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)

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

IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.
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PMID:Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. 137 52

We report a case of systemic lupus erythematosus (SLE) apparently induced by topical use of ophthalmic timolol maleate, a beta adrenergic blocking agent. The patient developed fever, malaise, pleurisy and recurrent sterile pleural effusions while taking no medication other than timolol. Antinuclear antibodies in a homogenous pattern, and markedly elevated histone antibodies (IgG anti-(H2A-H2B)-DNA) were present while antibodies to native DNA were absent. After discontinuation of the timolol, his symptoms improved promptly and the pleural effusions resolved. To our knowledge, this is the first report of timolol induced SLE.
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PMID:Drug induced systemic lupus erythematosus due to ophthalmic timolol. 800 9

The case is described of a 73 year old man who presented with a lupus-like syndrome related to treatment with isoniazid and had IgG antinuclear antibodies against the nucleo-histone complex (H2A-H2B)-DNA. After a short course of treatment with prednisone and discontinuation of isoniazid the patient's lupus symptoms resolved and a gradual decrease in antibodies to (H2A-H2B)-DNA occurred. This case suggests that isoniazid is capable of inducing an autoantibody specificity associated with drug related lupus.
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PMID:Systemic lupus erythematosus induced by isoniazid. 141 44

By using Western blot method, we studied the antihistone fraction antibodies in sera of patients with rheumatic diseases. After analysed with SDS-PAGE, the histone could be separated into H1, H3, H2B, H2A and H4 fractions. The positive rate of anti-histone fraction antibodies was highest (82.1%) in systemic lupus erythematosus (SLE) patients, especially in active stage. In 28 SLE patients, the positive rates of anti-H2B, -H1, -H3, -H2A and -H4 were 78.6%, 60.7%, 50.0%, 35.7% and 7.1% respectively. The results revealed that the determination of anti-histone fraction antibodies was beneficial to the diagnosis of SLE.
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PMID:[Study on anti-histone fraction antibodies in patients with rheumatic diseases]. 147 27

Antibodies to histones (AHA) are commonly found in patients with systemic lupus erythematosus (SLE). However, the full profile of AHA and their clinical associations remains unclear. A total of 111 patients with SLE were studied, including 13 patients in whom multiple serum samples were available over several years. IgM, IgG, and IgA antibodies to total core histones, histone complexes, and individual histones were determined by highly sensitive enzyme linked immunosorbent assays (ELISAs). Antibodies to histones were detected in 74% of serum samples, though only at low levels in half of these. Antibodies to each of the individual histones (H1, H2A, H2B, H3, H4) occurred with similar frequencies except for IgG and IgA antibodies to H4, which were uncommon. In contrast, antibodies to the histone complexes H2A-H2B and H3-H4 were detected in only two serum samples and thus do not appear to be a feature of SLE. All three major isotypes of AHA were common and usually occurred with similar frequencies to one another for the various histone specificities. There were few clinical or laboratory associations with AHA; the strongest was between IgG antibodies to total core histones and antibodies to native DNA. Similarly, there was no association between the presence of AHA and disease activity. However, for the patients as a group and in one patient alone, periods of SLE disease activity were associated with higher levels of AHA. Although the profile of antibodies to individual histones varied with time, no profile was identified that corresponded with any specific disease manifestations. It is concluded from this study that although AHA are common in patients with SLE, their clinical value in this syndrome must, at present, be considered limited.
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PMID:Antibodies to histones in systemic lupus erythematosus: prevalence, specificity, and relationship to clinical and laboratory features. 154 40

A long-term side effect of therapy with a variety of drugs is a syndrome resembling the idiopathic autoimmune disease, systemic lupus erythematosus. Essentially all patients with drug-induced lupus display autoantibodies to nuclear histone components whose specificity appears to be related to the higher order structure of histones existing in chromatin. IgG antibodies to H1 and the (H2A-H2B)-DNA complex were observed in most patients with lupus induced by procainamide, hydralazine, and quinidine, whereas the H3-H4 tetramer, comprising half the mass of the nucleosome core particle, was largely nonantigenic. IgM antibodies to (H2A-H2B)-containing chromatin subunits were common also. IgM reactivity was observed with the DNA-free H3-H4 tetramer and with H1, especially in hydralazine-induced lupus. These results suggest that IgM antihistone antibodies may result from autoimmunization with a nonnative form of chromatin, whereas IgG antibodies may be selected for reactivity with H1 and a native form of the (H2A-H2B)-DNA subunit of the nucleosome. The chemical basis for induction of autoimmunity by drugs is unclear because lupus-inducing drugs do not have a common structural feature or biological activity nor are they capable of specific reactions with histones, the principal target antigen. However, in the presence of activated neutrophils, procainamide is transformed metabolically to the cytotoxic procainamide-hydroxylamine. Mixing experiments and cell-free studies demonstrated that procainamide was cooxidized with H2O2 by myeloperoxidase released when neutrophils undergo the respiratory burst and degranulation reactions. Preliminary results indicate other lupus-inducing drugs are also biotransformed by this mechanism suggesting that a common denominator linking these drugs may be the capacity to be oxidized to reactive metabolites by the action of activated phagocytic cells.
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PMID:Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. 163 38

In SLE and in the (NZB x NZW)F1 murine model of this disease, IgG autoantibodies are frequently produced to DNA and histones. In the present study, we define a linear epitope on histone H2B that is recognized by (NZB x NZW)F1 mice. IgG antibodies from anti-H2B positive (but not anti-H2B negative) mice bound strongly to a peptide containing the first 15 N-terminal amino acids, a region that is exposed in chromatin. Competitive inhibition studies showed that the binding of autoantibodies to H2B in ELISA as well as the binding to soluble H2B was substantially blocked by this peptide. Studies with smaller peptides mapped the epitope to residues 3-12. Individual mice recognized different residues within this region, and a sequence search did not reveal proteins other than H2B that could elicit this spectrum of antibodies. Interestingly, these autoantibody specificities were not a component of those induced in preautoimmune mice by immunization with H2B/RNA complexes or with H2B peptide 1-30 containing the autoantigenic sequence. These findings argue that recognition of a specific N-terminal region of self histone contributes to the anti-H2B autoantibody response in lupus. Autoreactive B cells with specificity for this sequence seem to develop only after the autoimmune process has been initiated.
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PMID:Histone autoantigens in murine lupus. Definition of a major epitope within an accessible region of chromatin. 169 38

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

Using the Western blot method, the authors analyzed 85 sera obtained from patients with rheumatic diseases, focused on the presence of antihistones and antiactin autoantibodies. The authors detected a 32% incidence of the two investigated autoantibody specificities. In a group of 42 patients with systemic lupus erythematosus in 22 sera (52%) positive antihistone antibodies were present, whereby autoantibodies anti-H1 and anti-H2B were most frequent. In 15 sera in this group of patients (36%) antiactin autoantibodies were present.
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PMID:Autoantibodies against histones and actin in patients with rheumatic diseases assessed by the western blot method. 180 31


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