Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antigen-binding specificity of human hybridoma-derived monoclonal autoantibodies (mAb) was analysed with mAbs derived from the spleens of two patients with active systemic lupus erythematosus (SLE). From one patient 72 mAbs (RSP clones) and from the other 173 mAbs (RT clones) were obtained. The binding specificity of these mAbs was analysed by solid- and fluid-phase ELISA against the autoantigens ssDNA, dsDNA, cardiolipin, SmRNP, histones, Sm-D and SS-B (La) synthetic peptides, and foreign antigens including bacterial polysaccharides. In addition, antinuclear antibody activity and anti-dsDNA binding were confirmed by fluorescence staining methods. Reflecting the patient's serological profile, none of the antibodies from the RSP clones reacted with ssDNA or dsDNA but 12 reacted with cardiolipin. In addition, three mAbs reacted with H4, five with U1 RNP, two with Sm-D peptides and 12 with SS-B peptides. In contrast, from the RT fusion, nine mAbs reacted with ssDNA, HI and SS-B peptides, seven with cardiolipin, four with dsDNA, two with Sm-D peptides and one each with H2A, H3 and H4. In many cases one mAb showed reactivity with more than one antigen: for example, mAb RT 72 binds to ssDNA, dsDNA, cardiolipin, H1, H4 and an Sm-D peptide; RT 6 binds to H1, SmRNP and ubiquitinated histone H2A. However, none of the antibodies showed 'across the board' polyreactivity; indeed, the selectivity of the reactions was notable and marked variation in antibody affinity was recorded. Eight of the mAbs bound to Salmonella typhimurium and two to the Klebsiella polysaccharide K-30.(ABSTRACT TRUNCATED AT 250 WORDS)
Lupus 1992 May
PMID:Antigen-binding diversity of human hybridoma autoantibodies derived from splenocytes of patients with SLE. 130 76

MRL/Mp(-)+/+ mice produce antinuclear antibodies and develop a spontaneous autoimmune syndrome with lupus-like nephritis. We obtained a panel of seven histone-reactive IgG mAb from a single MRL/Mp(-)+/+ mouse. These antibodies do not react significantly with DNA or individual histones, but bind strongly to the histone H2A-H2B dimer and even more strongly to the H2A-H2B-DNA complex. These antibodies also bind to whole nuclei when tested by immunofluorescence, indicating that they recognize an epitope accessible in chromatin. The V region sequences of these antibodies have been determined. The H chain third complementarity-determining regions of these antibodies are similar to those found in anti-DNA antibodies even though the antibodies in our panel do not react with DNA in the absence of histones, suggesting that DNA is part of the subnucleosome epitope. Several of these antibodies are clonally related, supporting the hypothesis that the activation of these clones is Ag-driven. Analysis of the sequences of these antibodies indicates that they derive from autoreactive B cells that were clonally expanded and whose V region genes have undergone numerous somatic mutations.
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PMID:Monoclonal autoantibodies to subnucleosomes from a MRL/Mp(-)+/+ mouse. Oligoclonality of the antibody response and recognition of a determinant composed of histones H2A, H2B, and DNA. 137 30

Certain drugs are a frequent source of antinuclear antibody (ANA) induction, and ANA is invariably present in the few patients who progress to the drug induced lupus syndrome. This report concerns the fine specificity of the ANA response to hydralazine, penicillamine, and sulphasalazine therapy. Using highly purified individual histones in fluorimetric assays, antihistone antibodies are always detectable, often in large amounts, but the pattern of response to individual histones is variable and not drug specific. In addition to the response to the three histones H1, H2B, and H3 reminiscent of idiopathic systemic lupus erythematosus, antibody to histone H2A predominates in some drug induced cases. Contrary to previous thought, histones are not the sole target of the antinuclear response: we also demonstrate a significant correlation between ANA titre and antibody to poly(adenosine diphosphate-ribose). Like the histones, this is a macromolecule that can bind to deoxyribonucleic acid (DNA). It is proposed that drug induced damage to chromatin leads to ANA production, while drug induced impairment of complement activity may then enable these autoantibodies to mediate the lupus syndrome.
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PMID:Antibodies to the five histones and poly(adenosine diphosphate-ribose) in drug induced lupus: implications for pathogenesis. 288 34

To evaluate the role of histones and ubiquitin in lupus nephritis, we searched for glomerular deposits of histones and ubiquitin in renal biopsy specimens from 53 patients with systemic lupus erythematosus (SLE) and 30 with non-lupus glomerulonephritis. Glomerular immunofluorescence staining revealed positive for histone H2A, H1 + H3, H4 and ubiquitin in 49.1% (26/53), 45.3% (24/53), 32.1% (17/53) and 22.6% (12/53) of the SLE patients, respectively. Non-SLE renal biopsies revealed absence of positive staining with histone H2A, H1 + H3, H4 and ubiquitin. The positive incidence of histone H1 + H3 and ubiquitin in diffuse proliferative lupus nephritis was significantly different (p < 0.01) from that in minor glomerular abnormality. Levels of CH50 in patients with glomerular deposition of histone H1 + H3 (p < 0.001) and ubiquitin (p < 0.01) were significantly lower than in patients without deposition. Levels of anti-DNA antibody in patients with glomerular deposition of histone H1 + H3 were significantly higher than in patients without deposition (p < 0.05). Only the positive incidence of glomerular deposition of ubiquitin was correlated with the histological activity index (p < 0.05). These results suggest that histones and ubiquitin may play an important role in the induction of lupus nephritis.
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PMID:Participation of histones and ubiquitin in lupus nephritis. 756 55

In lupus diseases products of chromatin catabolism released from dead cells might be involved in the induction of autoantibody and in the development of glomerulonephritis. While the pathogenic role of anti-DNA antibodies is recognized, the role of antibodies directed against structural proteins of chromatin is still questioned. IgG antibodies to histones, ubiquitin, and ubiquitinated histone H2A (UH2A) have been investigated both in plasma and in glomerular eluates of NZB x NZW and MRL-lpr/lpr mice. In NZB x NZW mice, anti-ubiquitin and anti-UH2A antibodies were detected at 8 weeks of age, simultaneously with anti-double-stranded DNA antibodies, whereas anti-histone antibodies appeared later. In MRL-lpr/lpr mice, anti-DNA antibodies were detected at 4 weeks, whereas anti-histone, anti-ubiquitin, and anti-UH2A antibodies were not detected at that age but appeared in plasma rapidly thereafter. In both strains, increased anti-histone activity was found in IgG eluted from glomeruli. These results support the suggestion that anti-histone antibodies are likely to play a pathogenic role in lupus nephritis. They also indicate that, like human lupus, murine lupus is characterized by the production of anti-ubiquitin and anti-UH2A antibodies.
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PMID:Autoimmunity to histones, ubiquitin, and ubiquitinated histone H2A in NZB x NZW and MRL-lpr/lpr mice. Anti-histone antibodies are concentrated in glomerular eluates of lupus mice. 808 47

The histone H2A-H2B dimer is a component of nucleosomes in chromatin and a frequent target of autoantibodies in spontaneous and drug-induced lupus. We obtained a panel of several lgG mAbs reacting with H2A-H2B or DNA from MRL mice which develop a spontaneous lupus-like syndrome. Several of these antibodies do not react with individual histones, but bind strongly to the H2A-H2B dimer and some bind even more strongly to the H2A-H2B-DNA complex. Moreover, these antibodies not only bind to H2A-H2B dimers in the absence of DNA, but also exhibit significant binding to DNA in the absence of histones, indicating an overlap between the anti-histone and anti-DNA specificities. The analysis of the variable region gene sequences of these antibodies shows a recurrent usage of similar VH genes, suggesting a dominant role for the heavy chain in determining binding specificity. The heavy chain third complementarity determining regions of these antibodies are also remarkable for their frequency of D-D fusions and of D segments read in unusual reading frames and for many arginine residues that may contribute to DNA binding. In addition, several antibodies obtained from an individual mouse are clonally related and some differ through somatic mutations, indicating that autoreactive clones are positively selected by nuclear antigens.
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PMID:Relationships among antinuclear antibodies from autoimmune MRL mice reacting with histone H2A-H2B dimers and DNA. 831 54

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.
Lupus 1993 Apr
PMID:Genetic, immunologic and biotransformation studies of patients on procainamide. 833 41

Using proteomic analysis, we identified candidate autoantigens specific for central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). Proteins, extracted from cultured human neuroblastoma cells, were separated both by SDS-PAGE (1-DE) and two-dimensional electrophoresis (2-DE), and transferred to membranes. Western blot analysis was performed using serum samples from 30 SLE patients with CNS involvement (CNS-Lupus) and from 30 SLE patients without CNS involvement (non-CNS-SLE). The detected autoantigens were identified using MALDI-TOF/TOF MS. On the 1-DE Western blot, we detected 32 antigenic bands in the serum samples from the CNS-Lupus patients. Among them, four bands were detected significantly more frequently in the CNS-Lupus patients than in the non-CNS-SLE patients. Three bands were detected in four or more of the CNS-Lupus patients but in only one or none of the non-CNS-SLE patients. We thus selected these seven bands for the next investigations. Next, we detected protein spots corresponding to the selected seven bands by 2-DE Western blot and identified four proteins. They are peroxiredoxin-4, ubiquitin carboxyl-terminal hydrolase isozyme L1, splicing factor arginine/serine-rich 3, and histone H2A type 1. These four candidate autoantigens for the anti-neuronal cell antibodies would be a useful marker for CNS-Lupus.
Lupus 2010 May
PMID:Identification of autoantigens specific for systemic lupus erythematosus with central nervous system involvement. 2002 24