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 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

Thus, the nucleosome, the U1 snRNP, and the Ro scRNP appear to elicit hierarchies of antibodies in patients with SLE, just as any complex foreign protein might do when injected into an experimental animal. There must be a permissive factor in operation that allows these normally weak antigens (the great paradox of SLE!) to escape tolerance mechanisms. That factor could be an exogenous agent, such as a chemical that structurally alters selected macromolecules. Such a mechanism seems likely in patients with drug-induced lupus in whom autoimmune responses are focused against the same histone epitopes that are recognized by sera from patients with spontaneous SLE. Alternatively, foreign substances may elicit cross-reactive antibodies that recognize "self" determinants, or endogenous metabolic disturbances might enhance exposure of selected macromolecules to the immune system. In any case, it now seems clear that the result in SLE patients is autoimmunity with a repetitive focus. Future research should concentrate on the 3 particles described here in order to identify common denominators that set them apart from other cellular elements and which predispose them to a role as autoantigens, to determine the extent to which these particles make contact with the immune system, and to learn how structural, humoral, or metabolic alterations might predispose individuals to respond to them immunologically.
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PMID:The lupus autoantigens and the pathogenesis of systemic lupus erythematosus. 348 61

Treatment with the beta blocker acebutolol may trigger antinuclear antibody (ANA) production. We retrospectively studied 97 sera from 47 patients who developed ANA during acebutolol treatment. Anti-histone and anti-denatured (ss) DNA antibodies were found in 53% and 66% respectively of the sera tested. The activities of these two antibodies correlated well with the total ANA titer. Anti-native (ds) DNA were absent or present at low titer. This immunochemical pattern of acebutolol-induced ANA is similar to that reported for other drug-induced ANA. To date, the presence such isolated ANA is not known to expose patients to any particular risk other than exceptional and minor clinical manifestations of lupus which are rapidly reversible following therapy cessation.
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PMID:Specificity of acebutolol-induced antinuclear antibodies. 349 66

Unlike parental NZB or NZW mice, (NZB X NZW)F1 mice exhibit a lupus-like disease characterized by high serum levels of IgG antinuclear antibodies and a fatal immune-complex glomerulonephritis. At least three unlinked gene loci can be distinguished in NZW mice that conceivably contribute to a T cell-dependent autoimmune disease, including the MHC (H-2z) and the T cell receptor alpha and beta chain gene complexes. We undertook an (NZB X NZW)F1 X NZB backcross to determine the relative contribution of these NZW genes to lupus-like renal disease and autoantibody production in F1 mice. The incidence of severe renal disease and elevated levels of IgG antibodies to dsDNA and histone in the backcross mice was approximately half of that observed in (NZB X NZW)F1 mice. Furthermore, there was a strong correlation between the presence of the NZW H-2z haplotype and lupus-like disease in backcross mice. Approximately 90% of backcross mice with disease carried the NZW H-2z locus compared with 16% of mice without disease; nearly 90% of H-2d/z mice expressed severe autoimmune disease. In contrast, no association was apparent between the presence of the NZW T cell receptor alpha chain gene complex or beta chain gene complex and severe renal disease or autoantibody production. Thus, the NZW MHC or gene(s) linked to this locus appear to be the only dominant NZW genetic contribution to F1 disease.
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PMID:The contribution of NZW genes to lupus-like disease in (NZB x NZW)F1 mice. 349 6

The sera of patients with systemic lupus erythematosus (SLE) and drug-induced lupus (DIL) were used to study the antigenic regions of histone 1 (H1) that bind antibodies in these sera. ELISA and immunoblotting techniques using enzymatically and chemically derived peptides of H1 showed that the major antigenic domain is in the carboxyl (C) terminus. None of the 24 SLE or 11 DIL sera bound to the central hydrophobic polypeptide by ELISA. The reactivity of DIL sera with the purified H1 peptides was similar to that observed with SLE sera. This observation suggests a common immune pathway for DIL and SLE.
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PMID:Antibodies in procainamide-induced and systemic lupus erythematosus bind the C-terminus of histone 1 (H1). 349 39

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

Anti-histone antibodies (AHA) are spontaneously produced in NZB/NZW mice as part of their autoimmune disease. IgM AHA are usually not detected until after 4 mo of age, and older female mice switch to the production of IgG AHA. We studied the in vitro production of AHA by spleen cells from young (less than or equal to 12-wk-old) NZB/NZW mice. Despite the absence of elevated serum AHA activity, spleen cells from these mice demonstrated marked spontaneous autoantibody production in culture. In kinetic studies, little in vitro production was detectable after 1 day of culture, and maximal accumulation occurred on day 5. Elevated AHA production was apparent by cells from 2-wk-old NZB/NZW mice, and an age-dependent increase in autoantibody production was also noted. Only AHA of the IgM class were detected in cultures of young spleen cells. The in vitro production of IgM AHA in culture was T cell dependent, depletion of T cells resulting in a 70 to 90% reduction in production, which was corrected by the readdition of T cells. In cultures where both IgM AHA and total IgM secretion were measured, a much greater T cell dependence for AHA production was apparent. The requirement for T cells could also be partially replaced by factors present in concanavalin A supernatant. AHA secretion was induced by lipopolysaccharide by using cells from both NZB/NZW and non-autoimmune mice. Although production was greater with NZB/NZW cells, the difference was much less than that for spontaneous production. Thus, AHA-secreting cells that are dependent on in vitro T cell help are present in young NZB/NZW mice. These studies may help define the mechanisms responsible for selective autoantibody secretion in lupus-like disease.
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PMID:In vitro production of anti-histone antibodies by spleen cells from young autoantibody negative NZB/NZW mice. 387 28

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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