be presenting the clinical heterogeneity in SLE.
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PMID:Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features. 1650 1

E2F transcription factors are important regulators of proliferation, differentiation and apoptosis. We have previously shown that E2F2-/- mice develop late-onset autoimmune features, similar to systemic lupus erythematosus. E2F2-deficient T lymphocytes exhibit enhanced T cell receptor (TCR)-stimulated proliferation, which is presumably responsible for causing autoimmunity in E2F2-deficient mice. The comparison of E2F2-/- and wild-type T lymphocyte expression profiles by 2-DE followed by MS identification has revealed a set of deregulated proteins involved in TCR-mediated signaling, cell survival and stress responses. The deregulation of these proteins may account for the hyperproliferative phenotype that characterizes E2F2-/- T cells. Our work shows that proteomic analysis of gene-knockout strains can be a useful methodology to study the functional role of specific genes.
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PMID:Differential proteome profiles in E2F2-deficient T lymphocytes. 1654 83

T cells undergo full and productive activation when they traffic to lymph nodes where they encounter dendritic cells displaying foreign antigen in the context of MHC molecules on their surface. Recognition of these antigen-MHC complexes by the T cell's receptor for antigen, or T cell receptor, provides the first of two obligate signals needed to drive cell proliferation. The second antigen-independent signal is provided by the costimulatory receptor, CD28, as it engages its ligand on the antigen-presenting cells. Failure of the T cell to receive this second signal after antigen recognition leaves the T cell in a state of anergy. Understanding the role of T cell costimulatory receptors in T cell activation has led to the development of novel approaches for regulating immune responses in subjects with cancer or autoimmune disease by experimentally triggering or blocking costimulatory receptor signaling. In this review, we will discuss, first, several costimulatory pathways known to participate or regulate the progression of autoimmune disease, and, second, how manipulation of T cell costimulation and/or costimulation blockade has been used to treat systemic lupus erythematosus.
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PMID:Costimulatory molecules as immunotherapeutic targets in systemic lupus erythematosus. 1695 32

To understand the characteristics of T cell receptors recognizing antiphospholipid syndrome associated antigen, the characteristics of T cells were analyzed using T cell receptor beta variable region (TCRbetaV) gene spectrotyping in a case of antiphospholipid syndrome (APS). The results indicated that in the case of APS there were 2 dominant T cell clones. The TCRbetaVs sequences of the 2 T cell clones showed the TCRbetaVs belonged to 8 and 23 gene families respectively. The peptides of third complementarity-determining regions (CDR3) in the TCRbetaVs were CASSLLVAGGPRAYNEQFFGPG and CASSLAGFGQPQHFGDG. Comparing the motifs in CDR3 with another autoimmune disease, the motif YNEQFFGPG in TCRbetaV8 and motif QHFGDG in TCRbetaV23 were identical with that of idiopathic thrombocytopenic purpura and systemic lupus erythematosus reported before. In conclusion, some T cell clones proliferating in these autoimmune diseases may recognize the same antigens.
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PMID:[Characteristics of T cell receptors recognizing antiphospholipid syndrome associated antigens]. 1720 84

T cells from patients with systemic lupus erythematosus display numerous signalling abnormalities. The T cell receptor complex is rewired with the common FcRgamma chain replacing the CD3 zeta chain while the T cell surface membrane lipid rafts are aggregated. These two aberrations result in enhanced early signalling events and altered downstream signalling events. These are in turn responsible for an altered expression of cytokines such as interleukin-6 (IL-6), IL-10, IL-2, IFNy and CD40 ligand. While some of these abnormalities explain the enhanced ability of T cells to help B cells to produce autoantibodies, decreased IL-2 production results in enhanced susceptibility to infections, reduced activation-induced cell death and prolonged survival of autoreactive T cells, which promote help to autoreactive B cells.
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PMID:Altered signal transduction in SLE T cells. 1758 62

The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupled signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased CD3zeta and ZAP-70 expression correlating with functional anergy, with increased CD3zeta/ ZAP-70 expression and phosphorylation connoting acquisition of effector capacity. By contrast, the FcRgamma signaling subunit known to be expressed in human effector cells and in T cells from the autoimmune disease SLE is up-regulated upon activation, yet does not correlate with functional capacity in effector cells, and does not alter signaling or function in primary FcRgamma transfectants. Our results have implications for targeting signaling molecules in immunotherapy and evaluating the functional consequence of signaling alterations associated with autoimmunity and chronic diseases.
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PMID:Proximal signaling control of human effector CD4 T cell function. 1769 70

Systemic lupus erythematosus (SLE) patients have a decreased number of peripheral blood T cells containing signal-joint T cell receptor excision circles (Sj TRECs), which are considered an indicator of thymic output. The objective of this study was to investigate the mechanism of the decrease in such T cells. Peripheral blood T cells from SLE patients were classified into CD4+ and CD8+ cells. Sj TREC levels were measured by real-time PCR. Telomerase activity was determined by the telomeric repeat amplification protocol assay. The numbers of Sj TREC containing CD4+ and CD8+ cells were lower in the peripheral blood of SLE patients than in the controls. A correlation was found between the numbers of Sj TREC-positive CD4+ and CD8+ cells. The level of TRECs is influenced by an increase in cell division. To examine this increase, telomerase activity as an indicator of cell division was measured simultaneously; however, there was no correlation between the Sj TREC level and telomerase activity. These results suggest that decreased thymic output occurs in SLE patients.
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PMID:Decreased numbers of signal-joint T cell receptor excision circle-containing CD4+ and CD8+ cells in systemic lupus erythematosus patients. 1769 62

Lipid rafts is a blanket term used to describe distinct areas in the plasma membrane rich in certain lipids and proteins and which are thought to perform diverse functions. A large number of studies report on lipid rafts having a key role in receptor signalling and activation of lymphocytes. In T cells, lipid raft involvement was demonstrated in the early steps during T cell receptor (TCR) stimulation. Interestingly, recent evidence has shown that signalling in these domains differs in T cells isolated from patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we discuss these findings and explore the potential of lipid rafts as targets for the development of a new class of agents to downmodulate immune responses and for the treatment of autoimmune diseases.
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PMID:Lipid rafts in T cell signalling and disease. 1789 Jan 13

The current quality of autoimmune disease treatments is not satisfactory in regard to efficacy and safety. Antigen-specific immunotherapy is a future therapy that could achieve maximal efficacy with minimal adverse effects. T cells are essential components in antigen-specific immunity. However, we do not have a sufficient strategy for manipulating antigen-specific T cells. We propose that T cell receptor (TCR) gene transfer is a hopeful approach for antigen-specific immunotherapy. We confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis (CIA), arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. Arthritis-related TCR and TNFRIg transduced cells or TCR and Foxp3 transduced cells suppressed arthritis progression and bone destruction. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy.
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PMID:T cell receptor gene therapy for autoimmune diseases. 1791 37


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