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)

The MRL mouse strain spontaneously produces antinuclear autoantibodies that recognize DNA and the small nuclear ribonucleoprotein (snRNP) antigens. The monoclonal antibody 2.73 was derived from the lupus prone MRL/n line and is reactive with the 70K protein of the U1 snRNP particle. The epitope recognized by 2.73 was characterized by peptide and inhibition ELISA analysis. Several arginine/aspartic acid (RD) repeats of varying lengths are found in the carboxyl terminus of the 70K protein and are responsible for immunoreactivity with 2.73. We investigated the contribution of charge and found that the immunoreactivity of 2.73 and the 70K protein is specific for the RD repeats. The presentation of the epitope may also contribute to the epitopes immunoreactivity with the 2.73 mouse monoclonal autoantibody.
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PMID:Immunochemical analysis of an arginine-rich systemic lupus erythematosus autoepitope. 750 33

Two mouse cDNA clones were isolated by immunoscreening with an SLE serum. These clones encode an epitope which consists of a di-peptide repeat (Gly-Arg)n (n = 9 and 19 in isolated clones). These sequences, when expressed as fusion proteins, inhibit the binding of antibodies from one patient's serum to the SmD autoantigen. This cross-reactivity is based on the sequence identity with the carboxyterminal end of the human SmD [(Gly-Arg)g]. An Exonuclease III deletion analysis demonstrates that the minimal number of Gly-Arg repeats necessary for immune recognition on the Western blot is patient-specific, and varies from nine to three. The defined epitope is recognized by 35% of sera from patients with SLE as well as with other autoimmune diseases (rheumatoid arthritis, scleroderma, Sjogren's syndrome), in contrast to SLE-specificity of anti-Sm antibodies. Affinity-purified antibodies of the identified epitope cross-react with EBNA1 protein in EBV-infected B-cell lines.
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PMID:A heterogeneous immune response to an SmD-like epitope by SLE patients. 751 43

Immunoreactivity of the arginine/aspartic acid (RD) repeats of the 70K protein of U1 small nuclear ribonucleoprotein (snRNP) was determined to be conformationally dependent. The monoclonal autoantibody 2.73, isolated from a lupus-prone MRL/n mouse model, is reactive with the RD repeat regions of U1 snRNP 70K protein. Immunochemical analysis of the antigenic determinants with use of chemically synthesized peptides characterized the 2.73 epitope as the RD repeat [Pelsue, S., et al. (1993) Autoimmunity, 15, 231-236] Analysis by circular dichroism (CD) and nuclear magnetic resonance spectroscopy indicates conformational preferences in the immunoreactive peptides. Computer analyses of CD spectra obtained on the RD-containing peptides predict beta-turns and beta-sheet to be the preferred conformations of the RD repeats. This structure was also predicted by the Chou-Fasman algorithm. The RD repeat is believed to be a conserved structural motif; however, the biological function is still unclear. Immunological and biochemical analysis of autoimmune antibodies and their respective antigenic determinants has helped to characterize the possible mechanisms that lead to autoimmune diseases. This is the first report of a conformationally dependent, linear epitope of an autoantibody.
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PMID:Immunoreactivity between a monoclonal lupus autoantibody and the arginine/aspartic acid repeats within the U1-snRNP 70K autoantigen is conformationally restricted. 752 19

Autoantibodies directed against the Sm proteins of the spliceosome complex are found in approximately 25% of systemic lupus erythematosus (SLE) patients sera. To determine which regions of the Sm D polypeptide are involved in the lupus autoimmune response, binding to overlapping octapeptides of Sm D has been evaluated with sera from nine Sm D-positive patients, six patients with other autoimmune serology, and five normal human sera. Lupus patient sera which are Sm precipitin-positive bind various combinations of five regions of the peptide. The major antigenic region, Epitope 5 (REAVA(GR)10GGPRR), is bound by eight of nine Sm precipitin-positive sera tested. This region of Sm D shows significant sequence homology with Epstein-Barr nuclear antigen-1. To determine the fine specificity of the murine Sm response, four unique Sm D MoAbs derived from MRL lpr/lpr mice and three adult anti-Sm-positive MRL lpr/lpr mouse sera have been analysed. Two of these monoclonals, KSm 4 and Y12, as well as the MRL lpr/lpr sera tested, show binding with Epitope 5. Another of these monoclonals, KSm 2, binds octapeptides 84-91, DVEPKVKSKKREAVAG, which corresponds to Epitope 4 of this study. Antibodies from SLE patients with autoimmune serology other than anti-Sm bind the carboxyl glycine-arginine repeat (GR)10 peptides of Sm D. However, none of the antibodies tested from patients who do not have lupus and who have different autoimmune serology binds any of the Sm D octapeptides. Normal controls did not significantly bind any of the Sm D octapeptides. These results describe two major regions of shared antigenicity of Sm D between sera from SLE patients and MRL lpr/lpr mice, thereby establishing a basis for the cross-species similarity of autoimmunity to the Sm autoantigen in SLE.
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PMID:Sequential autoantigenic determinants of the small nuclear ribonucleoprotein Sm D shared by human lupus autoantibodies and MRL lpr/lpr antibodies. 752 40

Identification of the immunochemical and structural properties of pathogenic anti-DNA antibodies is a major goal for understanding their origins and the mechanisms whereby they induce tissue lesions. Herein, we report on the production of an IgG2a,k anti-DNA monoclonal antibody (4B1), derived from a 12-month-old (NZB x NZW)F1 lupus mouse, able to form glomerular immune deposits. mAb 4B1 is a polyspecific antibody able to bind to ssDNA, actin, tubulin, cardiolipin and to laminin as shown by solid phase ELISAs. Indirect immunofluorescence labeling of HEp-2 cells gave a cytoplasmic staining pattern similar to that obtained with anti-cytoskeleton antibodies. Western blot analysis demonstrated that mAb 4B1 bore idiotype D23, previously shown to be characteristic of natural antibodies derived from normal mice. After injecting the 4B1-secreting hybridoma intraperitoneally into normal (NZW x BALB/c)F1 mice, glomerular immune deposits were observed along the capillary wall. These deposits contained mainly IgM, IgG2a and mAb 4B1, as demonstrated by direct immunofluorescence using a biotinylated-rat anti-4B1 idiotype mAb and kidney eluate analysis. Nucleotide sequence analysis of the VH and VL genes showed that mAb 4B1 is encoded by VH Q52, DSP2.9 and JH2 genes with minimal mutations and by VK8 very similar to the canonic D23 light chain, and JK1 germline genes. No arginine residues were observed in the VH CDR and both chains lacked N-segment addition. Thus, no structural characteristics deduced from the primary structure of mAb 4B1 could explain its pathogenic potential. However, the immunochemical and structural properties suggest that autoantibodies closely related to natural autoantibodies may be pathogenic.
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PMID:An idiotype D23-bearing polyspecific, murine anti-DNA monoclonal antibody forms glomerular immune deposits. Pathogenic role of natural autoantibodies? 754 Feb 57

Ascaris hemoglobin consists of eight subunits, each of which contains a C-terminal peptide with the sequence Glu-Glu-Lys-His repeated four times. When plotted on a beta-strand, this sequence leads to alternate lysines and glutamates on one side of the strand, and alternate glutamates and histidines on the other side, suggestive of a polar zipper which links the subunits together. A computer search of the protein database showed that the same or similar sequences also occur in other proteins. Some contain long repeats of Asp-Arg or Glu-Arg, among them the small nuclear ribonucleo-U1 70K protein which is an autoantigen in Systemic Lupus Erythematosis. These repeats appear to constitute the dominant epitopes in the autoimmune reaction. Single chains with Asp-Arg repeats may form alpha-helices in which alternate positively charged ridges and negatively charged grooves compensate each other. Several separate chains with Asp-Arg repeats could compensate each other's charges optimally by zipping together to beta-sheets. Several homeodomains of Drosophila as well as the human transcription factor SP1 contain repeats of glutamines. Molecular modelling, circular dichroism, electron and X-ray diffraction studies of a synthetic poly(L-glutamine) showed that it forms beta-sheets held together by hydrogen bonds between the main chain and side chain amides. Published data suggest that the function of these glutamine repeats consists in joining essential transcription factors bound to distant segments of DNA. The study of the structure and function of glutamine repeats has assumed medical importance with the discovery that Huntington's Disease and four other dominantly inherited diseases are associated with a lengthening of glutamine repeats in the proteins coded for by the affected genes.
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PMID:Polar zippers: their role in human disease. 765 65

In the present experiments, two groups of BALB/c mice (five individuals in each group) were hyperimmunized through four consecutive immunizations with either BK virus (Group 1) or BK dsDNA complexed with methylated BSA (Group 2). All immune sera taken after the fourth immunization from both groups reacted strongly with polyomavirus BK dsDNA as well as with calf thymus dsDNA, and all sera contained antibodies that bound in the Crithidia luciliae assay. This indicates that polyomavirus BK was able to induce antibodies with binding characteristics similar to SLE anti-DNA antibodies. To further characterize these induced anti-DNA responses, 10 monoclonal anti-DNA antibodies (four from Group 1, and six from Group 2) were generated and selected for reactivity with S1-nuclease digested CT dsDNA. Their specificity for BK and CT dsDNA molecules, as well as their light and heavy chain variable region cDNA nucleotide sequences were analysed to compare them with known SLE derived anti-DNA antibodies. All of the 10 antibodies bound strongly to BK dsDNA, while seven also bound to CT dsDNA in competitive ELISA experiments. V-region analysis revealed that the induced antibodies resembled anti-DNA antibodies characteristic for murine SLE, and all but one contained arginine in the VH CDR3 region. The arginines present in the monoclonal antibodies originated either from an RF shift from RF1-->RF3 of the D-genes or from N-sequence additions. Taken together, the data demonstrate that anti-DNA antibodies in response to hyperimmunization with polyomavirus BK have the same characteristics as of those occurring spontaneously in SLE. As virus infection/replication in vivo implies expression of immunogenic (non-self) DNA-binding proteins that may render DNA immunogenic, the present results may therefore suggest one physiological mechanism for production of SLE-related anti-DNA antibodies.
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PMID:Molecular analyses of anti-DNA antibodies induced by polyomavirus BK in BALB/c mice. 777 Jul 29

Ascaris hemoglobin consists of 8 subunits, each of which contains a C-terminal peptide with the sequence Glu-Glu-Lys-His repeated 4 times. When plotted on a beta-strand, this sequence leads to alternate lysines and glutamates on one side of the strand, and alternate glutamates and histidines on the other side, suggestive of a polar zipper that links the subunits together. A computer search of the protein database showed that the same or similar sequences also occur in other proteins. Some contain long repeats of Asp-Arg or Glu-Arg, among them the small nuclear ribonucleo-U1 70K protein, which is an autoantigen in systemic lupus erythematosis. These repeats appear to constitute the dominant epitopes in the autoimmune reaction. Single chains with Asp-Arg repeats may form alpha-helices in which alternate positively charged ridges and negatively charged grooves compensate each other. Several separate chains with Asp-Arg repeats could compensate each other's charges optimally by zipping together to beta-sheets. Several homeodomains of Drosophila, as well as the human transcription factor SP1, contain repeats of glutamines. Molecular modeling, circular dichroism, and electron and X-ray diffraction studies of a synthetic poly(L-glutamine) showed that it forms beta-sheets held together by hydrogen bonds between the main-chain and side-chain amides. Published data suggest that the function of these glutamine repeats consists of joining essential transcription factors bound to distant segments of DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polar zippers: their role in human disease. 784 80

Among B/W-derived IgM mAb, 12.5H was selected because of its ability to recognize, in solid phase ELISAs, IgG mAb with DNA-binding activity. mAb 12.5H bound preferentially to IgG2a mAb and did not react with B/W- or BALB/c-derived IgG2a mAb with no DNA-binding activity, suggesting V region-mediated interactions. mAb 12.5H also bound to IgG2a isolated from the sera of old B/W mice but did not react with Ig present in the sera of young B/W (< 6 months) or BALB/c mice. Further analysis of IgM/IgG interaction showed that the binding of 12.5H to IgG polyclonal anti-DNA antibodies could be inhibited by DNA and that mAb 12.5H bound to the F(ab')2 fragments of B/W-derived IgG2a anti-DNA mAb, demonstrating that the interaction occurred through the variable regions of the molecules. When the antigen-binding capacity of mAb 12.5H was evaluated, it was demonstrated to bind to self-antigens such as myosin, actin, tubulin and histones, to bind poorly to ssDNA and not to react with dsDNA. mAb 12.5H gave a cytoplasmic staining pattern by indirect immunofluorescence on HEp-2 cells. Nucleotide sequence analysis of the H and L V genes showed features previously demonstrated to be recurrent in two categories of SLE autoantibodies, i.e. arginine residues in the VHCDR3 and at position 96 on the light chain, both considered to be characteristic of antibodies reacting with dsDNA and acidic amino-acid residues in VHCDR2 reported to be frequent on antihistone antibodies. Taken together, these results show that the B/W mouse repertoire contains IgM autoantibodies: (i) that react in an idiotypic manner with DNA binding antibodies and (ii) that, because of structural characteristics, may constitute the common precursor of different categories of SLE autoantibodies, and the prototype of the idiotypically connected SLE autoantibodies accounting for the production of autoantibodies upon immunization with cognate idiotype and the experimental model of cross-idiotype-induced lupus.
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PMID:Structural characterization of an (NZB x NZW)F1 mouse-derived IgM monoclonal antibody that binds through V region-dependent interactions to murine IgG anti-DNA antibodies. 788 30

The ability of immunoglobulins (Ig) G, A and M to bind to amino acids was studied in 27 patients with rheumatism (R), 28 with rheumatoid arthritis (RA) and 27 patients with systemic lupus erythematosus (SLE) with minimum degree of activity. The enhancement of the binding capacity of IgG with respect to arginine, glutamic acid, lysine and decrease of that of IgM towards serine was established to be of diagnostic value in R as was the enhancement of the above capacity of IgG and A with respect to proline and oxyproline in RA and enhancement of that of Ig of all three classes with respect to a broad range of amino acids in SLE. Information criteria were established of differential diagnosis of R, RA and SLE.
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PMID:[The differential diagnostic significance of the binding capacity of serum immunoglobulins with amino acids in rheumatism, rheumatoid arthritis and systemic lupus erythematosus with a minimal degree of activity]. 807 10


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