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)

The 52-kD SS-A/Ro protein is one of the antigenic targets strongly associated with the autoimmune response in mothers whose children have manifestations of neonatal lupus. In addition to the cDNA clone we previously reported for the full-length 52-kD SS-A/Ro protein, an interesting MOLT-4 cDNA clone, p52-2, was found to have an internal deletion of 231 nucleotides including the domain encoding the leucine zipper motif. To further investigate the nature of this deletion, genomic DNA clones were isolated from a lambda FIXII library. The complete gene for the full-length 52-kD protein (alpha form, 52 alpha) spans 10 kb of DNA and is composed of seven exons. Exon 1 contains only the 5' untranslated sequence, while the translation initiation codon is located 3 kb downstream in exon 2, which also encodes the three zinc finger motifs. Exon 4 encodes amino acids 168-245, including the coiled coil/leucine zipper domain. Exon 7 is the longest and encodes the rfp-like domain and the 3' untranslated region. The cDNA p52-2 can now be accounted for as a product of alternative messenger RNA (mRNA) derived from the splicing of exon 3 to exon 5, skipping exon 4, which results in a smaller protein (52 beta) with a predicted molecular weight of 45,000. An initial approach to identifying this alternatively spliced form in the human heart used a ribonuclease protection assay. Using an RNA probe corresponding to bases 674-964 of the full-length cDNA, two protected mRNA fragments were identified, a 290-bp fragment corresponding to expression of 52 alpha and a smaller fragment of 144 bp, the predicted size of 52 beta. Using reverse transcription followed by polymerase chain reaction, cDNAs from a 16-wk fetal heart, 24-wk heart, and adult heart were amplified with primers flanking exon 4. Two polymerase chain reaction products were observed in each tissue, one 1.0 kb likely representing 52 alpha and a second 0.78 kb, consistent with 52 beta. The 0.78-kb fragment identified in the 16-wk heart was cloned, and DNA sequencing confirmed the 52 beta type. Immunoprecipitation of in vitro-translated 35S-labeled 52 beta form was performed to evaluate the antigenicity of this novel form of 52-kD SS-A/Ro. 26 (87%) of 30 sera tested from mothers whose children were known to have neonatal lupus immunoprecipitated the 52 beta form.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart. 756 1

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.
 ...
PMID:Protein tyrosine kinase activity in T lymphocytes from patients with systemic lupus erythematosus. 980 21

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.
 ...
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

Understanding the development of autoimmunity is a crucial step toward improving the management, not only of autoimmune diseases, but also of tumors and primary immunodeficiency syndromes. The rapid expansion of knowledge on autoimmunity is fueling the development of a novel approach known as targeted immunotherapy. The present review will concentrate on ten areas where major advances have been achieved: 1) early regulation of B-cell mediated autoimmunity; 2) thymic regulation of tolerance to tissue-restricted antigens via the transcription factor AIRE; 3) role for a population of regulatory T cells (CD4+ CD25+ Tregs) with unique effects; 4) major role for dendritic cells in the development of autoimmunity in conditions such as lupus; 5) role for T cells in autoimmune diseases; 6) role for T cells in rheumatoid arthritis, with new data from a murine model of spontaneous arthritis related to a ZAP-70 mutation; 7) role for the environment via innate immunity, in particular mediated by the toll-like receptors (TLR); identification of new autoantigens with the description of sense-antisense peptides (e.g., proteinase 3-complementary proteinase 3); the immunosenescence concept, which suggests that some autoimmune diseases may be related to premature aging of the immune system; 10) identification of new immunotherapy targets, including costimulation pathway molecules (CD28, CTLA4), original activation systems (BAFF/BLyS), and receptors such as TLRs. These exciting insights into the pathogenic mechanisms underlying immune dysfunction will play a key role in advancing the field of immunorheumatology.
 ...
PMID:Novel concepts and treatments for autoimmune disease: ten focal points. 1558 31

A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorates systemic lupus erythematosus (SLE) in induced and spontaneous lupus models. Our objectives were to determine the effects of hCDR1 on TCR signaling and on its negative regulators, Foxj1 and Foxo3a. BALB/c mice were immunized with the SLE-inducing anti-DNA antibody, designated 16/6Id, and treated with hCDR1. hCDR1 treatment specifically inhibited IFN-gamma secretion by T cells in association with down-regulated T-bet expression and NF-kappaB activation; however, GATA-3 expression was not affected. Furthermore, TCR signaling (ZAP-70 phosphorylation) was inhibited, and the mRNA expression of the two modulators of Th1 activation, Foxj1 and Foxo3a, was significantly up-regulated. The latter were also elevated in SLE-afflicted (NZBxNZW)F1 mice that were treated with hCDR1. Addition of TGF-beta, which was elevated following treatment with hCDR1, to T cells from 16/6Id immunized mice, up-regulated Foxj1 and Foxo3a mRNA expression, similarly to hCDR1. In contrast, anti-TGF-beta antibodies added to hCDR1-treated T cells abrogated its effect. Thus, hCDR1 elevates TGF-beta, which contributes to the up-regulation of T cell Foxj1 and Foxo3a expression, leading to inhibition of NF-kappaB activation and IFN-gamma secretion, which is required for the maintenance of SLE.
 ...
PMID:The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses. 1705 18

Systemic lupus erythematosus (SLE) T cells display reduced expression of TCR zeta protein. Recently, we reported that in SLE T cells, the residual TCR zeta protein is predominantly derived from an alternatively spliced form that undergoes splice deletion of 562 nt (from 672 to 1233 bases) within the 3' untranslated region (UTR) of TCR zeta mRNA. The stability and translation of the alternatively spliced form of TCR zeta mRNA are low compared with that of the wild-type TCR zeta mRNA. We report that two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3' UTR region, but not an ARE located upstream are responsible for securing TCR zeta mRNA stability and translation. The stabilizing effect of the splice-deleted region-defined AREs extended to the luciferase mRNA and was not cell type-specific. The findings demonstrate distinct sequences within the splice-deleted region 672 to 1233 of the 3' UTR, which regulate the transcription, mRNA stability, and translation of TCR zeta mRNA. The absence of these sequences represents a molecular mechanism that contributes to altered TCR zeta-chain expression in lupus.
 ...
PMID:Stability and translation of TCR zeta mRNA are regulated by the adenosine-uridine-rich elements in splice-deleted 3' untranslated region of zeta-chain. 1711 3

Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.
 ...
PMID:Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. 1732 34

T cells from systemic lupus erythematosus (SLE) patients exhibit defective function of CD4(+) T cells that can be responsible for improper activation of B cells and antibody biosynthesis against host antigens. We compared the level of ZAP-70, LAT, and SLP-76, transcripts and proteins in CD4(+) T cells from SLE patients (n = 22) and healthy individuals (n = 15). We also determined DNA methyltransferase 1 (DNMT1) protein content in CD4(+) T cells of SLE patients. The CD4(+) T cells were isolated by positive biomagnetic separation technique. The quantitative analysis of messenger RNA (mRNA) was performed by reverse transcription and real-time quantitative polymerase chain reaction (RQ-PCR) SYBR Green I system. The protein level in the CD4(+) T cells was determined by Western blotting analysis. We found that the LAT protein level was significantly higher in SLE CD4(+) T cells than in controls (P = 0.006). Western blot analysis revealed that ZAP-70 protein content in SLE CD4(+) T cells may be reciprocally correlated with disease activity expressed in SLEDAI scale (R = -0.623, P = 0.002) or number of affected organ systems (R = -0.549, P = 0.008). We also observed reciprocal correlation between DNMT1 protein content in CD4(+) T cells and disease activity scored with SLEDAI scale (R = -0.779, P = 0.001) or number of affected organ systems (R = -0.617, P = 0.019), respectively. Our findings might indicate that LAT, ZAP-70, and DNMT1 protein levels in CD4(+) T cells can be associated with SLE disease.
 ...
PMID:Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus. 1749 76

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.
 ...
PMID:Proximal signaling control of human effector CD4 T cell function. 1769 70

Diminished expression of TCR zeta and reciprocal up-regulation and association of FcRgamma with the TCR/CD3 complex is a hallmark of systemic lupus erythematosus (SLE) T cells. In this study we explored whether differential molecular associations of the spleen tyrosine kinase Syk that preferentially binds to FcRgamma contribute to pathological amplification of signals downstream of this "rewired TCR" in SLE. We detected higher amounts of Syk expression and activity in SLE compared with normal T cells. Selective inhibition of the activity of Syk reduced the strength of TCR-induced calcium responses and slowed the rapid kinetics of actin polymerization exclusively in SLE T cells. Syk and ZAP-70 also associated differently with key molecules involved in cytoskeletal and calcium signaling in SLE T cells. Thus, while Vav-1 and LAT preferentially bound to Syk, phospholipase C-gamma1 bound to both Syk and ZAP-70. Our results show that differential associations of Syk family kinases contribute to the enhanced TCR-induced signaling responses in SLE T cells. Thus, we propose molecular targeting of Syk as a measure to control abnormal T cell responses in SLE.
 ...
PMID:Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells. 1901 7


1 2 Next >>