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)

A lupus-like disease characterized by a severe immune complex glomerulonephritis and IgG autoantibody production was induced in (C57BL/6 X DBA/2)F1 mice by injection of parental DBA/2 lymphoid cells. The ensuing graft-vs-host (GVH) reaction resulted in a 10- and a 100-fold increase in serum IgG antibody levels to denatured DNA and total histones, respectively, compared with that in F1----F1 control mice. The level of anti-DNA antibodies peaked 2 wk after injection of DBA/2 cells and preceded peak anti-histone levels by approximately 2 wk. Anti-histone antibodies were generated predominantly to histones H1, H2A, and H2B, a profile different from that observed in NZB/NZW and MRL-lpr/lpr mice. The marked increase in IgG antinuclear antibodies did not correlate with increases in total IgG serum levels and was not associated with comparable increases in antibodies to transferrin, hemoglobin, fibrinogen, or thyroglobulin. Selective autoantibody production was also observed in vitro, wherein GVH spleen cells produced high levels of IgG antibodies to total histones and denatured DNA but not to these non-nuclear protein antigens. In contrast, spleen cells stimulated in vitro with lipopolysaccharide produced equivalent amounts of antibodies to all antigens tested. Our results are in agreement with those of other investigators and collectively suggest that IgG autoantibodies in GVH disease, and possibly in spontaneous lupus-like disease, are not secondary to a generalized B cell activation, but may be selectively generated in response to self antigens with unique configurational properties.
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PMID:Autoimmunization in murine graft-vs-host disease. I. Selective production of antibodies to histones and DNA. 387 58

Cross-reactivity of a monoclonal rheumatoid factor with an antigen present on IgG and DNA-nucleoprotein was demonstrated, and evidence presented that the combining site of the antibody was involved in the reaction. The antigen on the DNA-nucleoprotein was shown to involve both DNA and histone fraction H2A + H2B and was trypsin sensitive. The relative binding affinity of the antibody appeared to be greater for IgG than the DNA-histone antigen. Similar polyclonal cross-reactive rheumatoid factors were found in a variety of diseases. A high incidence was found among patients with rheumatoid arthritis and mixed connective tissue disease. None were detected in patients with systemic lupus erythematosus and idiopathic cryoglobulinemia. Studies on one representative isolated polyclonal rheumatoid factor demonstrated the same reactivity with DNA-histone H2A + H2B as the monoclonal antibody. Cross-idiotype studies using antigen-binding inhibition methods demonstrated the same cross-idiotype on the polyclonal and the monoclonal rheumatoid factor which reacted with DNA-histone. This cross-idiotype was shown to be distinct from the cross-idiotypes previously demonstrated on monoclonal IgM proteins with anti-gamma-globulin activity.
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PMID:Evidence for a subset of rheumatoid factors that cross-react with DNA-histone and have a distinct cross-idiotype. 615 24

Sera of some patients with systemic lupus erythematosus and related diseases contain a polyclonal antibody population (cross-reactive antinuclear antibodies [X-ANA]) that react specifically with both core mononucleosomes and plasma membranes of viable nucleated cells. Native mononucleosomes and nucleosome cores assembled from long DNA and the inner histones were indistinguishable in terms of inhibition of binding of X-ANA to nuclei of tissue sections and to polynucleosomes on the walls of plastic tubes. In contrast, mononucleosomes selectively depleted of histones H2A and H2B did not inhibit these reactions. A method was developed for isolation of X-ANA from serum that took advantage of the dual specificity of these antibodies. Immunosedimentation in sucrose density gradients revealed that 125I-labeled Fab' fragments of highly pure X-ANA formed complexes with the inner histones H2A, H2B, H3, and H4 in 2 M NaCL, but not in 0.15 M salt. These results indicate that X-ANA recognize an epitope of the inner histone in 2 M salt, and that in 0.15 M NaCL this epitope is not formed unless the histones interact with DNA to generate a nucleosome structure. Furthermore, in light of the previous demonstration that the epitope is destroyed by trypsin, it may be localized in the N-terminal region of histone H2A or H2B.
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PMID:Human autoantibodies that react with both cell nuclei and plasma membranes display specificity for the octamer of histones H2A, H2B, H3, and H4 in high salt. 616 Dec 2

Fusion of spleen cells from autoimmune NZB/NZW female mice with drug-resistant myeloma cells (clones NSI/1, X63-Ag8.653 and NSO/1) produced hybrid clones which secreted antibodies to various nuclear components. Roughly 50% of the anti-nuclear hybridomas produced antibodies reacting with DNA, 20% with RNA and 30% reacted with other nuclear antigens. Two hybridomas of the latter group were cloned and studied in detail. They secreted antibodies which produced bright fluorescence staining of nuclei and metaphase chromosomes. The specificity of the antibodies was determined by testing them in an enzyme-linked immunosorbent assay and a radioimmunoassay against individual acid- and salt-extracted histones, against histones mixed two and three at a time and against histone complexes isolated as such from chromatin. One of the monoclonal antibodies was specific for histone H2B and reacted with the histone free in solution or when present as a H2A-H2B complex. The second monoclonal antibody recognized a specific conformation in the H3-H4 complex that was present only when the complex was obtained from chromatin by salt extraction. The same conformation, however, could be induced by adding histone H2B to a mixture of acid-extracted H3 and H4. Our findings show that the autoimmune syndrome in NZB/NZW mice resembles human systemic lupus erythematosus not only in the incidence of antibodies to DNA and RNA, but also in the production of autoantibodies to histones.
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PMID:Monoclonal autoantibodies to histones from autoimmune NZB/NZW F1 mice. 619 84

We characterized three monoclonal antibodies with histone reactivity which were derived from spleen cells obtained from unmanipulated NZB/NZW or MRL/1 mice. By using an enzyme-linked immunosorbent assay, we noted that all three antibodies reacted with chromatin histones as well as with total histones extracted from chromatin. None of the antibodies appeared to require DNA as part of the antigen. One antibody (BWH-1) recognized a determinant present in the nucleosome core H2A-H2B complex but showed little reactivity with any of the individual histones (H1, H2A, H2B, H3, or H4). In contrast, the other two monoclonal antibodies each recognized multiple individual histones in a unique pattern. Antibody MH-1 reacted with H2A, H2B, and H3; antibody MH-2 reacted with H2A, H3, and H4. MH-1 demonstrated cross-reactivity with poly-1-lysine but not poly-1-arginine or protamine sulfate; the opposite pattern of cross-reactivity was observed with MH-2. The antigenic determinants recognized by MH-2 were all trypsin-sensitive, suggesting that these determinants were present on the N-terminal regions of the respective individual histones. These studies revealed markedly different specificities of anti-histone monoclonal antibodies derived from murine models of systemic lupus erythematosus. These and other similarly derived antibodies may provide interesting tools to understand the specificity and biologic importance of anti-histone autoantibodies in different diseases.
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PMID:Monoclonal anti-histone autoantibodies derived from murine models of lupus. 633 55

By the technique of immunoblotting we have assessed the ability of sera from 24 patients with systemic lupus erythematosus to bind nuclear proteins. Of the 11 patients who had antibodies to histones, 10 had antibodies to histone H1 and 9 of these also had antibodies to histone H2B. Antibodies to the other histones (H2A, H3, and H4) were less apparent. Five of the 11 patients (and two others in the remainder of the sample of 24) also had antibodies to a small number of nonhistone proteins that are probably components of ribonucleoprotein particles, but there was no obvious correlation between the presence of antihistone antibodies and the known antiribonucleoprotein activity of these sera. Separate determinants on H1 and H2B were demonstrated by immunoblotting with affinity-purified anti-H1 and anti-H2B antibodies derived from serum that showed both specificities. The localization of the determinants within the histone polypeptide chains was shown by immunoblotting with large fragments produced by specific proteolytic or chemical cleavage of the histones. The strongest determinant on H1 was located within the COOH-terminal half, with a weaker determinant being present within the NH2-terminal half; the H2B determinant(s) was located entirely within the NH2-terminal half of the molecule. The selectivity with which the antihistone antibodies in systemic lupus erythematosus are produced against the more exposed histones in the nucleosome (and perhaps against the most exposed regions of these histones) is consistent with the involvement of intact chromatin structures as immunogens in this disease.
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PMID:Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B. 658 63

An enzyme-linked immunosorbent microassay (micro-ELISA) was improved for the detection of anti-histone antibodies. Detection of these antibodies in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerodermitis sclerosis (SCL), showed a positive correlation between the presence of antinuclear antibodies detected by indirect immunofluorescence and the level of anti-histone antibodies (p less than or equal to 0.02) having anti-H1 (p less than or equal to 0.001) and anti-H2B (p less than or equal to 0.01) specificities. These antibodies were more frequently detected, and at a higher level, in human SLE than in RA and SCL. Anti-H1 and anti-H2B (and less frequently anti-H3) antibodies were also found in mice with lupus-like syndrome (MRL/1, PN and Swan). Their level rose with age and they were prevalent in the severe forms, especially in MRL/1 and PN.
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PMID:Detection of antibodies to histones in human systemic lupus erythematosus and in murine lupus-like syndromes using micro-ELISA. 660 9

Anti-histone antibodies have been demonstrated in the sera of patients with both idiopathic and drug-induced lupus. We measured anti-histone antibodies in female NZB/NZW (F1) mice, which are considered to be a model of human SLE. Using a sensitive and quantitative enzyme-linked immunosorbent assay (ELISA), we detected minimal serum antibody activity in NZB/NZW mice younger than 4 mo of age and in nonautoimmune mice at all ages tested. Serum anti-histone antibodies progressively increased in NZB/NZW mice from 4 to 8 mo of age and showed an age-related maturation from IgM to IgG. The predominant antibody activity in the older mice was to the individual histones H2B and H3, and the pattern of reactivity to the histone proteins was similar to that seen in human SLE. We also studied the spontaneous in vitro production of anti-histone antibodies using spleen cells from NZB/NZW mice of different ages. Culture supernatants were analyzed for antibody activity by an ELISA with total histones as the antigen. Spleen cells from older NZB/NZW mice, with elevated serum levels, produced 10-fold higher levels of antibody activity compared to age-matched nonautoimmune mice. Antibody production was maximal at 4 days of culture and was inhibited by the addition of puromycin to the culture. Surprisingly, spleen cells from 1 to 3-mo-old NZB/NZW mice, with normal serum levels, also demonstrated significantly elevated production. The antibodies produced by these young mice were mostly IgM, whereas spleen cells from older mice produced mostly IgG anti-histone antibodies. The present results provide the basis for using the anti-histone antibody system to study further the immune abnormalities that allow for autoantibody production.
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PMID:In vivo and in vitro production of anti-histone antibodies in NZB/NZW mice. 686 18

Dogs can develop systemic lupus erythematosus syndromes that are clinically similar to those seen in humans. In contrast, previous observations suggest differences in their autoantibody reactivity patterns against histones and DNA which are components of the nucleosome in chromatin. The objective of this study was to assess comprehensively the levels of autoantibodies against histone, DNA and nucleosome antigens in a population of lupus dogs. The specificities of antibodies in lupus and control dog sera were determined using IgM- and IgG-specific reagents in an ELISA against a variety of chromatin antigens. When compared with control sera, IgG antibodies to individual histones H1, H2A, H3 and H4 were significantly higher in the lupus group. In contrast, we did not detect IgG antibodies specific for H2B, H2A-H2B, DNA, H2A-H2B-DNA or nucleosome in lupus dogs. There was no significant increase in any of the IgM specificities tested. Therefore, the reactivity pattern to nucleosome antigens in canine lupus is restricted to IgG antibodies against individual histones H1, H2A, H3 and H4. This stands in contrast with human and murine lupus, where autoantibodies are directed against a wide variety of nucleosomal determinants, suggesting that unique mechanisms lead to the expansion of anti-histone antibody clones in canine lupus. The high incidence of glomerulonephritis in dog lupus suggests that anti-DNA antibodies are not required for the development of this complication, whereas IgG anti-histone antibodies may be relevant to its pathogenesis.
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PMID:Autoantibodies to histone, DNA and nucleosome antigens in canine systemic lupus erythematosus. 752 50

A retrospective study of tuberculosis patients treated with isoniazid was undertaken in order to establish the prevalence and specificity of antibodies against histones, chromatin and denatured DNA. Each patient had an average of 2.7 +/- 0.4 antibody activities out of the 8 tested antigens using ELISA. These reactivities tended to be higher for non-native forms of the antigens such as denatured histones and DNA with essentially no reactivity to the (H2A-H2B)-DNA subunit of chromatin. Greater than half of the patients were isotype restricted to only IgA or IgM antihistone antibodies, and IgA antihistone antibodies were the most common and reactive. Thirty-five percent of the patients had elevated levels of one or more immunoglobulin classes, and the IgA level was strongly correlated with IgA antihistone activity. These results suggest that isoniazid treatment results in modest increases in antihistone antibodies of the specificities and class typical of drug-induced autoimmunity in the absence of lupus-like disease. The IgA antihistone predominance suggests that serum antoantibodies may be the consequence of stimulation by isoniazid of lymphocytes in the gut-associated Peyer's patches or intestinal lymphoid follicles.
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PMID:IgA antihistone antibodies in isoniazid-treated tuberculosis patients. 757 66


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