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

Two cDNA clones encoding the 52-kD form of a protein present in human Ro/SSA ribonucleoprotein complexes were cloned from a lambda gt11 human thymocyte cDNA library. These clones reacted with lupus patient sera which had anti-52-kD Ro/SSA antibodies, and with affinity-purified anti-52-kD Ro/SSA antibodies. Moreover, affinity-purified antibodies isolated from isopropyl-beta-D-thiogalactopyranoside-induced proteins of these clones reacted only with the 52-kD protein of lymphocytes in Western blots and precipitated Ro/SSA hY RNAs, confirming that the clones encode a 52-kD Ro/SSA antigen. The cDNA contains a single open reading frame of 1,425 nucleotides and encodes a predicted 475-amino acid polypeptide with a molecular mass of 54,108 D. This protein appears unique in that both a zinc finger and leucine zipper motif are present on this protein. Surprisingly, no homology was found between the 52-kD Ro/SSA gene or protein and three published 60-kD Ro/SSA sequences. However, significant similarity of the 52-kD Ro/SSA was detected with human rfp and mouse rpt-1. These three proteins each contain similar zinc finger motifs in approximately their first 145 amino acid residues. The cDNA and the protein expressed therefrom are useful in the analysis of the structural and functional properties of this autoantigen.
 ...
PMID:Protein heterogeneity in the human Ro/SSA ribonucleoproteins. The 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. 198 94

Abs to the 52-kDa SS-A/Ro protein are found in high prevalence in patients with Sjogren's syndrome (SS) and mothers whose children have the neonatal lupus syndrome (NLS). This study further defines the specificity of this response. By ELISA, 97% of 59 mothers of offspring with NLS had Abs to the 52-kDa recombinant protein compared with 80% in 132 non-NLS sera with anti-SS-A/Ro Abs (p < 0.004). Antigenic regions on the 52-kDa protein were evaluated by immunoprecipitation of [35S]-radiolabeled in vitro translation products. Ninety-five percent of 99 sera that contained anti-52-kDa Abs by ELISA reacted with a large fragment spanning amino acids (aa) 1-291. Two antigenic regions were identified, aa169-291 containing the leucine zipper that was recognized by 83% of the anti-52-kDa sera tested and aa1-78 containing the zinc finger domains that was recognized by only half the sera. No sera immunoprecipitated this N-terminal fragment exclusively. Recognition of one or both regions was not unique to any clinical subset of patients; however, a greater number of sera from patients with SS contained both specificities, whereas asymptomatic mothers whose children had NLS comprised the only clinical group in which the majority recognized the central region of the molecule. Reactivity with both epitopes was demonstrated significantly more often in sera with high titers of Abs to the 60-kDa rSS-A/Ro protein by ELISA in association with the anti-52-kDa response compared with anti-52-kDa responses associated with low titers of anti-60-kDa Abs (p < 0.04). Eighty-one percent of 16 sera that recognized the N-terminal epitope were from patients with the combination of HLA-DRB1*0301, DQA1*0501, and DQB1*0201 alleles, compared with 30% of 10 that recognized only the central epitope (p < 0.02). In summary, this study demonstrates that there are at least two antigenic determinants on the 52-kDa SS-A/Ro protein, one "immunodominant" and the other recognized by a more "restricted" subset of anti-52-kDa SS-A/Ro Abs.
 ...
PMID:Autoantibody responses to the "native" 52-kDa SS-A/Ro protein in neonatal lupus syndromes, systemic lupus erythematosus, and Sjogren's syndrome. 751 55

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

Early Growth Response (EGR) zinc finger transcription factors are induced under diverse mitogenic signals on different cell types such as lymphocytes. Their genetic expression does not require de novo protein synthesis, which suggests its role as immediate response mediators between cell surface receptor signaling and gene expression regulation. EGR factors are involved in modulating the immune response, by means of the induction of differentiation of lymphocyte precursors, activation of T and B cells, as well as their involvement in central and peripheral tolerance. The maturation state, particularly for B cells, and signaling through the T or B cell receptors seems to be quite relevant for the induction of the expression of these transcription factors. EGR-1 functions as a positive regulatory factor for B and T cells mediated by transcriptional regulation of key cytokines and costimulatory molecules, and its interaction with NFAT. On the opposite, EGR-2 and 3 act as negative regulators involved in anergy induction and apoptosis. EGR-2 and 3 deficiency has been related to the development of lupus like disease in murine models. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expansion of effector and activated T cells.
 ...
PMID:Early growth response transcription factors and the modulation of immune response: implications towards autoimmunity. 2003 3

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology and is considered to be an autoimmune disease. Autoantibodies are important tools for accurate diagnosis of PBC. Here, we employed serum profiling analysis using a human proteome microarray composed of about 17,000 full-length unique proteins and identified 23 proteins that correlated with PBC. To validate these results, we fabricated a PBC-focused microarray with 21 of these newly identified candidates and nine additional known PBC antigens. By screening the PBC microarrays with additional cohorts of 191 PBC patients and 321 controls (43 autoimmune hepatitis, 55 hepatitis B virus, 31 hepatitis C virus, 48 rheumatoid arthritis, 45 systematic lupus erythematosus, 49 systemic sclerosis, and 50 healthy), six proteins were confirmed as novel PBC autoantigens with high sensitivities and specificities, including hexokinase-1 (isoforms I and II), Kelch-like protein 7, Kelch-like protein 12, zinc finger and BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. To facilitate clinical diagnosis, we developed ELISA for Kelch-like protein 12 and zinc finger and BTB domain-containing protein 2 and tested large cohorts (297 PBC and 637 control sera) to confirm the sensitivities and specificities observed in the microarray-based assays. In conclusion, our research showed that a strategy using high content protein microarray combined with a smaller but more focused protein microarray can effectively identify and validate novel PBC-specific autoantigens and has the capacity to be translated to clinical diagnosis by means of an ELISA-based method.
 ...
PMID:Identification of new autoantigens for primary biliary cirrhosis using human proteome microarrays. 2264 70

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+ T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+ T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element A was significantly upregulated after PMA/ionomycin stimulation in lupus CD4+ T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.
 ...
PMID:Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus-Derived T Cells. 2994 62