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 antibody response of rabbits immunized with a total histone mixture containing randomly coiled H1/H5, H2A, H2B, H3 and H4 devoid of DNA was investigated in direct and competitive ELISA. The antisera were tested with isolated histones and chromatin and with a series of overlapping synthetic peptides covering the entire sequences of the four core histones and two peptides of H1. It was found that the New Zealand (NZ) white rabbits immunized with the total histone (TH) mixture complexed with RNA produced IgG antibodies reacting with histones and with a number of histone peptides but not with chromatin. The antisera also contained IgG antibodies which bound components that correspond to common target antigens in autoimmune diseases such as native dsDNA, peptides of Sm-D antigen, ubiquitin, branched peptides of ubiquitinated H2A and poly(ADP-ribose). By competition experiments, it was shown that these antibodies corresponded to non-crossreacting antibody populations. New Zealand rabbits immunized with TH in the absence of RNA or random outbred rabbits immunized with the RNA-complexed histone fraction produced antibodies reacting with histone, chromatin and very few histone peptides, while no activity with non-related antigens was observed. The pattern of reactivity of antisera raised in NZ rabbits with RNA-complexed TH was found to be very similar to that observed in sera of patients with systemic lupus erythematosus while, in contrast, the antibody response was very different in NZ or outbred rabbits immunized with various native nuclear particles and with individual histones. Altered nucleosome particles rather than native nucleosomes may represent the antigenic stimulus giving rise to autoantibodies.
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PMID:New Zealand white rabbits immunized with RNA-complexed total histones develop an autoimmune-like response. 171 87

This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single-stranded DNA (mean +/- SEM 30 +/- 2.6%), double-stranded DNA (13 +/- 1.1%), Z-DNA (optical density 0.54 +/- 0.06), and poly A (7.2 +/- 0.6%) was seen (P less than 0.001). Thirty-four patients (65.4%) had antibodies to total histones, most frequently, the H2A/2B dimer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug-related lupus.
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PMID:Serologic evaluation of patients receiving procainamide. 138 15

Increasing evidence suggests that autoantibodies in the rheumatic diseases are a consequence of immune selection by self-material, but the nature of the in vivo immunogen is unknown. Insight into this problem may be obtained by measuring autoantibody binding to various forms of a target antigen. Antihistone antibodies arising as a side effect of therapy with various drugs offer an opportunity to explore this premise because many forms of histone have been characterized and adapted to ELISA formats. Two patterns of antibody reactivity were observed. All 21 patients with symptomatic procainamide-induced lupus and 7 of 12 patients with quinidine-induced lupus had IgG antibodies reacting predominantly with the (H2A-H2B)-DNA complex and with chromatin. In contrast, antibodies in 19 of 24 patients taking procainamide without accompanying lupus-like symptoms did not show any pattern. The second pattern was observed in 18/19 chlorpromazine-treated patients and 14/17 patients with hydralazine-induced lupus in which IgM antibodies displayed more reactivity with DNA-free histones than with the corresponding histone-DNA complexes and almost no binding to H1-stripped chromatin. Absorption studies were entirely consistent with these results. Thus, the two patterns of reactivity with nucleosomal components reflect the molecular substructure of chromatin, suggesting that two processes underlie antihistone antibody induction by drugs. In one, IgG autoantibodies appear to be elicited by chromatin, whereas in the other, autoimmune tolerance to native chromatin appears largely intact, and IgM antibodies may be driven by DNA-free histone.
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PMID:Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. 186 77

Nucleosomes released spontaneously in short-term culture from murine spleen cells have a significant immunoproliferative effect in vitro, including the stimulation of anti-DNA antibody responses. The present studies show that during short-term cultures, tonsil lymphoid cells also undergo spontaneous apoptosis revealed morphologically (electron microscopy) by the appearance of changes in nuclear chromatin, typical of apoptosis and similar to morphologic changes of apoptosis in cultured normal splenic lymphocytes. This process is followed by the release, in the greater than 30-kDa cell free supernatant fraction, of core histones (H2A, H2B, H3, H4) and low molecular weight DNA (approx 160 bp) constituents of nucleosomes. The greater than 30-kDa tonsil lymphocyte cell-free supernatant material containing the constituents of core nucleosomes, as well as the greater than 30-kDa supernatant fractions of tonsil cell lysates harvested at the same time, had a significant immunoproliferative effect on human or murine lymphocytes, increasing both DNA and immunoglobulin synthesis (protein A plaque-forming cells). Thus the release of immunoproliferative nucleosomes form dying human lymphoid cells provides an autocrine lymphocyte stimulatory network which may be important in immunoproliferative disorders and in normal cell turnover. Apoptosis in vivo may also provide a potential source for the circulating nucleosomal DNA identified in plasma in some systemic lupus erythematosus patients as well as contributing to increased polyclonal B lymphocyte stimulation and autoantibody responses in this disorder.
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PMID:The spontaneous apoptotic cell death of normal human lymphocytes in vitro: the release of, and immunoproliferative response to, nucleosomes in vitro. 204 34

The sera of patients with systemic lupus erythematosus (SLE) and drug-induced lupus (DIL) were used to study the antigenic epitopes on nuclear histones that bind antibodies in these sera. ELISA and immunoblotting techniques showed that antibodies from both patient groups bound all classes of intact histone: H1 greater than H2B greater than H2A greater than H3 greater than H4. The different classes of histone were enzymatically or chemically cleaved to produce a series of peptide fragments which were then used to map the reactive epitopes by ELISA and immunoblotting. Ten of 11 DIL sera and 11 of 12 SLE sera bound the carboxy and amino terminal peptides. Only one sera of each group bound to the central hydrophobic polypeptide. The reactivity of DIL sera with fractionated histone polypeptides was similar to that observed with SLE sera. This observation suggests that the histone epitopes reacting with DIL sera are no less restricted than those reacting with SLE.
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PMID:Antibodies from patients with drug-induced and idiopathic lupus erythematosus react with epitopes restricted to the amino and carboxyl termini of histone. 241 12

We have identified regions within core histones that are antigenic for autoantibodies in systemic lupus erythematosus (SLE) and drug-induced lupus. An immunoblotting technique was used to determine the reactivity of lupus antibodies for intact histones and for trypsin-resistant histone fragments that lack the amino- and carboxyl-terminal amino acids that are normally exposed in native nucleosomes. In SLE, the predominant anti-histone response was restricted to epitopes in the trypsin-sensitive regions. Of 20 SLE sera that had strong antibody activity for multiple intact histones, 17 showed minimal activity with any of the corresponding trypsin-resistant fragments. A markedly different pattern of reactivity was present in sera of patients with procainamide (Pr)-induced lupus in which antibodies to H2A, H2B, and the H2A-H2B complex had strong fragment activity. Interestingly, recognition of trypsin-resistant fragments was also noted in a small number of SLE sera that contained antibodies to the H2A-H2B complex. In contrast to both SLE and Pr-induced lupus, antibodies induced by hydralazine (Hy) reacted primarily with H3 and H4. Furthermore, these antibodies bound equally well to the corresponding trypsin-resistant regions that are thought to be relatively unexposed in native nucleosomes. Thus, the specificities of anti-histone antibodies in SLE, Pr-induced lupus, and Hy-induced lupus are markedly different, but in each disease reactivity appears to be restricted to a limited number of histone determinants. The data raise the possibility that autoantigen in the form of native nucleosomes may be recognized in SLE and possibly in Pr-induced lupus. In contrast, the propensity of Hy to induce autoantibodies to determinants usually not recognized in SLE or Pr-induced lupus may suggest a different immunogenic stimulus in this disease.
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PMID:Anti-histone antibodies in idiopathic and drug-induced lupus recognize distinct intrahistone regions. 243 24

The specificity of autoantibodies present in the serum of 151 patients with systemic lupus erythematosus (SLE) was investigated by ELISA using as antigen individual histones as well as 17 different core histone synthetic peptides. Many of the sera reacted with four terminal peptides (residues 1-21 and 130-135 of H3, 1-29 of H4 and 1-25 of H2B) while fewer reacted with internal peptides (residues 65-85 of H2A and 40-55 of H3). Of the 151 SLE sera, 88% reacted with one or more of the six core histone peptides whereas only 57% reacted with one or more of the complete core histone molecules. Antibodies to mononucleosomes from chicken erythrocytes were also prepared in rabbits. The rabbit antisera were tested by ELISA using as antigen chromatin subunits, native and denatured DNA, individual histones and 23 natural and synthetic peptides of histones. The antinucleosome antibodies were found to recognize the same peptide fragments as those recognized by the SLE sera.
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PMID:Reactivity of autoantibodies in systemic lupus erythematosus with synthetic core histone peptides. 247 14

A broad range of autoreactivity among a group of 12 French patients with rheumatoid arthritis (RA) and 58 of their healthy first degree relatives has been identified. Over 15% of the patients were found to have antibodies to ssDNA, histone H1, H2A, and H2bB. Among the relatives, IgG and IgM rheumatoid factor and antibodies to ssDNA, H2A, and H4 were present in more than 10%. Even more remarkable, a common anti-DNA antibody idiotype designated PR4, known to be present in 70% of patients with systemic lupus erythematosus (SLE), was found in approximately 30% of both patients with RA and their healthy relatives. This is quite different from its lack of increased expression in relatives of patients with SLE and suggests that in the family members of those with RA a particular combination of environmental influence on germline gene expression is responsible.
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PMID:Serological abnormalities, including common idiotype PR4, in families with rheumatoid arthritis. 248 Jul 54

The HEp2 cell cultures appeared highly sensitive in detecting the antinuclear antibodies (ANAb) in systemic sclerosis, principally anticentromere antibodies of the CREST syndrome. The immunoblotting used with either complex cellular extracts from HeLa and rabbit thymus or purified nuclear components (high mobility group (HMG) proteins and histones) is able to identify precisely the ANAb targets and to contribute to diagnosis. With nuclear extracts of HeLa cells, the sera from 75.8% of CREST syndrome subjects stained 18 and 22 kD proteins. Corresponding antibodies were also detected in 72.7% of these patients, on HEp2 centromers by indirect immunofluorescence. With the same extracts, 33.3% of sera from diffuse sclerosis/acrosclerosis patients contain antibodies staining 86, 73, 32 and 30kD. These sera also stain 77, 66 and 63kD from thymus extracts. Corresponding antibodies will be the anti-SCL-70 antibodies defined by double immunodiffusion. The anti-HMG antibodies were infrequent in systemic sclerosis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and consequently without interest for diagnosis. The anti-whole histones antibodies which are less frequent in diffuse sclerosis/acrosclerosis (35.7%) than in SLE (41.3%) recognize especially H1 and H2A in the first diseases, H1 and H2B in SLE and H1 and H3 in RA.
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PMID:Antinuclear antibodies detected by indirect immunofluorescence on HEp2 cells and by immunoblotting in patients with systemic sclerosis. 249

Two peptides of eight (T2) and 10 (T1) residues corresponding to the branched moiety of ubiquitinated histone H2A have been synthesized and used for raising specific antibodies in rabbits. Antisera to peptide T1 reacted in ELISA with T1 and with H2A but not with ubiquitin; antisera to peptide T2 reacted with T2 but not with H2A or ubiquitin. When tested in immunoblotting, both peptide antisera reacted with ubiquitinated H2A but not with unconjugated H2A or with ubiquitin. Sera from patients with systemic lupus erythematosus (SLE) were shown previously to react with ubiquitin in ELISA and immunoblotting. When tested for their ability to react in ELISA with synthetic peptides T1 and T2, 96% of the SLE sera (diluted 1:500) that recognized ubiquitin also reacted with peptide T2. Of the SLE sera that did not react with ubiquitin, only 13% possessed antibodies able to bind peptide T2. Antibodies from seven SLE sera, purified on a T2-immunoadsorbent column, were also able to react either with H2A, and in three cases also with ubiquitin.
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PMID:A branched, synthetic octapeptide of ubiquitinated histone H2A as target of autoantibodies. 254 Dec 20


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