Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036421 (PSS)
 10,989 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the expression of a cDNA clone encoding 695 carboxyl-terminal amino acids of human DNA topoisomerase I (topoI) in Escherichia coli. More than 96% of the anti-HeLa topoI-positive sera from patients with a connective tissue disease displayed also an immunoreactivity with this recombinant protein (the HTopoA protein). Sera from patients with a definite diagnosis systemic sclerosis and reacting with HeLa topoI, all reacted with the HTopoA protein as well. Sera from patients with systemic sclerosis that did not contain anti-topoI antibodies (about 30% of the systemic sclerosis sera), as concluded from HeLa immunoblot, displayed also no immunoreactivity with our recombinant antigen. By expressing different fragments of HTopoA, we were able to assign at least three different autoimmune epitope regions on the HTopoA protein and we show that over a period of 5 years the amount of anti-topoI antibodies against these regions may fluctuate.
 ...
PMID:A recombinant topoisomerase I used for autoantibody detection in sera from patients with systemic sclerosis. 169 Oct 63

One of the most characteristic serologic features of systemic sclerosis (scleroderma) is the occurrence of autoantibodies against nuclear and most notably against nucleolar antigens. This humoral autoimmune response is one of best studied immunologic phenomena in scleroderma. Detailed molecular information on the structure and function, as well as on reactive epitopes of autoantigens targeted by specific serum antibodies, has been revealed by clinical, immunologic, and biochemic studies in several laboratories. Autoantigens such as DNA topoisomerase I (Scl-70), centromere proteins, RNA polymerase I, U3 RNP-associated fibrillarin, PM-Scl, and 7-2 RNP antigens were shown to be specific targets of scleroderma patients and were observed to have clinical correlates within the scleroderma disease spectrum. Therefore, autoantibodies in scleroderma are not only valuable diagnostic tools but also prognosticators of the disease. Although autoantibodies in scleroderma do not appear to play a pathogenetic role in the disease process, the knowledge of the structure and function of their reactive antigens may help in answering questions concerning the etiology of the disease.
 ...
PMID:Autoantibodies against nuclear, nucleolar, and mitochondrial antigens in systemic sclerosis (scleroderma). 240 6

Sera of patients suffering from the autoimmune disease progressive systemic sclerosis (PSS) are known to contain autoantibodies which have been reported to recognize a 70 kDa antigenic protein, designated the Scl 70 antigen. By immunoblotting of nuclear extracts from HeLa cells with sera from scleroderma patients we observed that the size of the antigen present in such cells depends on the conditions of antigen isolation. When protease inhibitors were included in the extraction buffer, a 95 kDa protein was identified instead of a 70 kDa protein. When protease inhibitors were omitted, a number of polypeptides in the size range 66 to 95 kDa was found. Furthermore, antibodies which had been affinity purified on the 95 kDa antigen, crossreacted with the 66 to 95 kDa polypeptides. These results suggest that the smaller proteins were degradation products of the 95 kDa antigen. Immunofluorescence studies on PtK-2 cells with the antibody specific for the 95 kDa protein gave staining of nuclei, nucleoli and of chromosomes and the nucleolar organizer region in mitotic cells. Since this distribution of antigens within the nucleus was reminiscent of the intranuclear distribution of DNA topoisomerase I found by others we probed purified DNA topoisomerase I from calf thymus directly with the autoantibodies from PSS patients, and also the 95 kDa antigens of HeLa cell nuclei with antibodies raised against the bovine DNA topoisomerase I. From the crossreaction pattern observed with the different antigens and antibodies we conclude that DNA topoisomerase I is one of the antigenic components against which autoantibodies are formed in scleroderma patients.
 ...
PMID:Scl 70 autoantibodies from scleroderma patients recognize a 95 kDa protein identified as DNA topoisomerase I. 242 64

The possibility that viruses play a role in the etiology of various autoimmune diseases has been proposed. One approach to the search for these agents involves identifying potential crossreactive epitopes in viruses that infect cells of the immune system or of the target tissues. Antibodies to DNA topoisomerase I are the marker autoantibodies for diffuse systemic sclerosis. The major epitope of the antigen was therefore sought through cloning and sequencing of the cDNA for human topoisomerase I and eventually by the synthesis of the smallest possible peptide recognized by sera from patients with the diffuse form of systemic sclerosis. The antigenic 11-amino acid sequence contains 6 sequential amino acids that are identical to a sequence present in the group-specific antigen (p30gag) of some mammalian retroviruses. This sequence is separated by only 1 amino acid from the retroviral epitope sequence that crossreacts with autoantibodies against the marker antigen for mixed connective-tissue disease and systemic lupus erythematosus, the 70-kDa polypeptide of U1 ribonucleoprotein particles. These findings suggest that a retroviral agent may be involved in the pathogenesis of systemic sclerosis and other connective tissue diseases and that antibodies to intracellular antigens are not involved in the pathogenesis of autoimmune disease but may be useful as footprints for tracking the potential etiological agent of autoimmune disease.
 ...
PMID:Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis. 247 24

Patients with rheumatic diseases often have circulating autoantibodies to nuclear components. The clinical significance of the antibodies is controversial, although in some cases they are valuable in the diagnosis of the disease. This report presents results of a study of Scl-70, an autoantigen recognized by sera of many patients with the most severe form of progressive systemic sclerosis. It was possible to show, by three independent criteria, that Scl-70 is the abundant nuclear enzyme DNA topoisomerase I. Therefore, antibody probes of high titer and high affinity are now available for the study of this important nuclear enzyme.
 ...
PMID:High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. 300 10

Five recombinant fusion proteins with overlapping amino acid sequences encompassing the entire DNA topoisomerase I (topo I) molecule were generated, purified, and used as antigens for an enzyme-linked immunosorbent assay (ELISA). IgG, IgA, IgM, and "total" (total of IgG, IgA, and IgM isotypes) anti-topo I antibodies were measured using a mixture of these five fusion proteins in 73 systemic sclerosis (SSc) sera positive for anti-topo I antibody by double immunodiffusion (DID) and 184 control sera negative for anti-topo I antibody by DID. Fragment-specific anti-topo I antibodies were also measured by ELISA using each topo I recombinant protein as antigen. IgG, IgA, IgM, and total anti-topo I antibodies were detected in 67 (92%), 56 (77%), 16 (22%), and 70 (96%) of 73 SSc sera positive for anti-topo I antibody by DID, respectively. The specificity of the total anti-topo I ELISA was 99% when compared with DID. The total anti-topo I ELISA levels were strongly correlated with DID titers (r = 0.907, P < 0.0001). Three sera which recognized a conformational epitope on native topo I or had predominantly IgM anti-topo I antibody showed a false-negative result with the total anti-topo I ELISA. Three SSc sera negative for anti-topo I antibody by DID were positive by the total anti-topo I ELISA, and two were confirmed to recognize the N-terminus of topo I. IgG and IgA antibody levels to the N-terminal and central portion of topo I were correlated with each other, but those to the C-terminus were not. These findings indicate that the ELISA using recombinant fusion proteins is a highly sensitive and specific alternative to conventional DID for the detection of anti-topo I antibody.
 ...
PMID:Detection of anti-DNA topoisomerase I antibody by an enzyme-linked immunosorbent assay using overlapping recombinant polypeptides. 755 48

The in vitro T cell proliferative response to DNA topoisomerase I (topo I) was examined in 26 systemic sclerosis (SSc) patients with anti-topo I antibody, 10 SSc patients without anti-topo I antibody, and 21 healthy donors. Using recombinant fusion proteins encompassing the entire human topo I amino acid sequence, a topo I-specific proliferative response was detected in PBMC cultures from 25 (96%) anti-topo I-positive SSc patients, 4 (40%) anti-topo I-negative SSc patients, and 13 (62%) healthy donors. Molecular typing at MHC class II loci revealed that all SSc patients and healthy donors having either DRB1*1501,2 (DR15), DRB1*1101,3,4 (DR11), or DRB1*07 (DR7) were responders. Characterization of the topo I-induced T cell proliferative response showed that (a) the responding cells were CD4+ T cells; (b) antigen-presenting cells were necessary for the response; (c) the response was restricted by HLA-DR, and to a lesser extent by HLA-DQ; and (d) the estimated frequency of the responding T cells determined by limiting dilution analysis was 1/9,277-1/24,853. PBMC cultures from anti-topo I-positive SSc patients showed a high T cell proliferative response after only 3 d of culture with topo I. Anti-topo I-negative SSc patients and healthy donors had no proliferative response after 3 d, but did respond after 7 d of culture. T cell proliferative responses to six truncated topo I fragments tested individually showed different patterns of T cell proliferation that were dependent upon the responder's HLA-DR alleles. These results indicate that T cells reactive with topo I are components of the normal T cell repertoire, and that the topo I-specific T cell proliferative response is not associated with the presence or absence of SSc or anti-topo I antibody, but is restricted by MHC class II alleles.
 ...
PMID:T cell proliferative response induced by DNA topoisomerase I in patients with systemic sclerosis and healthy donors. 761 31

To elucidate the mechanisms controlling anti-DNA topoisomerase I (topo I) antibody production in patients with systemic sclerosis (SSc), in particular the role of interactions between topo I-specific Th cells and B cells, we established an in vitro system for the analysis of anti-topo I antibody production. In vitro anti-topo I antibody synthesis in PBMC cultures was induced by recombinant topo I and PWM, and was measured by a topo I-specific ELISA. Anti-topo I antibody was detected in PBMC culture supernatants from 11 (61%) of 18 anti-topo I-positive SSc patients. In contrast, anti-topo I antibody was not detected in the PBMC culture supernatants from 4 anti-topo I-negative SSc patients or 10 healthy donors. Characterization of in vitro anti-topo I antibody production showed that 1) the anti-topo I antibody isotype produced was IgG; 2) the anti-topo I antibody levels in culture supernatants correlated with those in patients' sera; 3) CD4+ T cells were necessary for antibody synthesis; and 4) antibody synthesis was restricted by HLA-DR, but not by HLA-DQ or DP. In addition, separation of cultured T and B cells by a semipermeable membrane or culture with anti-CD40 ligand mAb blocked in vitro anti-topo I antibody production. These results indicate that a contact-mediated and HLA-DR-restricted collaboration between topo I-specific T and B cells is essential for in vitro anti-topo I antibody production in a subset of SSc patients.
 ...
PMID:T and B cell collaboration is essential for the autoantibody response to DNA topoisomerase I in systemic sclerosis. 765 Mar 98

In more than 95% of patients with systemic sclerosis and in about 60% of patients suffering from idiopathic inflammatory myopathies autoantibodies directed at different nuclear or cytoplasmic antigens can be detected with different methods. Scleroderma-associated autoantibodies can be visualized as antinuclear antibodies (ANA) by immunofluorescence assays using cultured monolayer cells. In case of a negative ANA result the diagnosis of systemic sclerosis is unlikely. In individual patients the different autoantibodies (against DNA topoisomerase I (Scl-70), centromeric antigens, fibrillarin, To (Th), RNA polymerases, NOR-90, U1-nRNP, PM-Scl, Ku) are mutually exclusive. They can be detected early in the course of diseases, most often are persistent, and are closely associated with immunogenetic markers. They are characteristic for distinct subsets of patients homogeneous in clinical manifestations as well as in disease outcome. Myositis-associated autoantibodies are directed to nuclear (about 60% of myositis patients; PM-Scl, Mi-2) or cytoplasmic antigens (about 35-40%; Jo-1 and other aminoacyl-tRNA-synthetases, signal recognition particle (SRP), KJ and others) and likewise are related to distinct clinical, prognostic, and immunogenetic traits leading to the description of characteristic antibody-based syndromes. Based on published results and on our own investigations, the diagnostic potential of scleroderma- and myositis-associated antibodies is evaluated and a new classification of systematic myositic and sclerodermatous disease is proposed.
 ...
PMID:[Diagnostic significance of scleroderma and myositis-associated autoantibodies]. 772 5

Anti-DNA topoisomerase I (anti-topo I) antibody profiles were compared before and after lung cancer in 2 patients with systemic sclerosis (SSc). Both patients developed adenocarcinoma of the lung late in the course of SSc and died of the cancer. Anti-topo I antibody levels, determined by double immunodiffusion and enzyme-linked immunosorbent assay, increased markedly at the time of diagnosis of lung cancer. Furthermore, patients' sera obtained after lung cancer reacted with multiple epitopes on the entire topo I molecule, some of which had not previously been recognized. These results further support the concept that anti-topo I antibody production in SSc patients is due to an antigen-driven process.
 ...
PMID:Enhancement of anti-DNA topoisomerase I autoantibody response after lung cancer in patients with systemic sclerosis. A report of two cases. 863 Jan 22


1 2 3 Next >>