Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cell activation is dependent upon calcium influx and protein kinase C activation, with subsequent lymphocyte proliferation dependent upon IL-2. Abnormalities in T cell proliferation, including abnormal calcium influx and defective protein kinase C activation, have been identified in aged mice and humans and many autoimmune diseases including diabetes, lupus and scleroderma. Since UCD line 200 chickens, which spontaneously develop a scleroderma-like disease, have both thymic defects and a diminished peripheral blood lymphocyte response to IL-2, we have further investigated T cell function in these birds. Interestingly, line 200 T cells respond poorly in vitro to a variety of diversely acting T cell mitogens including concanavalin A, phytohemagglutinin and anti-chicken CD3 monoclonal antibody. Moreover, they do not respond well even to phorbol myristate acetate in conjunction with ionomycin. Addition of exogenous IL-2-containing supernatant concurrently with mitogenic stimulation also had no significant effect. Analysis of intracellular free calcium demonstrated that the lymphocytes from diseased birds had a reduced influx of calcium (or release for intracellular stores) following stimulation. These data clearly reflect a unique defect in T cell activation associated with avian scleroderma. Analysis of chicken CD3, CD4 and CD8 expression revealed a 39% decrease in peripheral blood CD4+ cells in scleroderma birds, although this decrease was not sufficient to explain the 80-90% decrease observed in proliferation assays and calcium influx. Our data support the hypothesis that avian scleroderma is mediated via abnormal function of lymphocyte co-stimulatory molecules or intracellular calcium regulators.
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PMID:Avian scleroderma: evidence for qualitative and quantitative T cell defects. 138 34

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

Several immuno-regulatory abnormalities have been described in SLE patients. T cell dysfunction in SLE includes defective in vitro proliferative responses to several stimuli, reduced IL-2 production and a poor helper function. It has been widely proposed that this defective T cell immunoregulatory function has a key role in the hyperactivity of B cells and auto-antibody production in SLE. However, it has not been elucidated whether or not this cell dysfunction is intrinsic to lymphocytes or is due to other factors such as anti-lymphocyte auto-antibodies. In this study we have evaluated some important early cell activation events in T and non-T lymphocytes from patients with systemic lupus erythematosus (SLE). Peripheral blood lymphocytes from SLE patients and controls were isolated. The intracellular pH (pHi), cytosolic calcium (Ca2+i) and CD69 expression were determined by spectrofluorometry and flow cytometry. Modifications of these parameters in response to protein kinase C (PKC) activators, mitogenic lectins and calcium ionophores were also studied. We found a significant reduction in the increase of pHi in response to PKC activators (PMA) in SLE cells. In addition, the induction of CD69 expression by PMA was significantly lower in T cells from SLE patients. By contrast, freshly isolated non-stimulated SLE cells exhibited a significantly higher pHi, as well as an increased baseline expression of the early cell activation antigen CD69. On the other hand, the increase in Ca2+i in response to a Ca2+ ionophore (4Br-A23187) or thapsigargin in Ca(2+)-free solutions, was smaller in SLE lymphocytes. We concluded that T cells from SLE patients exhibit abnormalities in several key early cell activation events (pHi, Ca2+i and CD69 expression). These abnormalities could have an important role in the T cell dysfunction observed in SLE. The presence of T cells with a preactivated phenotype in the peripheral blood of SLE patients, could be a reflection of the ongoing autoimmune phenomena that is occurring in these patients.
Lupus 1997
PMID:Abnormalities in CD69 expression, cytosolic pH and Ca2+ during activation of lymphocytes from patients with systemic lupus erythematosus. 911 19

Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.
Lupus 1998
PMID:Defective early T and T-dependent B cell activation in systemic lupus erythematosus. 969 35

Skin is one of the main target organs in lupus erythematosus and in some circumstances, skin lesions precede systemic manifestations. Previous studies have demonstrated that Ro/SSA antigen antibody might be involved in the pathogenesis of lupus erythematosus. The present study was performed to investigate the factors regulating expression of Ro/SSA antigens on the cell surface of keratinocytes. Cultured normal human keratinocytes were treated with 50-200 mJ/cm(2) of ultraviolet B (UVB) irradiation, 10(-9) to 10(-5) mol/l of 17beta-estradiol, 5-10 microg/l of phorbol 12-myristate 13-acetate (PMA), and 42 and 45 degrees C heat shock, respectively. The Ro/SSA antigen expressions were determined by indirect immunofluorescence. The results showed that keratinocytes receiving UVB irradiation expressed Ro/SSA antigen on cell membranes in a dose-dependent fashion. 17beta-estradiol treatment also induced Ro/SSA antigen expression dose-dependently. Keratinocyte expression of Ro/SSA antigens was also induced by heat shock stimulation. The 45 degrees C heat shock showed a stronger effect than 42 degrees C heat shock. Keratinocytes incubated for 24 h after heat shock had more antigen-expressing cells than those incubated for 6 h after heat shock. PMA at 5 and 10 microg/l also strongly induced Ro/SSA antigen expression. These results suggest that Ro/SSA antigen expression can be regulated by many factors and that protein kinase C signal transduction pathway might be involved in this process.
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PMID:Induction of Ro/SSA antigen expression on keratinocyte cell membrane by heat shock and phorbol 12-myristate 13-acetate as well as estradiol and ultraviolet B. 1106 43

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-gamma, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14+ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GM-CSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.
Lupus 2002
PMID:Dysregulation of the granulocyte-macrophage colony-stimulating factor receptor is one of the causes of defective expression of CD80 antigen in systemic lupus erythematosus. 1209 May 68

T cells from patients with lupus or treated with the lupus-inducing drug hydralazine have defective ERK phosphorylation. The reason for the impaired signal transduction is unknown but important to elucidate, because decreased T cell ERK pathway signaling causes a lupus-like disease in animal models by decreasing DNA methyltransferase expression, leading to DNA hypomethylation and overexpression of methylation-sensitive genes with subsequent autoreactivity and autoimmunity. We therefore analyzed the PMA stimulated ERK pathway phosphorylation cascade in CD4(+) T cells from patients with lupus and in hydralazine-treated cells. The defect in these cells localized to protein kinase C (PKC)delta. Pharmacologic inhibition of PKCdelta or transfection with a dominant negative PKCdelta mutant caused demethylation of the TNFSF7 (CD70) promoter and CD70 overexpression similar to lupus and hydralazine-treated T cells. These results suggest that defective T cell PKCdelta activation may contribute to the development of idiopathic and hydralazine-induced lupus through effects on T cell DNA methylation.
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PMID:Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. 1791 42

Anti-ribosomal phosphoprotein autoantibodies have been shown to be significantly associated with multiple manifestations of systemic lupus erythematosus (SLE). High levels of interleukin-10 (IL-10) have been demonstrated to contribute to lupus susceptibility and severity. In this study, we investigated the molecular mechanisms of anti-ribosomal phosphoprotein monoclonal antibody (anti-P mAb)-induced autoimmune responses. Anti-P mAb promoted IL-10 overproduction in a dose- and time-dependent manner in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and primary human macrophages. Anti-P mAb enhanced phosphorylation of Akt (PKB; protein kinase B), extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 1/2 (JNK1/2), while phosphorylation of p38 remained unaltered. Furthermore, anti-P mAb decreased glycogen synthase kinase 3 (GSK3) activity and reduced the phosphorylation of I kappaB alpha in LPS-activated macrophages. The Syk, phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), JNK and ERK signalling pathways involved in anti-P mAb-triggered IL-10 secretion were also confirmed using various pharmacological inhibitors. In addition, nuclear factor (NF)-kappaB had negative regulatory effects on anti-P mAb-triggered IL-10 secretion. Using reporter plasmids containing the nuclear factor binding sites of NF-kappaB, cAMP-enhanced activation protein 1 (AP-1), serum response element (SRE) or cyclic AMP response element (CRE), treatment of anti-P mAb led to activation of the corresponding factors that bind to the AP-1 site, SRE and CRE in the LPS-activated macrophages. Furthermore, by transfection with reporter plasmids bearing various lengths of the IL-10 promoter, the AP-1 binding site, SRE and CRE were shown to be required for anti-P mAb-induced effects. Collectively, our results provide a molecular model for anti-P mAb-induced IL-10 overproduction in LPS-activated macrophages, which may play a role in the pathogenesis of SLE.
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PMID:Anti-ribosomal phosphoprotein autoantibody triggers interleukin-10 overproduction via phosphatidylinositol 3-kinase-dependent signalling pathways in lipopolysaccharide-activated macrophages. 1877 81

The pathogenesis of systemic lupus erythematosus (SLE) is incompletely understood. Studies in both lupus animal models and human disease indicate a clear role for epigenetic defects, particularly DNA methylation, in the pathogenesis of lupus. T-cell DNA from active lupus patients is hypomethylated, which results in overexpression of methylation-regulated genes, T-cell autoreactivity, and autoimmunity in vivo. Inducing an extracellular signal-regulated kinase (ERK) signaling defect in T cells using a transgenic mouse model resulted in reduced DNA methyltransferase 1 (DNMT1) expression, overexpression of methylation-sensitive genes, and anti-double-stranded DNA (anti-dsDNA) antibody production. ERK signaling is known to be defective in lupus T cells, and this defect is now explained by impaired T-cell protein kinase C (PKC) delta activation. Herein, we discuss how defective epigenetic regulation is involved in the pathogenesis of lupus, which includes both DNA methylation and histone modification changes.
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PMID:Epigenetic regulation and the pathogenesis of systemic lupus erythematosus. 1913 48

The cDNA and the genomic sequence of ribosomal protein S13 (RPS13) of the giant panda (Ailuropoda melanoleuca) was cloned using reverse transcription-polymerase chain reaction (RT-PCR) and touchdown-PCR, respectively. These two sequences were sequenced and analyzed, and the cDNA of the RPS13 gene was overexpressed in Escherichia coli BL21. We compared the nucleotide sequences of the coding region and the amino acid sequences with those of seven other mammalian species retrieved from GenBank. The cDNA fragment of the RPS13 cloned from the giant panda is 496 bp in size, containing an open-reading frame of 456 bp, encoding 151 amino acids. The length of the genomic sequence is 2277 bp, with five exons and four introns. The coding sequence shows a high degree of homology to those of Homo sapiens, Bos taurus, Canis lupus familiaris, Macaca mulatta, Mus musculus, Rattus norvegicus, and Pan troglodytes; the degree of homology was 91.23, 94.30, 94.74, 92.11, 87.94, 87.72, and 91.45%, respectively. The homologies for the deduced amino acid sequences reached as high as 99%. Primary structure analysis revealed that the molecular weight of the putative RPS13 protein is 17.22325 kDa, with a theoretical pI of 10.42. Based on topology prediction, there is one protein kinase C phosphorylation site, one casein kinase II phosphorylation site, two N-myristoylation sites, and one ribosomal protein S15 signature in the RPS13 protein of the giant panda. The RPS13 gene can be expressed in E. coli and the RPS13 protein fused with the N-terminally GST-tagged form, which gave rise to the addition of an expected 43-kDa polypeptide.
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PMID:cDNA, genomic sequence cloning and overexpression of the ribosomal protein S13 gene in the giant panda (Ailuropoda melanoleuca). 2126 84


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