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)

Upregulation of integrin adhesive receptors has been implicated in various pathological conditions. We examined expression and function of integrin adhesive receptors on peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), particularly those with the complication of vasculitis, and found that VLA-4 and LFA-1 expression was increased in SLE patients with vasculitis, while LFA-1 but not VLA-4 expression was increased in those without vasculitis. These results suggested a role of VLA-4 in the pathogenesis of vasculitis in SLE. Functional studies further demonstrated that adhesion to cytokine-activated human umbilical cord vein endothelial cells and to the CS-1 alternatively spliced domain of fibronectin was significantly increased in SLE patients with vasculitis. Analysis of the functional epitopes on the alpha 4 chain demonstrated that antigen densities of all the functional epitopes were increased in those with vasculitis, indicating that the increased expression of VLA-4 resulted from the increased number of VLA-4 molecules, and was not secondary to an increase in one particular functional epitope. Immunoprecipitation studies further support these results. Interestingly, high molecular weight bands associated with VLA-4 were observed in about half of the SLE patients with vasculitis. These results introduce a possibility that upregulation of integrin adhesive receptors has a potential role in the pathogenesis of vasculitis in SLE.
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PMID:Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis. 825 55

The soluble IL-6 receptor (sIL-6R) occurring in various body fluids of healthy persons and patients with various diseases is an agonist since its complex with IL-6 binds to gp130 making IL-6 receptor negative cells responsive for IL-6. The generation as well as the functional role of soluble IL-6 receptor is poorly understood. We measured the sIL-6R levels by ELISA sandwich technology in sera and in supernatants of lymphocyte cultures without and after incubations with dexamethasone. Our results indicate, that the sIL-6R levels in sera of patients with inactive systemic lupus erythematosus (SLE) and active rheumatoid arthritis (RA) were higher than those of the control group, active SLE and inactive RA. In vitro dexamethasone treatment stimulated generation of sIL-6R in both healthy persons and in active SLE, however it strongly suppressed sIL-6R in both RA groups. At mRNA level, we found that in SLE both the mRNA coding the cell-bound and an alternatively spliced variant corresponding to soluble IL-6R transcript increases, however the strong decrease of sIL6R protein in RA was not found at mRNA level.
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PMID:Soluble interleukin-6 receptor in plasma and in lymphocyte culture supernatants of healthy individuals and patients with systemic lupus erythematosus and rheumatoid arthritis. 1120 77

A vast majority of systemic lupus erythematosus (SLE) patients display decreased expression of TCR zeta-chain mRNA, a critical signaling molecule implicated in the selection of the TCR repertoire and in the prevention of autoimmunity. To identify the molecular mechanisms involved in the downregulation of TCR zeta-chain transcripts in SLE T cells, we investigated the possibility of polymorphisms/mutations in the promoter and the 3' untranslated region. PCR, cloning and sequence analysis of the promoter region from the genomic DNA showed significantly higher number of polymorphisms in SLE T cells compared to non-SLE control subjects (P = 0.044). Promoter sequence was also analysed from granulocytes to delineate the possibility of somatic mutations in activated SLE T cells. Promoter polymorphisms were significantly higher in granulocytes of SLE patients compared to non-SLE controls (P = 0.048), suggesting that these polymorphisms were of genomic origin. Nucleotide analysis of the promoter sequence revealed a -76T insertion compared to the published sequence, in all of the SLE samples and controls. RT-PCR analysis of the TCR zeta-chain 3' untranslated region showed a 344 bp product in addition to the expected 906 bp product. Cloning and sequence analysis of the 344 bp product indicated that it is an alternatively spliced form with both splicing donor and acceptor sites, resulting in deletion of nucleotides 672-1233 of TCR zeta-chain mRNA. Unlike the nomal TCR zeta-chain, the expression of TCR zeta-chain with the alternatively spliced 344 bp 3' untranslated region was higher in SLE T cells compared to non-SLE controls. The number of mutations/polymorphisms in the 906 bp TCR zeta-chain 3' untranslated region were significantly higher in SLE T cells compared to non-SLE subjects (P = 0.032). Frequent mutations/polymorphisms and aberrant splicing of the downstream 3' untranslated region may affect the stability and/or transport of TCR zeta-chain mRNA, leading to its downregulation in SLE T cells.
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PMID:Polymorphisms/mutations of TCR-zeta-chain promoter and 3' untranslated region and selective expression of TCR zeta-chain with an alternatively spliced 3' untranslated region in patients with systemic lupus erythematosus. 1124 39

In contrast to most of the soluble cytokine receptor antagonists properties, the soluble IL-6 receptor (sIL-6R) occurring in various body fluids of healthy persons and patients with various diseases is an agonist. The enhancing effect is due to its ability to form complex with IL-6 and to bind to gp130 making constitutively IL-6 receptor negative cells responsive for IL-6. The generation as well as the functional role of soluble IL-6 receptor is poorly understood. Earlier, we found that the sIL-6R levels in sera of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were higher than those of the control group measured by ELISA sandwich technology. In the present study we detected different levels of sIL-6R in the supernatants of lymphocyte cultures of healthy persons and patients with RA as well as SLE. Moreover, we found, that in vitro dexamethasone treatment stimulated generation of sIL-6R in both healthy persons and in active SLE, while it strongly suppressed production of sIL-6R in both RA groups. At mRNA level, we found that in SLE both the IL-6R mRNA encoding the membrane spanning and alternatively spliced (soluble) variants increased. Surprisingly, the strong decrease of sIL6R protein in RA was not found at mRNA level.
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PMID:A synthetic corticosteroid, dexamethasone regulates generation of soluble form of interleukin-6 receptor of human lymphocytes, in vitro. 1237 10

The reduction or absence of TCR zeta-chain (zeta) expression in systemic lupus erythematosus (SLE) patients is thought to be related to the pathogenesis of SLE. Recently, we reported the predominant expression of zeta mRNA containing an alternatively spliced 3'-untranslated region (3'UTR; zetamRNA/as-3'UTR) and a reduction in the expression of zeta mRNA containing the wild-type 3'UTR (zetamRNA/w-3'UTR) in T cells from SLE patients. Here we show that AS3'UTR mutants (MA5.8 cells deficient in zeta protein that have been transfected with zetamRNA/as-3'UTR) exhibit a reduction in the expression of TCR/CD3 complex and zeta protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab compared with that in wild-type 3'UTR mutants (MA5.8 cells transfected with zetamRNA/w-3'UTR). Furthermore, the real-time PCR analyses demonstrated that the half-life of zetamRNA/as-3'UTR in AS3'UTR mutants (3 h) was much shorter than that of zetamRNA/w-3'UTR in wild-type 3'UTR mutants (15 h). Thus, the lower stability of zetamRNA/as-3'UTR, which is predominant in SLE T cells, may be responsible for the reduced expression of the TCR/CD3 complex, including zeta protein, in SLE T cells.
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PMID:TCR zeta mRNA with an alternatively spliced 3'-untranslated region detected in systemic lupus erythematosus patients leads to the down-regulation of TCR zeta and TCR/CD3 complex. 1292 98

Complement receptor 2 (CR2/CD21) plays a major role in the immune response by linking innate and adaptive immunity to foreign pathogens and proteins. In addition, several lines of evidence strongly support a role for CR2 in the maintenance of tolerance to self-antigens. Both the absence of CR2 expression (along with the alternatively spliced gene product CR1) and the presence of a dysfunctional CR2 protein are tightly associated with the development of autoreactivity to nuclear antigens. Altered levels of expression of CR2 in patients with systemic lupus erythematosus support a clinically relevant role for this phenotype. Several possible mechanisms could underlie the loss of self-tolerance related to CR2, but the effect is most likely related to the failure of one or more specific checkpoints that limit autoreactivity during B cell development and immune reactions.
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PMID:Complement receptor 2 and autoimmunity. 1471 74

SLE T cells may play a key role in autoantibody production in SLE B cells. In addition, accumulating evidence has shown that SLE T cells participate in the attack on target cells or tissues through the overproduction of pro-inflammatory cytokines or an increase in cell-to-cell adhesion. Thus, the functional abnormality of SLE T cells appears to be pivotal to an understanding of SLE pathogenesis. Accumulating evidence suggests that potential defects may reside in the proximal signal transduction around the TCR-CD3 complex. We have demonstrated that the expression of TCR zeta chain is significantly decreased in peripheral blood T cells from SLE patients. To explore the mechanism of defective expression of TCR zeta chain, we examined mRNA of TCR zeta, and found that two alternatively spliced variants such as exon 7 (-) and short 3'-UTR are detected in SLE. We review the possible role of the TCR zeta defects in autoimmunity and discuss how the splicing variants lead to downregulated protein expression of TCR zeta chain.
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PMID:Altered expression of the T cell receptor-CD3 complex in systemic lupus erythematosus. 1520 89

We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.
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PMID:CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B. 1545 83

The molecular mechanisms involved in the aberrant expression of T cell receptor (TCR) zeta chain of patients with systemic lupus erythematosus are not known. Previously we demonstrated that although normal T cells express high levels of TCR zeta mRNA with wild-type (WT) 3' untranslated region (3' UTR), systemic lupus erythematosus T cells display significantly high levels of TCR zeta mRNA with the alternatively spliced (AS) 3' UTR form, which is derived by splice deletion of nucleotides 672-1233 of the TCR zeta transcript. Here we report that the stability of TCR zeta mRNA with an AS 3' UTR is low compared with TCR zeta mRNA with WT 3' UTR. AS 3' UTR, but not WT 3' UTR, conferred similar instability to the luciferase gene. Immunoblotting of cell lysates derived from transfected COS-7 cells demonstrated that TCR zeta with AS 3' UTR produced low amounts of 16-kDa protein. In vitro transcription and translation also produced low amounts of protein from TCR zeta with AS 3' UTR. Taken together our findings suggest that nucleotides 672-1233 bp of TCR zeta 3' UTR play a critical role in its stability and also have elements required for the translational regulation of TCR zeta chain expression in human T cells.
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PMID:Decreased stability and translation of T cell receptor zeta mRNA with an alternatively spliced 3'-untranslated region contribute to zeta chain down-regulation in patients with systemic lupus erythematosus. 1574 65

A soluble form of cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) was recently found and shown to possess B7 binding activity. sCTLA-4 is generated by alternatively spliced mRNA. The mRNA encoding sCTLA-4 consists of 3 exons: exon 1 encodes a leader peptide, exon 2 the ligand binding domain, and exon 4 the cytoplasmic tail, but it lacks the transmembrane domain encoded by exon 3. The altered transcript is detected in resting CD4 and CD8 T cells and its expression is inhibited after 24--48 h of activation and returns to the prestimulation level after 72--120 h of activation. Low levels of sCTLA-4 have been detected in normal human serum and increased serum levels have been observed in several autoimmune diseases (e.g. Graves' disease, myasthenia gravis, systemic lupus erythematosus, and systemic sclerosis). The biological significance of increased sCTLA-4 serum level has not been clarified. On one hand, sCTLA-4 may bind B7 expressed on antigen-presenting cells and is thus able to interfere with the B7:CD28-mediated costimulation of T cell responses. On the other hand, sCTLA-4 may also be capable of interfering with B7:CTLA-4 interactions, thereby blocking the negative signal imparted via the full-length form of CTLA-4. This double-edged nature of B7 blocking by sCTLA-4 may result in different outcomes of the clinical course of disease.
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PMID:The soluble CTLA-4 receptor: a new marker in autoimmune diseases. 1608 18


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