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)

To address the molecular mechanism underlying the functional defects of peripheral T cells in systemic lupus erythematosus (SLE), we focused on early signaling events. We demonstrated that protein expression of the TCR zeta chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc). Among those patients showing decreased TCR zeta chain expression, we found two patients with pronounced TCR zeta chain abnormalities, including an aberrant 14 kDa form in one and only trace expression in the other. RT-PCR, SSCP and subsequent cloning of the transcripts revealed that bases 468503, corresponding to exon 7, were deleted in both patients. Since exon 7 spans the GTP/GDP binding site and N-terminal tyrosine in the third ITAM domain of TCR zeta chain, the transcript lacking exon 7 may be responsible for altered signal transduction via TCR in these SLE patients.
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PMID:TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus. 970 Oct 29

T cells from patients with systemic lupus erythematosus (SLE) display antigen receptor-mediated signaling aberrations associated with defective T cell receptor (TCR) zeta chain expression. We determined the prevalence of TCR zeta chain deficiency in SLE from a large cohort of unselected racially diverse patients with different levels of clinical disease activity as determined by SLE Disease Activity Index (SLEDAI). Our data show that the occurrence of TCR zeta chain deficiency is 78% in SLE patients. There was no relationship between the deficiency of TCR zeta chain and the SLEDAI scores or theapy. TCR zeta chain deficiency was also not associated with age, race or gender and persisted over a 3 year follow-up period. Thus, there is a high prevalence of TCR zeta chain deficiency in SLE patients that is independent of disease activity, and persists over time indicating an important role for TCR zeta chain deficiency in SLE pathogenesis.
Lupus 2003
PMID:Prevalence of T cell receptor zeta chain deficiency in systemic lupus erythematosus. 1258 26

Abnormal expression of key signaling molecules and defective function of T lymphocytes play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). Probing on altered expression of genes that may predispose to SLE revealed that the expression of TCR zeta chain is defective in the majority of SLE patients. Current research has been directed towards understanding the molecular basis of TCR zeta chain deficiency and dissecting the T cell signalling abnormalities in SLE T cells. Latest developments suggest that interplay of abnormal transcriptional factor expression, aberrant mRNA processing/editing, unbiquitination, proteolysis, and the effects of oxidative stress as well as changes in chromatin structure invariably contribute to TCR zeta chain deficiency in SLE T cells. On the other hand, multiple factors, including altered receptor structure, modulation of membrane clustering, lipid-raft distribution of signaling molecules, and defective signal silencing mechanisms, play a key role in delivering the increased TCR/CD3-mediated intracellular calcium response in SLE T cells.
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PMID:Dissecting the molecular mechanisms of TCR zeta chain downregulation and T cell signaling abnormalities in human systemic lupus erythematosus. 1520 87

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

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

It is widely accepted that T cells with defective function play a central role in the pathogenesis of systemic lupus erythematosus (SLE). The detailed molecular mechanism underlying the aberrant function of SLE T cells is now being revealed. The TCR zeta chain, transcription factor, elf-1, inflammation signal transducer NF-kB, and PKC theta have been identified as the responsible molecules. In contrast to the defective signal transduction molecules, surface structures such as adhesion molecules, and co-stimulators have been reported to increase in their expression and function. Glucocorticoids and immunosuppressive agents have greatly improved the outcome of acute diseases and 5-year survival rate. However, it is suggested that long-term survival and quality of life appears to be unsatisfactory. Although the medical management of SLE is not sufficient to warrant long-term survival of young patients, recent progress in anti-cytokine biologics therapy against rheumatoid arthritis (RA) has facilitated searching for the molecular targets of SLE. In this report, we briefly review the molecular basis of SLE pathogenesis, and discuss possible therapeutic targets in this disease, focusing particularly on signal transduction and adhesion molecules in T cells.
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PMID:Therapeutic targets of misguided T cells in systemic lupus erythematosus. 1610 36

Because of the consensus that T cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), we explored the molecular basis of the defective function of SLE T cells for expression of signal transduction molecules, as well as surface structures such as adhesion molecules, by extensively testing peripheral blood T cells from SLE patients. Upregulated expression and function of adhesion molecules was observed in T cells from patients with active SLE who had specific clinical manifestations such as vasculitis, epithelitis and arthritis, but proximal signal transduction was defective. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR zeta chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR zeta chain, including spliced variants lacking exon 7 and with a short 3' UTR, were detected in SLE T cells. Although attenuated expression of the TCR zeta chain is also observed in patients with cancers, infections and other autoimmune diseases, sustained attenuation of TCR zeta expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR zeta defects in SLE.
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PMID:T cell abnormalities in systemic lupus erythematosus. 1622 48

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