Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies to soluble liver antigen (SLA) are considered a specific marker of autoimmune hepatitis. We have performed immunoscreening of a human liver gene expression library with an anti-SLA-positive serum. A reactive clone with a 35-kd open reading frame (ORF) and a 563 base pair (bp) 3' untranslated region (UTR) was isolated (soluble liver antigen [SLA]-p35), showing strong homology to an independently isolated putative SLA/liver-pancreas antigen (LP) sequence (Acc. No. AF146396), and a UGA serine tRNA-protein complex (tRNP)((Ser) Sec) related protein (AJ238617), as well as different expression sequence tag (EST)-clones from lymphatic and oncofetal tissues. Expressed in Escherichia coli, SLA-p35 showed dose-dependent and complete blocking of reactivity to native SLA antigen after preabsorption with the 35-kd recombinant protein. It recognized 67/85 (78.8%) precharacterized anti-SLA-positive sera in dilutions up to 1:40,000 in immunoblot, without detectable cross reactivity in the controls. The commercially available SLA/LP enzymelinked immunosorbent assay (ELISA), by comparison, recognized 63/85 samples (74.1%). Of the negative samples, 18% showed strong inhibition rates (80% and above) in the polyclonal inhibition ELISA. We conlude that the complementary DNA now isolated by 3 independent approaches encodes for the major but not sole antigenic component of soluble liver antigen. Although its truncated form presented here may serve to improve diagnostics based on the new recombinant polypeptide, it currently cannot fully replace the polyclonal inhibition ELISA.
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PMID:Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis. 1123 Jul 39

A descriptive lengthwise and prospective study of 37 patients with reactive hepatitis caused by hemorrhagic dengue virus, who were clinically humorally and ecographically followed up for one year, was made to characterize the disease and its development. The results were analyzed as percentages and yielded the predominance of the morbid process in females and young people and of fever as a symptom and hepatomegalia as a sign. Thrombocytopenia and increased hematocrit followed transaminanse levels as the most altered lab values whereas the perivesicular edema was the most striking element from the echographic viewpoint. The follow-up allowed us to observe a rapid clinical recovery and the normalization of transaminanse levels but the persistence of the serine-globulin index inversion and of hepatomegalia in almost one quarter of the patients were also noted.
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PMID:[Reactive hepatitis caused by the hemorrhagic dengue virus]. 1182 34

fgl2 prothrombinase, by its ability to generate thrombin, has been shown to be pivotal to the pathogenesis of viral-induced hepatitis, cytokine-induced fetal loss syndrome, and xeno- and allograft rejection. In this study, the molecular basis of fgl2 prothrombinase activity was examined in detail. Purified fgl2 protein generated in a baculovirus expression system had no measurable prothrombinase activity, whereas the activity was restored when the purified protein was reconstituted into phosphatidyl-L-serine-containing vesicles. Reconstituted fgl2 catalyzed the cleavage of human prothrombin to thrombin with kinetics consistent with a first order reaction, with an apparent V(max) value of 6 mol/min/mol fgl2 and an apparent K(m) value for prothrombin of 8.3 microM. The catalytic activity was totally dependent on calcium, and factor Va (500 nM) enhanced the catalytic efficiency of fgl2 by increasing the apparent V(max) value to 3670 mol/min/mol fgl2 and decreasing the apparent K(m) value for prothrombin to 7.2 microM. By a combination of site-directed mutagenesis and production of truncated proteins, it was clearly shown that residue Ser(89) was critical for the prothrombinase activity of fgl2. Furthermore, fgl2 prothrombinase activity was not inhibited by antithrombin III, soybean trypsin inhibitor, 4-aminobenzamidine, aprotinin, or phenylmethylsulfonyl fluoride, whereas diisopropylfluorophosphate completely abrogated the activity. In this work we provide direct evidence that fgl2 cleaves prothrombin to thrombin consistent with serine protease activity and requires calcium, phospholipids, and factor Va for its full activity.
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PMID:Kinetic analysis of a unique direct prothrombinase, fgl2, and identification of a serine residue critical for the prothrombinase activity. 1199 72

Autoantibodies to the ribosomal phospho (-P) proteins P0, P1, and P2, collectively referred to as Rib-P, are specifically found in 10-40% of patients with systemic lupus erythematosus (SLE). These antibodies are believed to be correlated with lupus nephritis, hepatitis, and central nervous system involvement. The major immunoreactive epitope of these ribosomal antigens has been localized to the carboxy terminus, which is a highly conserved domain of all three proteins and contains two phosphorylated serine residues. The phosphorylated amino acids of the P proteins are known not to be critical epitope determinants. Furthermore, epitope-mapping studies have shown that the major epitope is located within the last 11 C-terminal amino acids. Using peptide arrays we identified more precisely this shared epitope as the six C-terminal amino acids GFGLFD and elucidated the molecular recognition events of anti-Rib-P antibodies at the amino acid level. We identified Phe(111) and Phe(114) of Rib-P2 as the key residues for the interaction, with further contributions of Gly-112 and Asp-115. This amino acid stretch is also present in proteins of several pathogenic micro-organisms such as Trypanosoma cruzi, Brugia malayi, Pseudomonas aeruginosa, Candida albicans, several Leishmania species, and Bartonella henselae. Using newly developed ELISA systems with a C-terminal peptide (C22) and the recombinant proteins (P0, P1, and P2) as antigens we found a high specificity of anti-Rib-P antibodies for SLE and demonstrated positive correlations with anti-U1-C, anti-Sm-B/B' and anti-D and anti-dsDNA antibodies. The sensitivity and specificity in the peptide (C22) based assay varied between 12.8%/100% and 23.4%/96.7% for SLE, depending on the assigned cutoff. In contrast to other studies, we found no significant correlation of anti-Rib-P reactivity with central nervous system manifestations or renal involvement in SLE patients. We conclude that the epitope motif GFGLFD in the C-termini of the ribosomal P proteins is the key determinant of anti-Rib-P antibodies, and that the C22 peptide and the recombinant proteins can be used equally well for the detection of anti-Rib-P antibodies. The role of the major Rib-P epitope in the development of anti-ribosomal P antibodies and in the pathogenesis of SLE remains a subject of further investigation.
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PMID:Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins. 1268 28

The study was carried out for the purpose of determining the diagnostic criteria applicable to the cirrhotic stage of chronic viral B-hepatitis (CVBH) by using the data of the phosphor-lipid spectrum of the blood serum. The phosphor-lipid spectrum of the blood serum was examined in 70 patients with CVBH and in 20 patients with small-nodular hepatic cirrhosis. Reliably lower contents of lysophosphatidyl serine (LPS), of lysophosphatidyl ethanolamine (LFE) and of phosphatidyl ethanolamine (PE) were found in patients with CVBH at the cirrhotic stage as compared to patients with CVBH, who did and did not abuse the alcohol. However, the latters had a higher level of the relative content of phosphatidyl choline (PC) as compared to the controls.
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PMID:[Phospholipids in blood serum and the differential diagnosis of chronic hepatitis B and the cirrhotic stage of the disease]. 1268 14

Tumor necrosis factor (TNF) plays a key role in several types of fulminant and acute hepatitis, and induces massive apoptosis and necrosis of hepatocytes. Our previous studies described the central role played by several matrix metalloproteinases (MMPs) and one or more unknown serine proteases. The aim of this study was to investigate the involvement of serine proteases of the fibrinolytic pathway, known to be activators of several MMPs, in TNF-induced hepatitis and fibrinogen (FG) breakdown. Experiments were performed in a model of TNF-induced hepatitis, consisting of administration of TNF in combination with D-(+)-galactosamine (GalN) to mice deficient in urokinase-type plasminogen (PG) activator (u-PA), tissue-type PG activator (t-PA) or PG. Lethality, transaminase release, increased plasma clotting time and FG levels were measured. In PA- and PG-deficient mice, TNF/GalN still induced hepatitis, as well as increased clotting time and FG breakdown. MMP-9 activation still occurred in the liver despite the lack of plasmin. The data suggest that the serine proteases involved in TNF-induced lethal hepatitis are no constituents of the fibrinolytic cascade.
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PMID:Serine proteases of the fibrinolysis pathway are not involved in lethal hepatitis and fibrinogen breakdown induced by tumor necrosis factor. 1282 1

The coronavirus, mouse hepatitis virus strain JHM, causes acute and chronic neurological diseases in rodents. Here we demonstrate that two closely related virus variants, both of which cause acute encephalitis in susceptible strains of mice, cause markedly different diseases if mice are protected with a suboptimal amount of an anti-JHM neutralizing antibody. One strain, JHM.SD, caused acute encephalitis, while infection with JHM.IA resulted in no acute disease. Using recombinant virus technology, we found that the differences between the two viruses mapped to the spike (S) glycoprotein and that the two S proteins differed at four amino acids. By engineering viruses that differed by only one amino acid, we identified a serine-to-glycine change at position 310 of the S protein (S310G) that recapitulated the more neurovirulent phenotype. The increased neurovirulence mediated by the virus encoding glycine at position S310 was not associated with a different tropism within the central nervous system (CNS) but was associated with increased lateral spread in the CNS, leading to significantly higher brain viral titers. In vitro studies revealed that S310G was associated with decreased S1-S2 stability and with enhanced ability to mediate infection of cells lacking the primary receptor for JHM ("receptor-independent spread"). These enhanced fusogenic properties of viruses encoding a glycine at position 310 of the S protein may contribute to spread within the CNS, a tissue in which expression of conventional JHM receptors is low.
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PMID:Enhanced virulence mediated by the murine coronavirus, mouse hepatitis virus strain JHM, is associated with a glycine at residue 310 of the spike glycoprotein. 1297 Apr 10

Whether the hepatitis delta virus (HDV) DNA vaccine can induce anti-HDV antibodies has been debatable. The role of the isoprenylated motif of hepatitis delta antigens (HDAg) in the generation of immune responses following DNA-based immunization has never been studied. Plasmids p2577L, encoding large HDAg (L-HDAg), p2577S, expressing small HDAg (S-HDAg), and p25L-211S, encoding a mutant form of L-HDAg with a cysteine-to-serine mutation at codon 211, were constructed in this study. Mice were intramuscularly injected with the plasmids. The anti-HDV antibody titers, T-cell proliferation responses, T-helper responses, and HDV-specific, gamma interferon (IFN-gamma)-producing CD8(+) T cells were analyzed. Animals immunized with p2577S showed a strong anti-HDV antibody response. Conversely, only a low titer of anti-HDV antibodies was detected in mice immunized with p2577L. Epitope mapping revealed that the anti-HDV antibodies generated by p2577L vaccination hardly reacted with epitope amino acids 174 to 194, located at the C terminus of S-HDAg. All of the HDAg-encoding plasmids could induce significant T-cell proliferation responses and generate Th1 responses and HDV-specific, IFN-gamma-producing CD8(+) T cells. In conclusion, HDAg-specific antibodies definitely exist following DNA vaccination. The magnitudes of the humoral immune responses generated by L-HDAg- and S-HDAg-encoding DNA vaccines are different. The isoprenylated motif can mask epitope amino acids 174 to 195 of HDAg but does not interfere with cellular immunity following DNA-based immunization. These findings are important for the choice of a candidate HDV DNA vaccine in the future.
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PMID:Varied immunity generated in mice by DNA vaccines with large and small hepatitis delta antigens. 1464 54

We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 micro mol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT deficiency, strengthening the likelihood of a causative association. Although his deficiency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.
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PMID:Glycine N -methyltransferase deficiency: a new patient with a novel mutation. 1473 80

BACKGROUND: Antibodies to a cytosolic soluble liver antigen (SLA) are specifically detected in patients with autoimmune hepatitis (AIH). The target of anti-SLA has been identified as a ~50 kDa UGA serine tRNA-associated protein complex (tRNP(Ser)Sec), through the screening of cDNA libraries. A recent report questioned the identity of tRNP(Ser)Sec as the real SLA antigen. The latter study identified alpha-enolase as a major anti-SLA target, through proteomic analysis. METHODS: In an attempt to explain the observed discrepancy we have investigated reactivity of SLA positive sera against alpha-enolase and tRNP(Ser)Sec using rat and primate liver homogenate and the recombinant antigens. Thirty-three serum samples, 11 from SLA-positive patients and 22 from SLA negative controls were investigated. SLA antibodies were detected by an inhibition ELISA and confirmed by immunoblot using human liver homogenate. Autoantibody reactivity was further evaluated using preparations of primate and rat liver homogenates. Anti-alpha-enolase antibody reactivity has been tested by immunoblot using recombinant alpha-enolase. An affinity purified goat polyclonal anti-alpha-enolase IgG antibody was used as reference serum sample. Anti-tRNP(Ser)Sec antibody reactivity was detected by ELISA or dot blot using recombinant tRNP(Ser)Sec antigen. RESULTS AND DISCUSSION: The affinity purified IgG antibody directed to human alpha-enolase gave a band of approximately 48 kDa in both human and rat liver homogenates. A high titre anti-tRNP(Ser)Sec antibody serum gave a single band of ~50 kDa in both liver preparations. All but one anti-SLA antibody positive sera reacted with a ~50 kDa but none immunofixed a 48 kDa band. All anti-SLA antibody positive sera reacted strongly with the recombinant full length tRNP(Ser)Sec protein. None of the anti-SLA negative sera reacted with tRNP(Ser)Sec. Anti-SLA positive, and anti-SLA negative sera reacted equally against recombinant alpha-enolase by immunoblot. Pre-incubation of anti-SLA positive sera with tRNP(Ser)Sec completely abolished the 50 kDa band. The findings of the present study indicate that alpha-enolase and tRNP(Ser)Sec are both expressed in primate and rat liver and have a respective MW of 48 and 50 kDa. They also show that anti-tRNP(Ser)Sec - but not anti-alpha-enolase - correlates with anti-SLA antibody reactivity. CONCLUSION: Our findings indicate that tRNP(Ser)Sec is the most likely target of anti-SLA.
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PMID:Antibodies to soluble liver antigen and alpha-enolase in patients with autoimmune hepatitis. 1567 47


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