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)

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

Nucleosome-specific T helper (Th) cells provide major histocompatibility complex class II-restricted, cognate help to nephritogenic antinuclear autoantibody-producing B cells in lupus. However, the lupus Th cells do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. Thus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome particle as a whole. Therefore, herein we tested 145 overlapping peptides spanning all four core histones in the nucleosome. We localized three regions in core histones, one in H2B at amino acid position 10-33 (H2B(10-33)), and two in H4, at position 16-39 (H4(16-39)) and position 71-94 (H4(71-94)), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoepitopes also triggered the pathogenic Th cells of (SWR x NZB)F1 lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production of Th1-type cytokines, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the isotypes of nephritogenic autoantibodies induced in the lupus mice. Interestingly, the Th cell epitopes overlapped with regions in histones that contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identification of the disease-relevant autoepitopes in nucleosomes will help in understanding how the pathogenic Th cells of spontaneous systemic lupus erythematosus emerge, and potentially lead to the development of peptide-based tolerogenic therapy for this major autoimmune disease.
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PMID:Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. 867 66

Systemic lupus erythematosus (SLE) is characterised by the production of a variety of autoantibodies against cell surface, nuclear and cytoplasmic antigens. The antigen or antigens responsible for the induction of this disease is/are unknown. We have analysed the antigenicity and pathogenicity of free histones and histones complexed with RNA in Balb/c, B10 Br, C57BL/6 and MRL-lpr/lpr mice by giving 1 microgram and 25 micrograms of each antigen intraperitoneally in complete and incomplete Freund's adjuvant. The same number of control animals were injected with either adjuvant or PBS. In the initial experiment we gave three doses of antigen at three weekly intervals. B10 Brown and C57BL/6 mice had no response to the antigens. Balb/c mice developed a mild transient antibody response against H1 histone, branched peptide of ubiquitinated H2A (peptide T4) and also against ssDNA. However in repeated experiments when the histone-RNA complex was injected into young MRL-lpr/lpr animals at two weekly intervals, a significantly increased antibody response was detected against H1, peptide T4 and some histone peptide residues (204-218 of H1, 1-20 and 65-85 of H2A, 1-25 of H2B, 1-21 of H3 and 1-29 of H4) compared to the control groups. Moreover, this group also showed elevated serum anti-DNA antibody levels and early impairment of renal function assessed by the urine protein levels. These experiments have demonstrated that there is a genetic variation in antibody responses against histones and histone-RNA complexes and that histone-RNA complexes exaggerate the disease in young MRL-lpr/lpr mice by inducing antibodies to basic regions of histones and other autoantigens.
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PMID:Effect of histone and histone-RNA complexes on the disease process of murine systemic lupus erythematosus. 867 99

The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short ( < 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non-albuminuric age-matched controls, with young (12 weeks old) non-albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti-nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti-DNA was higher while anti-nucleosome and anti-H2A/H2B-DNA subnucleosome reactivities were lower compared with age-matched non-albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti-glomerular basement membrane (GBM)-tubular basement membrane (TBM) antibodies were already present in 12-week-old non-albuminuric mice. These eluates showed no anti-nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti-ECM, anti-DNA and anti-nucleosome reactivities were higher than in eluates of age-matched non-albuminuric mice. The deposition of anti-nucleosome antibodies preceded the deposition of anti-DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti-GBM-TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti-ECM and anti-nuclear (anti-nucleosome and anti-DNA) antibodies, but the difference with non-albuminuric mice seems to be more quantitative than qualitative.
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PMID:Significance of anti-nuclear and anti-extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice. 869 21

IgG antibody specific to double-stranded DNA (dsDNA) has been recognized as a predictive indicator of the renal involvement in systemic lupus erythematosus. However, we recently experienced two cases of overt lupus nephritis without IgG anti-dsDNA antibody. In both cases, high titers of antibody to the histone dimer (H2A-H2B)-dsDNA complex were detected. They responded well to the corticosteroid therapy, with a cytotoxic agent in one case, and the titers of anti-(histone-DNA) antibody was decreased along with the improvement of proteinuria. Based on the recent reports suggesting a pathogenic role of this antibody in lupus nephritis, we suggest that measurement of the anti-(histone-DNA) antibody is necessary in lupus nephritis patients, especially when IgG anti-dsDNA antibody is not detectable.
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PMID:[Two cases of lupus nephritis having a high titer of anti-(histone-DNA) complex antibody without IgG anti-dsDNA antibody]. 875 39

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

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.
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PMID:Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus. 910 33

Chromatin, a huge polymer of nucleosomes, has been implicated as an important target of autoantibodies in idiopathic and drug-induced lupus for decades, but the antigenicity of chromatin has only recently been dissected. IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, is present in the majority of patients with systemic lupus erythematosus, in > 90% of patients with lupus induced by procainamide and in individual patients with lupus induced by a variety of other drugs, but is not seen in people taking these medications who are clinically asymptomatic. Anti-[(H2A-H2B)-DNA] accounted for the bulk of the anti-chromatin activity in drug-induced lupus. The earliest detectable autoantibody in lupus-prone mice recognized similar epitopes in the (H2A-H2B)-DNA subnucleosome complex; as the immune response progressed, native DNA and other constituents of chromatin became antigenic. The importance of chromatin-reactive T cells in the anti-[(H2A-H2B)-DNA] response is suggested by the presence of somatic mutations in antibody VH and VL regions, their predominant IgG isotype and the similarity in kinetics of their production to that of conventional T cell dependent antigens. Together with the serologic data from human lupus-like disease, these results are consistent with chromatin being a common stimulant for both B and T cells. While chromatin-reactive antibodies are closely associated with systemic disease and have recently been implicated in glomerulonephritis in SLE, the absence of renal disease in drug-induced lupus indicates that additional abnormalities are required to manifest the serious pathogenic of anti-[(H2A-H2B)-DNA] antibodies.
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PMID:Autoantibody to the nucleosome subunit (H2A-H2B)-DNA is an early and ubiquitous feature of lupus-like conditions. 911 24

Recently, anti-nucleosome antibodies, which do not bind to DNA or to individual histones, have been identified in longitudinal studies in lupus mice. These anti-nucleosome antibodies occur early in spontaneous SLE and are formed prior to other anti-nuclear specificities. However, nucleosomal epitopes are yet to be fully characterized. We selected a panel of six monoclonal anti-nucleosome antibodies (mAbs) (#2, #32, #34, PL2-6, LG8-1 and LG10-1) derived from lupus mice. These mAbs were tested in ELISA on subnucleosome structures and on a panel of 53 histone peptides, covering the entire sequence of the five histones. Two mAbs reacted with one of these peptides, but the reactivity hardly exceeded the background reactivity. Based on the nucleosome and subnucleosome ELISA we identified different recognition patterns. Three mAbs showed the highest reactivity towards the intact nucleosome. For two of them (#32 and LG8-1) the nucleosomal epitope was primarily located on H2A-H2B/DNA, whereas for mAb #34 this primary epitope was located on H3/H4/DNA. Two mAbs (#2 and PL2-6) showed the highest reactivity with H2A-H2B/DNA and one mAb (LG10-1) recognized H3-H4/DNA. In the subnucleosome ELISA all but one (mAb #32) recognized more than one epitope, including DNA complexed to a variety of cationic molecules. Comparing these reactivities we identified for all mAbs one specific nucleosomal epitope, whereas reactivity with other subnucleosomes was comparable to the reactivity towards DNA complexed with cationic molecules. In inhibition experiments both in ELISA and in immunofluorescence it was found that only one of the mAbs (i.e. PL2-6), recognizing an epitope on H2A-H2B/DNA as primary epitope, could be inhibited by H2A-H2B/DNA in fluid phase. The two mAbs recognizing an epitope on H3-H4/DNA as primary epitope could be inhibited by H3-H4/DNA in fluid phase. From these analyses, we conclude first that for these nucleosome specific mAbs linear histone peptides are not very important. Second, that these mAbs all recognize different epitopes on both H2A/H2B-DNA and H3/H4-DNA and third that some solid phase H2A/H2B-DNA epitopes are not expressed on fluid phase H2A/H2B-DNA. Our findings suggest that in SLE the nucleosome can act as auto-antigen and that there is no immunodominant beta cell epitope within the nucleosome.
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PMID:Specificity of monoclonal anti-nucleosome auto-antibodies derived from lupus mice. 911 74


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