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)

Dogs can develop systemic lupus erythematosus syndromes that are clinically similar to those seen in humans. In contrast, previous observations suggest differences in their autoantibody reactivity patterns against histones and DNA which are components of the nucleosome in chromatin. The objective of this study was to assess comprehensively the levels of autoantibodies against histone, DNA and nucleosome antigens in a population of lupus dogs. The specificities of antibodies in lupus and control dog sera were determined using IgM- and IgG-specific reagents in an ELISA against a variety of chromatin antigens. When compared with control sera, IgG antibodies to individual histones H1, H2A, H3 and H4 were significantly higher in the lupus group. In contrast, we did not detect IgG antibodies specific for H2B, H2A-H2B, DNA, H2A-H2B-DNA or nucleosome in lupus dogs. There was no significant increase in any of the IgM specificities tested. Therefore, the reactivity pattern to nucleosome antigens in canine lupus is restricted to IgG antibodies against individual histones H1, H2A, H3 and H4. This stands in contrast with human and murine lupus, where autoantibodies are directed against a wide variety of nucleosomal determinants, suggesting that unique mechanisms lead to the expansion of anti-histone antibody clones in canine lupus. The high incidence of glomerulonephritis in dog lupus suggests that anti-DNA antibodies are not required for the development of this complication, whereas IgG anti-histone antibodies may be relevant to its pathogenesis.
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PMID:Autoantibodies to histone, DNA and nucleosome antigens in canine systemic lupus erythematosus. 752 50

A retrospective study of tuberculosis patients treated with isoniazid was undertaken in order to establish the prevalence and specificity of antibodies against histones, chromatin and denatured DNA. Each patient had an average of 2.7 +/- 0.4 antibody activities out of the 8 tested antigens using ELISA. These reactivities tended to be higher for non-native forms of the antigens such as denatured histones and DNA with essentially no reactivity to the (H2A-H2B)-DNA subunit of chromatin. Greater than half of the patients were isotype restricted to only IgA or IgM antihistone antibodies, and IgA antihistone antibodies were the most common and reactive. Thirty-five percent of the patients had elevated levels of one or more immunoglobulin classes, and the IgA level was strongly correlated with IgA antihistone activity. These results suggest that isoniazid treatment results in modest increases in antihistone antibodies of the specificities and class typical of drug-induced autoimmunity in the absence of lupus-like disease. The IgA antihistone predominance suggests that serum antoantibodies may be the consequence of stimulation by isoniazid of lymphocytes in the gut-associated Peyer's patches or intestinal lymphoid follicles.
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PMID:IgA antihistone antibodies in isoniazid-treated tuberculosis patients. 757 66

A longitudinal study was undertaken to characterize the autoantibodies induced during the course of procainamide treatment and to relate this information to the appearance of symptomatic drug-induced lupus. IgG, IgA, and IgM Abs to histones, native and denatured DNA, chromatin, and (H2A-H2B)-DNA were determined by ELISA in serial serum samples obtained over the course of an average of 2.1 yr on 22 patients undergoing treatment with procainamide and on an additional 9 patients after discontinuation of procainamide because of drug-induced lupus. Ten patients in the prospective group developed lupus-like symptoms after an average of 1.8 +/- 2.1 yr of procainamide treatment. Of the total of 19 patients with drug-induced lupus, 16 had IgG Abs to the (H2A-H2B)-DNA complex at the time of diagnosis; this autoantibody was first detected 0.9 +/- 1.3 yr before diagnosis in 7 patients. In contrast, the 9 patients who remained asymptomatic during treatment with procainamide for an average of 4.3 +/- 2.2 yr had negligible levels of IgG anti-[(H2A-H2B)-DNA], although IgA and IgM Abs of this specificity were not uncommon. Abs to denatured DNA and histones were elicited coordinately, but these specificities did not discriminate symptomatic from asymptomatic procainamide-treated patients. We conclude that chronic exposure to procainamide commonly elicited autoantibodies with specificities for denatured epitopes on DNA and histones and for native regions on the (H2A-H2B)-DNA subunit of chromatin. However, rapid switch to the IgG class of anti-[(H2A-H2B)-DNA] occurred only in patients who went on to develop symptomatic disease.
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PMID:IgG but not other classes of anti-[(H2A-H2B)-DNA] is an early sign of procainamide-induced lupus. 786 14

Two patients developed drug induced lupus secondary to sulfasalazine (SSZ). One patient was receiving SSZ for Crohn's disease and was subsequently treated with olsalazine, which lacks the sulfapyridine component of SSZ. Her inflammatory bowel disease (IBD) remained controlled and she did not develop a recurrence of lupus, suggesting that olsalazine is safe in patients with IBD and a history of SSZ induced lupus. The SSZ induced antibodies were predominantly IgG against the (H2A-H2B)-DNA complex. Since lupus induced by 7 other drugs was associated with a similar antibody response, our findings support the existence of a common pathway for autoantibody induction.
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PMID:Antihistone antibody profile in sulfasalazine induced lupus. 786 27

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

Autoantibodies reacting with chromatin and its components, histones and DNA, are characteristic of the human autoimmune disease SLE and drug-induced lupus, but the mechanisms of their induction remain unknown. Serial serum samples collected over short intervals from lupus-prone MRL/MP-lpr/lpr and BXSB mice were tested by ELISA on chromatin and its substructures to characterize the initial autoimmune response to these antigens. Direct binding studies demonstrated that the early autoantibodies recognized discontinuous epitopes on native chromatin and the (H2A-H2B)-DNA subnucleosome. As the immune response progressed, native DNA and other chromatin constituents generally became antigenic. Based on adsorption studies and IgG subclass restriction, antibodies to native DNA were more related to chromatin than to denatured DNA. The kinetics of autoantibody appearance and the Ig class distribution were similar to the kinetics and distribution seen in antibodies induced by immunization with an exogenous T-dependent antigen. These results are most consistent with the view that autoantibodies reacting with chromatin are generated by autoimmunization with chromatin, and antibodies to native DNA are a subset of the wide spectrum of antichromatin autoantibodies.
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PMID:Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. 847 12

Agranulocytosis is a well recognized but uncommon complication of procainamide (PA) therapy, whereas a lupus-like syndrome occurs in approximately 20% of patients treated chronically with PA. In order to gain insight into the immunopathogenic relationships among these conditions, we compared the humoral immune abnormalities in these patient groups as well as in asymptomatic PA-treated patients. A relatively uniform profile of IgM but not IgG autoantibody reactivity with a set of chromatin-related antigens was observed in eight elderly men who developed agranulocytosis after treatment with PA. In contrast PA-induced lupus patients had predominant reactivity with [(H2A-H2B)-DNA] in both IgM and IgG classes. Five of eight patients with agranulocytosis had elevated levels of neutrophil-reactive IgG which appeared to be due to immune complexes based on Fc gamma receptor blocking studies. However, 12 of 15 patients with PA-induced lupus, none of whom had neutropenia, had similar levels of neutrophil-reactive IgG, suggesting that this reactivity was not causally related to agranulocytosis. Agranulocytosis developed after less than 3 months treatment with PA in six of eight patients. This time course was similar to that seen in 77 PA-induced agranulocytosis patients reported in the literature plus 127 patients reported to the U.S. Food and Drug Administration in whom 90% developed agranulocytosis within 3 months of starting PA. In contrast, the mode duration of treatment with PA before lupus-like symptoms develop is 10-12 months. These findings, together with the different profiles of autoantibodies and clinical presentations, suggest that agranulocytosis arises from a different mechanism than that underlying PA-induced lupus.
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PMID:Procainamide-induced agranulocytosis differs serologically and clinically from procainamide-induced lupus. 862 53

Four monoclonal antibodies (mAb) derived from an (NZB x NZW)F1 mouse bound to nucleosomes, total histones and to the H2A-H2B dimers but not to individual histones or DNA. Sequencing of their heavy (H)- and light (L)-chain variable region genes showed that they derived by somatic mutations from the same B cell precursor. The distribution of negatively and positively charged amino acids in the H-chain complementarity-determining regions was very similar to that observed not only in anti-H2A-H2B mAb derived from different lupus-prone mouse strains but also in anti-DNA mAb. Combined analysis of the mAb structures and their interactions with immobilized H2A-H2B dimer or total histones by plasmon resonance allowed us to assign the H-chain mutations a major role in the binding profiles of these anti-nucleosome mAb. Interestingly, four of the five H-chain mutations that distinguished mAb 3F6 from 2E1 generated negatively or positively charged amino acid residues, and two of them occurred at positions 56 and 76, which are frequently involved in the maturation process of anti-DNA antibodies. A modeling study of the 3F6 variable fragment (Fv) predicted that acidic residues occupy the cleft of the Ab combining site and have the potential to participate in electrostatic interactions. Thus, the demonstration that (NZB x NZW)F1-derived anti-H2A-H2B antibodies share certain structural features and mutation patterns with anti-DNA mAb suggest that common selection and maturation processes account for the production of these lupus-related autoantibodies.
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PMID:Structural properties and mutation patterns of anti-nucleosome monoclonal antibodies are similar to those of anti-DNA antibodies. 876 65

Lupus anti-DNA may have higher homology with germline than those from normal subjects. However, in NZB/NZW mice, bacterial DNA is more antigenic than mammal DNA, which could indicate an antigen-driven origin. High-affinity antibodies to double-stranded DNA cross-react with small nuclear ribonucleoprotein and ribosomal P proteins. These cross-reactive anti-DNA may penetrate live cells. Antibodies to ribosomal P proteins are associated with neuropsychiatric, renal, and hepatic lupus involvement. IgG antibodies to (H2A-H2B)-DNA complexes antedate procainamide-induced lupus. Autoantibodies to some La/Ro peptides in a mother indicates that her children may develop neonatal lupus and determine who will have congenital heart block. Perinuclear antineutrophil cytoplasmic antibodies are present in 25% of systemic lupus erythematosus patients without correlation with anti-DNA or disease activity. Different antiphospholipid antibodies require different protein cofactors for reactivity. Those to anionic phospholipids require beta 2-glycoprotein I, whereas anti-phosphatidylethanolamine antibodies require kininogen or its binding protein. Antibodies to phospholipid-free beta 2-glycoprotein I are associated more strongly with clinical antiphospholipid syndrome than are antiphospholipid antibodies.
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PMID:Autoantibodies in systemic lupus erythematosus. 894 42


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