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 Ku (p70/p80) autoantigen, a heterodimer consisting of 70 kDa (p70) and 80 kDa (p80) protein subunits, is one of a group of DNA-associated autoantigens identified as targets of autoantibodies produced by patients with SLE and related disorders. Many of these DNA-protein antigens are involved in organizing the genome into transcriptionally active (euchromatin) and inactive (heterochromatin) domains. The bulk of available evidence indicates that the Ku antigen is also involved in organizing the genome, although its precise role remains unclear. Molecular cloning of the protein subunits of Ku has revealed that the structure of p70 resembles that of certain transcriptional activator proteins, and there is some evidence in vitro that Ku may increase transcriptional activity from at least two promoters. Moreover, examination of the distribution of Ku in the polytene chromosomes of insects suggests an association with transcriptionally active chromatin. The DNA-binding domain of Ku has been localized to the C-terminus of p70, whereas p80 does not appear to bind DNA, and may be involved in interactions with other proteins. Epitope mapping and mutagenesis experiments have shown that the immunodominant epitope of p70 lies within the DNA-binding domain. Surprisingly, this autoepitope is not conserved between humans and mice, raising the possibility that the interaction of Ku with DNA might exhibit species specific functional differences. At least seven additional autoepitopes have been identified on the Ku particle, located on p70, p80, or both subunits. Autoantibodies to p70, p80, and DNA are produced tandemly by patients with SLE, providing evidence for an antigen-driven immune response targeting the entire Ku particle. The multiple specificities of anti-Ku autoantibodies and the tandem production of antibodies to the various constituents of the Ku particle are consistent with a role of either "molecular mimicry" or "intermolecular help" in the generation of autoimmunity to this antigen.
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PMID:Antibodies to the p70/p80 (Ku) antigens in systemic lupus erythematosus. 162 75

The Ku (p70/p80) autoantigen is a DNA-protein complex recognized by sera from certain patients with SLE and related diseases. Although human autoantibodies react with at least eight different epitopes of the human Ku complex, they had little reactivity with rodent Ku Ag on immunoblots. Small amounts of 70- and 80-kDa proteins were immunoprecipitated from murine cell extracts, however, suggesting that the Ku particle is not unique to human cells. This was confirmed by isolating cDNA clones encoding murine Ku Ag by plaque hybridization with a human p70 cDNA probe. The murine p70 cDNA clones had a deduced amino acid sequence 82.9% identical to that of human p70, and comparable amounts of murine and human p70 mRNA were detected in 3T3 and K562 cells, respectively. The poor reactivity of human autoantibodies with murine p70 was attributable to specific amino acid substitutions in an immunodominant conformational epitope located on amino acids 560-609 of human p70. Several amino acids critical for antigenicity of this region were defined by mutagenesis studies. Other conformational epitopes of Ku were also antigenically poorly conserved among species. Species-specific epitopes recognized by lupus autoantibodies are unusual but not unique to Ku. In general, poorly conserved autoepitopes have been conformational, rather than sequential, suggesting that the antigenicity of conformational epitopes may be particularly sensitive to evolutionary change.
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PMID:Antigenic determinants of the Ku (p70/p80) autoantigen are poorly conserved between species. 170 85

High titer autoantibodies to the Ku Ag, a DNA-protein complex containing 70- and approximately 80-kDa protein subunits (p70 and p80, respectively), are found in sera of certain patients with systemic lupus erythematosus and related disorders. Autoepitopes of the Ku Ag were identified and partially characterized by expressing fragments of the p70 and p80 cDNA as fusion proteins in bacteria. Systemic lupus erythematosus sera reacted on immunoblots with at least three epitopes of p70 (amino acids 560-609, 506-535, and 115-467), and three epitopes of p80 (amino acids 682-732, 558-681, and 1-374). These six antigenic regions had distinct amino acid sequences, and were also immunologically distinct, as determined by using immunoaffinity-purified auto-antibodies to particular epitopes. Detailed mapping of the strongly antigenic region near the C terminus of p70 revealed a complex conformational or discontinuous epitope, the antigenicity of which was abolished by deleting either amino acids 560-571 or 601-609. The C terminus of p80 may also contain a discontinuous or conformational epitope(s). Although only some sera reacted with p70 or p80 on immunoblots, all sera that immunoprecipitated the native Ku complex reacted with native Ku by ELISA, and inhibited the binding of mAb directed at epitopes of native Ku. Taken together, these studies indicate that anti-Ku autoantibodies target a diversity of independent epitopes located on p70, p80, and the intact Ku complex, and that a significant portion of the autoantibodies in most patients' sera is directed against conformational/discontinuous epitopes.
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PMID:Epitopes of the p70 and p80 (Ku) lupus autoantigens. 170 16

Anti-Ki (Ku, p70/p80) autoantibodies, named after the prototype patient Kikuta by Tojo et al., occur in approximately 10% of patients with SLE, often in association with anti-Sm autoantibodies. The immunofluorescent staining pattern characteristic of anti-Ki antibodies is diffuse speckled nuclear, although some substrates show nucleolar staining as well. Anti-Ki sera specifically immunoprecipitated two protein antigens, Ki86 (Mr 86,000) and Ki66 (Mr 66,000), from radiolabeled cell extracts. The Ki system was found to be immunologically identical to the Ku system described by Mimori et al. and the p70/p80 system described by Reeves. The Ki primary in vitro translation products were identified and proved similar in size to the cellular antigens. The Ki antigens were purified from human spleen by immunoaffinity chromatography followed by SDS-PAGE. The purified Ki antigens proved to be closely related by amino acid composition, and did not appear to be phosphorylated, glycosylated, or associated with RNA. The Ki antigens were found to bind to DNA, in agreement with the observations on the Ku and p70/p80 antigens. They were found to be widely conserved in mammals and were coordinately expressed in all tissues tested. Anti-Ki autoantibodies were purified by antigen-affinity chromatography and were tested by immunoblotting. The antibodies were classified as class I, II, or III, depending on their reactivity with the Ki antigens in immunoblots. Class I antibodies cross-reacted with both Ki antigens, class II antibodies reacted solely with Ki66, and class III antibodies reacted solely with Ki86. These results suggest that at least three different epitopes are present on the Ki autoantigens and that patients differ in their autoantibody response to each epitope.
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PMID:Identification of Ki (Ku, p70/p80) autoantigens and analysis of anti-Ki autoantibody reactivity. 241 10

The Ku (p70/p80) autoantigen consists of two phosphoproteins of molecular mass approximately 70,000 and 80,000 forming a macromolecular complex that binds DNA. Autoantibodies from a patient with systemic lupus erythematosus were used to isolate cDNA clones encoding the human approximately 70-kDa Ku antigen (p70) from a lambda gt11 expression library. The deduced amino acid sequence of p70 consisted of 609 amino acid residues and was confirmed by partial amino acid sequencing. The protein contains two acidic domains of 61 residues (31% Glu + Asp) and 19 residues (53% Glu + Asp) that are similar in size and charge to those found in a number of proteins involved in transcriptional activation. The 61-residue acidic region is rich in serine, raising the possibility that its charge might be modulated by phosphorylation. The predicted amino acid sequence also contains two regions with periodic repeats of either leucine alone, or leucine alternating with serine every seventh position. The latter repeat displays sequence and secondary structural similarities with the "leucine zipper" regions of the c-myc and v-myc oncogene products. The p70 antigen does not appear to have extensive sequence homology with the 80-kDa Ku autoantigen based on analysis of RNA blots and immunological criteria. A major antigenic determinant or determinants recognized by human autoantibodies is located near a leucine repeat on the carboxyl-terminal 190 amino acid residues of p70.
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PMID:Molecular cloning of cDNA encoding the p70 (Ku) lupus autoantigen. 246 42

Levels of anti-Ku (p70/p80) antibodies were measured longitudinally in sera from four individuals with systemic lupus erythematosus or related disorders. Antibodies to the native Ku antigen (p70/p80 complex) varied over a range of up to 577-fold. Large fluctuations were also observed in the levels of autoantibodies to several distinct epitopes of the Ku (p70/p80) antigen. Levels of these individual autoantibody populations generally paralleled one another, suggesting that they are coordinately regulated. A similar pattern of anti-DNA antibody fluctuation was seen in some sera. To examine the possibility that these autoantibodies were generated by polyclonal B cell activation, the levels of anti-Ku (p70/p80) and anti-DNA antibodies were compared to the levels of antibodies to Escherichia coli proteins, tetanus toxoid, and bovine insulin, transferrin, cytochrome c, serum albumin, and thyroglobulin. In sera from the same individual, anti-Ku (p70/p80) antibodies were sometimes produced in the complete absence of polyclonal activation, and at other times were accompanied by increased polyclonal activation. Anti-DNA antibody levels more closely paralleled the level of polyclonal activation than did the anti-Ku (p70/p80) levels. These studies suggest that anti-Ku (p70/p80) antibodies are generated by an antigen-selective mechanism, but that polyclonal activation frequently, although not invariably, accompanies autoantibody production. This observation is consistent with the possibility that polyclonal activation might be secondary to autoantibody production.
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PMID:Role of antigen selectivity in autoimmune responses to the Ku (p70/p80) antigen. 252 51

Serum samples from 94 patients with systemic lupus erythematosus (SLE) from a medical unit in Singapore were analysed for autoantibodies of 10 different specificities. The prevalence of antibodies to the following antigens was as follows: double stranded (ds) DNA (43%), histone (81%), Sm (26%), nuclear ribonuclear protein (nRNP) (32%), SS-A(Ro) (63%), SS-B(La) (12%), SL/Ki (9%), ribosomal RNP (rRNP) (16%), p70/p80 (5%), proliferating cell nuclear antigen (PCNA) (3%). Except for a higher prevalence of anti-SS-A(Ro), other autoantibodies were within the range reported from Western countries, indicating a high uniformity of autoantibody profiles in SLE in different countries. Patients with neuropsychiatric manifestations showed a higher plurality of antibodies per patient than patients without neuropsychiatric symptoms, 4.22 v 2.77. Patients with anti-Sm were more likely to have active lupus disease. There was no increased prevalence or specific type of autoantibody in those with renal manifestations.
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PMID:Clinical and autoantibody correlations in Orientals with systemic lupus erythematosus. 326 94

We have previously shown that sera from some patients with SLE and related disorders contain autoantibodies to a DNA-binding protein complex designated p70/p80. The present study shows that anti-p70/p80 autoantibodies are frequently accompanied by anti-DNA antibodies and cryoglobulins. When the cryoglobulins were isolated, they were found to be specifically enriched in both anti-p70/p80 and anti-DNA activities. The anti-p70/p80 and anti-DNA antibodies were found to be distinct populations of autoantibodies rather than a single crossreactive species, since they could be separated from one another by chromatography on DNA-cellulose. Certain human anti-DNA mAbs could inhibit the binding of autoimmune polyclonal anti-p70/p80 antibodies to p70/p80, suggesting that anti-DNA antibodies might also associate with the variable regions of some anti-p70/p80 antibodies in the cryoglobulins. Binding of one murine anti-p70/p80 mAb (111-12) also was inhibited by certain human anti-DNA mAbs, but the binding of another murine mAb (162-11) to a different epitope of p70/p80 was not. These studies suggest that certain anti-DNA antibodies may interact with the variable regions of a population of anti-p70/p80 antibodies. The cryoglobulins found in the sera containing both anti-p70/p80 and anti-DNA antibodies may represent immune complexes consisting, in part, of idiotype and antiidiotype.
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PMID:Interaction between anti-DNA and anti-DNA-binding protein autoantibodies in cryoglobulins from sera of patients with systemic lupus erythematosus. 348 4

Certain DNA binding proteins are thought to organize the mammalian genome into distinct 3 dimensional structures, each characteristic of a given differentiated state. Autoantibodies to 2 types of DNA binding protein complexes, the nuclear lamina and p70/p80 (Ku), were identified in sera of patients with collagen vascular diseases. The intranuclear distribution, DNA binding, and behavior during mitosis of these antigens were examined using autoimmune sera and murine monoclonal antibodies. In vivo, the antigens have different intranuclear distributions and solubility characteristics. However, both antigens appear to reversibly bind to DNA during interphase and to rapidly dissociate from DNA during mitosis. Although the binding affinity of p70/p80 to DNA is heterogeneous, the interaction between p70/p80 and DNA in vitro is stable over 2 h or more. The rapid dissociation of p70/p80 from DNA during mitosis may therefore be mediated by a modification in either chromatin structure or in the p70/p80 antigen itself. Other proteins that reversibly interact with DNA, such as the lamins and nuclear pores, may have a role in the organization of DNA into transcribable euchromatin and nontranscribable heterochromatin. Autoantibodies to these proteins, and possibly those reactive with p70/p80, or other DNA binding proteins may be useful probes for studying both chromatin organization and the causes of autoimmune diseases such as systemic lupus erythematosus.
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PMID:Antinuclear antibodies as probes to explore the structural organization of the genome. 349 71

A comparative study of tyrosine phosphorylation was performed on peripheral blood lymphocytes from systemic lupus erythematosus (SLE) patients and from healthy donors. Freshly isolated SLE lymphocytes presented an elevated tyrosine phosphorylation level when compared to healthy donors lymphocytes (p = 0.005). Among all phosphorylated proteins, those called p120, p110, p80 and p55-p60 were more phosphorylated. The level of tyrosine phosphorylation of p120 and p110 proteins discriminated significantly (p = 0.0048, respectively, p = 0.02) between SLE patients and healthy donors. Lymphocytes form SLE patients and healthy donors were then stimulated by cross-linking T cell antigens (CD3, CD4, CD8) to further distinguish the signal transduction between normal and pathologic lymphocytes. No statistical differences in the tyrosine phosphorylation pattern, following CD4 or CD8 cross-linking, were observed between SLE patients and healthy donors lymphocytes. CD3 cross-linking induced an effect on tyrosine phosphorylation different in SLE patients versus healthy donors lymphocytes. Thus, the lymphocytes of SLE patients were refractile in anti-CD3 stimulation in comparison with the healthy donors lymphocytes. Chi-square analysis demonstrated that a significantly larger number of healthy donors responded to anti-CD3 stimulation compared to SLE patients (p = 0.03). The high frequency of tyrosine phosphorylation of p110 and p80 proteins, following CD3 stimulation, in normal versus SLE lymphocytes, suggested that these proteins could be involved in abnormal signal transduction in SLE cells.
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PMID:Tyrosine phosphorylation in peripheral lymphocytes from patients with systemic lupus erythematosus. 914 80


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