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)

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 frequency of IgG and IgM anti-total histones and anti-histone subfractions were studied in 63 patients with SLE and 257 patients with other autoimmune conditions employing the ELISA. IgG anti-histone antibodies were found in 17 of 63 (25%) sera of lupus patients and in only 16 of 257 (6%) sera of patients with other autoimmune conditions. The latter incidence did not differ statistically from that of 115 healthy control subjects. Furthermore, the concomitant appearance of both IgG and IgM anti-histone antibodies was observed only in SLE patients. Anti-histone subfraction (H1, H2A, H2B, H3, H4) activity was determined in sera containing anti-total histone antibodies. There was a higher preponderance for antibodies to H1, H2A, H2B in SLE. We conclude that anti-histone antibodies seem to be a marker for lupus and its variants (e.g. drug induced lupus) and should be routinely looked for in SLE patients.
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PMID:Anti-histone antibodies in SLE and other autoimmune diseases. 275 6

Of seven patients with quinidine-induced polyarthropathy, four had positive antinuclear antibodies and could be considered to have had quinidine-induced lupus erythematosus. The remaining three patients had milder symptoms, which occurred soon after the start of quinidine therapy, and did not have antinuclear antibodies. To confirm the association, the latter three patients were rechallenged with quinidine therapy, which caused recurrence of symptoms within 1 week. Antihistone antibodies, which are characteristic of drug-induced lupus erythematosus associated with procainamide and hydralazine therapy, were detected in all patients with quinidine-induced lupus erythematosus. An unusual characteristic of antihistone antibodies seen in two patients was the presence of high levels of IgG antibodies to histone H1 as well as H2A.H2B and H3.H4 complexes, without antibodies to the individual core histones.
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PMID:Two distinct quinidine-induced rheumatic syndromes. 325 71

Antinuclear antibodies develop in most patients who are given prolonged procainamide therapy, but clinical symptoms resembling those of lupus appear in only 15 to 20 percent of such persons. No objective marker for symptomatic procainamide-induced lupus has been described. However, IgG antibodies to the histone complex H2A-H2B have previously been reported in this disorder, and it has been suggested that antiguanosine antibodies may be a marker for major manifestations of procainamide-induced lupus. We therefore tested for these antibodies in 20 symptomatic and 31 asymptomatic patients treated with procainamide. Most of the symptomatic patients had multiple manifestations of drug-induced lupus; resolution of symptoms after the discontinuation of procainamide was required for inclusion in the symptomatic group. All 20 symptomatic patients had elevated IgG antibodies to H2A-H2B, in contrast to only 2 asymptomatic patients (P less than 0.001). This activity was absent in patients not treated with procainamide and in patients with lupus induced by hydralazine or quinidine. IgG antiguanosine was elevated as compared with normal controls in 13 of 20 symptomatic and 19 of 31 asymptomatic patients--a finding that did not distinguish between symptomatic and asymptomatic patients. We conclude that IgG antibodies to H2A-H2B are a sensitive and specific marker for procainamide-induced lupus. The striking correlation between antibodies to H2A-H2B and symptomatic disease suggests a possible association between this antibody and the underlying pathogenic events.
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PMID:Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. 325 87

Despite the protean nature of the clinical characteristics of systemic lupus erythematosus (SLE), autoantibodies represent an almost constant feature. Furthermore they are common to both human SLE and murine lupus. Nonetheless, the mechanism by which they arise has not been established. Amongst the several processes that have been proposed, evidence has emerged supporting specific antigen drive as a significant mechanism. We have documented the age- and sex-related differences in the prevalence of antibodies to both chromatin-related (histone and DNA) and non-chromatin-related (Sm) antigens in MRL mice. Our finding of an association between antihistone antibodies and anti-denatured DNA antibodies is consistent with chromatin being the putative antigen. Additionally, antibodies to the individual histones H1 and H2B, the most exposed histones in chromatin, were more prevalent than antibodies to the remaining histones (H2A, H3, H4). This, again, supports specific antigen drive as a mechanism for autoantibody production. However, associations were also found between antibodies to histone and DNA and antibodies to Sm. As Sm is a non-chromatin protein antigen, the associations between antibodies to Sm and those to histone and DNA suggest that mechanisms in addition to specific antigen drive are important in autoantibody production.
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PMID:Relationship of age and sex to autoantibody expression in MRL-+/+ and MRL-lpr/lpr mice: demonstration of an association between the expression of antibodies to histones, denatured DNA and Sm in MRL-+/+ mice. 326 Aug 38

The injection of (C57BL/6 X DBA/2)F1 mice with parental DBA/2 lymphoid cells leads to a lupus-like disease in which IgG autoantibodies are targeted to certain nuclear and cell surface antigens. To investigate further the extent of antibody diversity in this graft-vs-host (GVH) model, we studied the specificity of antihistone antibodies induced by the GVH reaction. High levels of IgG antibodies to histones H1 and H2B were detected whereas responses to H2A, H3, and H4 were only marginally elevated above pre-GVH levels. Immunoblotting analysis further revealed that the response to H2B was focused on epitopes that most likely reside in the N-terminal region. In contrast, F1 mice immunized with H2B/RNA complexes in adjuvant produced antibodies to the N terminus as well as to other regions of the H2B molecule. Thus, the antihistone response stimulated by the GVH reaction is only a fraction of the potentially activatable B cell repertoire. We also determined whether antibodies that arise spontaneously in genetically predisposed lupus strains were restricted in their histone reactivity. The response to core histones was highly variable among individual animals of the NZB/NZW and MRL-lpr/lpr strains despite their inbred nature. However, nearly all mice exhibited a preferential reactivity for epitopes in histone regions that are lost after partial trypsin digestion of chromatin. These data demonstrating autoantibody responses that are limited to particular histone regions support a mechanism by which B cells are selectively activated in murine lupus. The predominant production of antibodies to histone regions that are exposed in nucleosomes raises the possibility that chromatin is an antigenic stimulus for histone-specific B cells in this disease.
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PMID:Selective production of autoantibodies in graft-vs-host-induced and spontaneous murine lupus. Predominant reactivity with histone regions accessible in chromatin. 333 41

Antihistone antibodies were searched for in autoimmune prone strains of mice: MRL/1, MRL/n, PN, and NZB by micro-enzyme-linked immunosorbent assay (micro-ELISA with total histones or H1 fraction as antigen) and immunoblotting using a solution of total histones containing H1, H2A, H2B, H3, and H4. In addition, we specified the localization of H1 fraction epitopes recognized by mouse anti-H1 autoantibodies using immunoblotting with H1 digested by alpha-1-chymotrypsin. All strains of autoimmune mice synthesize antihistone antibodies, principally MRL/1, then MRL/n and PN, and finally NZB. Among MRL/1 mice, the histone fractions best recognized by antihistone antibodies, are, in decreasing order: H1, H3, H4, H2B, and H2A. With MRL/n and, even more strikingly with PN mice, the antihistone antibodies recognize preferentially H1 and H2B as they do in human lupus. Finally, the binding of antihistone antibodies from NZB mice is slightly stronger for H2B than for the other histone fractions. The anti-H1 autoantibodies from MRL/1, MRL/n, and PN mice are mainly directed at epitopes located on the C terminal of the histone molecule.
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PMID:Antihistone antibodies detected by micro-ELISA and immunoblotting in mice with lupus-like syndrome (MRL/1, MRL/n, PN, and NZB strains). 372 26

Sera drawn from 75 patients with systemic lupus erythematosus, 141 healthy relatives (from the families of 51 patients), and 115 healthy control subjects were examined, by enzyme-linked immunosorbent assay, for IgG and IgM antibodies to total histones and their subfractions. Compared with the controls, statistically significant numbers of patients and their relatives had antihistone antibodies of both isotypes. Among the relatives, the sera from females, notably sisters of the patients, contained the highest levels of anti-total histone antibody. Anti-H2A/H2B and H3 antibodies were most prevalent among the lupus patients, but many of the relatives had IgM anti-H4 antibodies. These findings indicate that antihistone antibodies can serve as a genetic marker in patients with systemic lupus erythematosus.
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PMID:Detection of antibodies to total histones and their subfractions in systemic lupus erythematosus patients and their asymptomatic relatives. 382 58

Patients treated with procainamide and other drugs commonly develop antinuclear antibodies and occasionally symptoms of lupus erythematosus. However, the pathological events which lead to clinical symptoms in some patients but only abnormal serology in others have not been established. The present study examines the incidence, amount, immunoglobulin class, and antigen-binding specificity of anti-histone and anti-denatured DNA (anti-dDNA) antibodies in three groups of patients. These comprised a prospective study of patients treated with procainamide, patients with clinical drug-induced lupus symptoms, and a group undergoing therapy for many years without any symptoms. Procainamide elicited IgG and IgM anti-dDNA antibodies concordantly. Anti-histone IgM antibodies also appeared de novo during this period but IgG anti-histone antibodies were detected less frequently. Asymptomatic patients tended to have an antibody profile consisting of highly elevated anti-dDNA, IgM antibodies reactive with all histones and IgG antibodies specific for only one or two histone classes. In contrast symptomatic patients usually had little anti-dDNA or antibodies to individual histones but had pronounced IgG antibodies to the histone complex H2A-H2B. This unique antibody was characteristics of procainamide-induced lupus and was not detected in patients whose disease was induced by hydralazine. Anti-(H2A-H2B) decreased after procainamide was discontinued, concomitant with subsidence of symptoms. The finding that autoantibodies elicited by procainamide in patients with lupus symptoms have a characteristic immunoglobulin class and specificity may be of pathogenic significance and suggests that patients susceptible to procainamide-induced lupus have a unique immune response. In addition, this information could be of diagnostic value in predicting which procainamide-treated patients will develop overt symptoms of lupus.
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PMID:IgG antibodies to the histone complex H2A-H2B characterize procainamide-induced lupus. 387 29

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


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