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

We previously reported that difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, exerted significant beneficial effects on the lifespan and disease expression of MRL-lpr/lpr mice, which spontaneously develop a lupus-like syndrome. Polyamine levels in splenic T-cells of MRL-lpr/lpr mice were significantly higher than those of Balb/c mice. In the present investigation, we examined the role of endogenous polyamines in transmembrane Ca2+ influx, generation of InsP3 and tyrosine phosphorylation of the p56lck protein in concanavalin A-stimulated splenic T-cells. Cytosolic free calcium concentrations ([Ca2+]i) in concanavalin A-stimulated T-cells of MRL-lpr/lpr and Balb/c mice were 250 +/- 25 and 450 +/- 42 nM respectively. Treatment of MRL-lpr/lpr mice with DFMO increased [Ca2+]i to 360 +/- 30 nM (P < 0.05). InsP3 levels of concanavalin A-stimulated MRL-lpr/lpr splenic T-cells were only 20% higher than those of unstimulated controls, whereas those of Balb/c T-cells were 90% higher. DFMO treatment increased InsP3 levels in concanavalin A-treated MRL-lpr/lpr T-cells to 67%. Western-blot analysis showed a 7-fold higher level of p56lck phosphorylation of MRL-lpr/lpr splenic T-cells than that of Balb/c mice. DFMO treatment reduced tyrosine phosphorylation of p56lck of MRL-lpr/lpr mice significantly (P < 0.001). Two-colour flow-cytometric analysis revealed no significant difference in the CD4+/CD8+ ratio in splenic T-cells of MRL-lpr/lpr mice after DFMO treatment. Polyamine levels in splenocytes were significantly reduced by DFMO treatment. These data show that DFMO treatment could alter signal-transduction pathways of splenic T-cells of MRL-lpr/lpr mice. Increased levels of polyamines in T-cells of untreated lpr mice contribute to defective signal-transduction pathways and the pathogenesis of lupus-like symptoms.
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PMID:Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations. 757 51

The CD4 molecule represents a major functional T-cell surface molecule, defining an important T-cell subset, which also is expressed on monocyte, dendritic, and Langerhans cells. Various in vivo studies have demonstrated its implication in various steps of physiological T-cell activation: 1. CD4 interacts with its physiological ligand, the class II molecules, thus increasing the affinity of the conjugation between CD4+CD(3+)-TCR+ and class II+ antigen-presenting cells. 2. Through CD4, the signal transduction machinery is stimulated via its association with p56lck. In addition, CD4 has proved to be the receptor for gp120, the surface glycoprotein of HIV, that allows the virus to penetrate the CD4+ T cells and monocytes. Based on in vitro studies in various animal models, CD4 mAbs have proved to be efficient in the prevention and/or therapy of a variety of immunologically based diseases: 1. When injected early in the prodromic phase of autoimmune diseases (AID) such as diabetes, either delay or prevention is achieved with or without maintenance after therapy. 2. These mAbs have proved to be self-tolerogenic, thus allowing prolonged in vivo therapy and suppression of immunogenicity of mAb of a distinct specificity. In humans, CD4 mAbs are, or could be, used and evaluated in AID (lupus, diabetes, rheumatoid arthritis, etc.), transplantation, leukemias and lymphomas expressing CD4, and, finally, in AIDS patients, in whom CD4 mAbs can block HIV-CD4 binding and deliver a negative signal to T cell, thus blocking T-cell activation and HIV transcription. CD4 mAbs at least provide evidence that the CD4 molecules are suitable for immunomodulation and could be the target for a new pharmacological antagonist.
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PMID:Therapeutic applications of anti-CD4 antibodies. 847 11

We have recently identified in SLE sera naturally occurring anti-idiotypic antibodies against anti-phosphotyrosine antibodies. Analysis of immunochemical properties of these anti-idiotypic antibodies suggest that they are of beta/gamma type mimicking the antigen. The interaction between these anti-idiotypes and SH2 domains of various fusion proteins was analysed by immunoprecipitation and immunoblotting. Our data demonstrate that these anti-idiotypic antibodies specifically bind SH2 domains, with the highest affinity for SH2 domain of lck protein tyrosine kinase. The significance of this interaction is discussed.
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PMID:Naturally occurring anti-idiotypic antibodies to anti-phosphotyrosine in systemic lupus erythematosus interact with SRC-homology 2 domains. 872 77

Preliminary evidence suggests there is a toxin in the sera of systemic lupus erythematosus patients which reacts with a commercial enzyme-linked immunosorbent assay kit for the detection of the marine toxin, okadaic acid. Data is presented which supports the hypothesis that an okadaic acid-like toxin may be the principle agent of lymphocyte dysregulation in systemic lupus erythematosus and other immune-dysregulated states. The okadaic acid-like toxin can produce the specific abnormalities in T-lymphocyte phenotype and function typical of systemic lupus erythematosus, principally through its ability to inhibit serine/threonine phosphatases necessary for secondary signalling processes and through its ability to inhibit calcium which is crucial to protein kinase C-mediated signalling of T-lymphocytes. The disruption probably occurs through the protein tyrosine kinase p56lck pathway crucial for IL-2. Additionally, the toxin's ability to disrupt voltage-sensitive ion channels in cell membranes may be responsible for the multi-organ pathology observed in systemic lupus erythematosus patients, particularly neurological, cardiac and nephritic. Data from a different study conducted by the author suggests that latent and persistent viruses are reactivated in active lupus. This activation could be the result of the toxin's ability to act as an immune modulator, or its ability to act as a transactivating factor.
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PMID:Okadaic acid-like toxin in systemic lupus erythematosus patients: hypothesis for toxin-induced pathology, immune dysregulation, and transactivation of herpesviruses. 889 23

CD4+ T cells play a crucial role in the development of lupus in MRL-lpr/lpr mice: incomplete deletion/silencing of self-reactive CD4+ T cells leads to T cell activation, which causes both polyclonal B cell activation and T cell infiltration of multiple organs. Furthermore, anti-CD4 antibody therapy ameliorates disease and prolongs survival. Because CD4 is normally involved in both tolerance induction and T cell activation, we questioned whether signaling through CD4 was normal among T cells in this strain. For this purpose, signal transduction in CD4+ T cells derived from MRL-lpr/lpr and normal mice were compared, using an autoreactive CD4+ T cell clone and freshly isolated CD4+ T cells derived from mice of varying ages. Tyrosine phosphorylation was similar among MRL and normal CD4+ T cells after cross-linking with either anti-TCR antibody or anti-CD3 antibody, and following co-culture with Con A. In constrast, cross-linking of surface CD4 resulted in deficient tyrosine phosphorylation of cellular proteins in MRL T cells. By comparison, lck protein expression in MRL CD4+ T cells was found to be lower than normal. However, following stimulation with Con A, lck enzyme activity, as detected by autophosphorylation of lck, was comparable in MRL and normal T cells. The observed differences were present in the autoreactive T cell clone as well as in T cells isolated from both pre-diseased and diseased mice, and they could not be explained by variation in surface density of CD4. These results raise the possibility that abnormal signaling through CD4 may contribute to impaired tolerance and expansion of autoreactive T cells exhibited in MRL-lpr/lpr mice.
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PMID:Abnormal signal transduction through CD4 leads to altered tyrosine phosphorylation in T cells derived from MRL-lpr/lpr mice. 891 30

We have recently observed an abnormal pattern of protein tyrosine phosphoryl-ation in resting T lymphocytes obtained from peripheral blood of patients with systemic lupus erythematosus (SLE). To examine whether these findings may be related to dysregulated protein tyrosine kinase (PTK) function, we tested the relative amount and enzyme activity of the main PTKs involved in the earliest signalling steps triggered via the CD3 pathway. Cell lysates from peripheral blood T cells in SLE patients showed lower amounts of p59(fyn) and p56(lck) as shown by immunoblot. In contrast, the amount of ZAP-70, a PTK of the syk family, was comparable in both groups. However, p59(fyn) immuno-precipitates obtained from unstimulated peripheral blood SLE T cells showed enhanced PTK activity as compared to controls, whereas the PTK activity of p56(lck) and ZAP-70 molecules was comparable in both groups. The unchecked activity of the TCR/CD3-associated src kinase p59(fyn) may alter the balance needed for regulated T cell responses in SLE patients.
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PMID:Protein tyrosine kinase activity in T lymphocytes from patients with systemic lupus erythematosus. 980 21

In this study we analyzed the activity and the expression of p56lck protein tyrosine kinase in peripheral blood lymphocytes (PBLs) from systemic lupus erythematosus (SLE) patients and from healthy donors. The p56lck activity, determined by a non-radioactive Tyrosine Kinase Assay Kit, was significantly higher in active SLE PBLs and discriminated this group of patients from inactive SLE patients (p = 0.002) and healthy donors (p = 0.009). p56lck level decreased in SLE lymphocytes (especially for inactive SLE lymphocytes, p = 0.005) when compared to healthy donors. These differences were also reflected by the specific activity of p56lck that was clearly elevated in active SLE lymphocytes when compared to inactive SLE (p = 0.022) or healthy donors lymphocytes (p = 0.006). A positive correlation between the activity of p56lck and the tyrosine phosphorylation level in active SLE lymphocytes was found.
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PMID:p56lck activity and expression in peripheral blood lymphocytes from patients with systemic lupus erythematosus. 1043 72

In this study we investigated one of the possible mechanisms of p56lck down-regulation in peripheral blood lymphocytes (PBLs) from Systemic Lupus Erythematosus (SLE) patients and we correlated p56lck dysregulation with accelerated apoptosis in SLE PBLs. PBLs from SLE patients and healthy donors were isolated. p56lck protein expression and lck mRNA level were estimated by immunoblotting and RT-PCR, respectively. FACS analysis was used to evaluate the apoptosis and p56lck levels in apoptotic and non-apoptotic PBLs. A non-radioactive Tyrosine Kinase Assay Kit was used to measure p56lck activity. Our results demonstrated that PBLs from SLE patients displayed lower levels of lck mRNA and p56lck protein as compared to healthy donors. The apoptosis of fresh or cultured PBLs was enhanced in SLE patients, especially in anti-DNA negative group. The expression of p56lck was inverse correlated with apoptosis of fresh and cultured SLE PBLs, especially in anti-DNA negative patients. Double staining FACS analysis showed that p56lck expression was lower in apoptotic than in non-apoptotic PBLs. p56lck specific activity was directly correlated to apoptosis in SLE PBLs. While the low expression of p56lck may be the result of lower degree of synthesis, the increased specific activity could directly correlated to the extent of apoptosis in SLE PBLs. Based on our observations, we assume that the p56lck dysregulation could play a role in SLE pathogenesis.
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PMID:Dysregulation of p56lck kinase in patients with systemic lupus erythematosus. 1168 90

A pilot study was performed to evaluate the efficacy of Pycnogenol treatment in systemic lupus erythematosus (SLE) patients. Eleven SLE patients were treated with first line medication according to disease activity and in addition, six of them received Pycnogenol and five a placebo. The SLE disease activity index (SLEDAI), serum anti-dsDNA antibodies, fibrinogen, C-reactive protein levels, erythrocyte sedimentation rate, production of reactive oxygen species (ROS) by neutrophils, spontaneous apoptosis and p56(lck) specific activity in peripheral blood lymphocytes were evaluated. Pycnogenol treatment determined a significant reduction of ROS production, apoptosis, p56(lck) specific activity and erythrocyte sedimentation rate. In addition, the decrease of SLEDAI was significant in the Pycnogenol treated group compared with the placebo group (p = 0.018). The results obtained suggest that Pycnogenol could be useful for second line therapy to reduce the inflammatory feature of SLE.
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PMID:Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients. 1174 63

Systemic lupus erythematosus (SLE) is characterized by abnormalities in T lymphocyte receptor-mediated signal transduction pathways. Our previous studies have established that lymphocyte-specific protein tyrosine kinase (LCK) is reduced in T lymphocytes from patients with SLE and that this reduction is associated with disease activity and parallels an increase in LCK ubiquitination independent of T cell activation. This study investigated the expression of molecules that regulate LCK homeostasis, such as CD45, C-terminal Src kinase (CSK), and c-Cbl, in lipid raft domains from SLE T cells and investigated the localization of these proteins during T cell receptor (TCR) triggering. Our results indicate that the expression of raft-associated ganglioside, GM1, is increased in T cells from SLE patients and LCK may be differentially regulated due to an alteration in the association of CD45 with lipid raft domains. CD45 tyrosine phosphatase, which regulates LCK activity, was differentially expressed and its localization into lipid rafts was increased in T cells from patients with SLE. Furthermore, T cells allowed to "rest" in vitro showed a reversal of the changes in LCK, CD45, and GM1 expression. The results also revealed that alterations in the level of GM1 expression and lipid raft occupancy cannot be induced by serum factors from patients with SLE but indicated that cell-cell contact, activating aberrant proximal signaling pathways, may be important in influencing abnormalities in T cell signaling and, therefore, function in patients with SLE.
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PMID:Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. 1508 97


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