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 antigenic domains of histone 5 (H5), a highly conserved variant of histone 1 (H1), were studied in relation to their reactivity with autoantibodies found in the sera of patients with systemic lupus erythematosus (SLE) and drug-induced lupus (DIL). While some H5 antibodies cross-react with H1, adsorption and immunoblotting studies have identified H5-specific antibodies as well. After proteolytic cleavage of H5 peptides, the reactivity of sera from these patients was tested by Western immunoblotting. All SLE (9/9) and DIL (7/7) sera bound an antigenic determinant in the carboxyl (C) terminus of H5 while none of the sera bound to the amino (N) terminus or the central hydrophobic domain. Although the reactivity of DIL sera with the purified H5 peptides was weaker than that of SLE sera, the antigenic domains bound by both groups of sera were the same. These observations demonstrate that the H5 domains reacting with DIL sera are restricted to the carboxyl terminus and are therefore no less restricted than those reacting with SLE sera. Further, the potential epitopes in the carboxyl terminus of H5 do not have a high degree of sequence identity with known mammalian peptides.
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PMID:Antibodies from patients with systemic lupus erythematosus and drug-induced lupus bind determinants on histone 5 (H5). 169 56

The presence of a positive lupus anticoagulant (LA) has recently been associated with reproductive failure. LA positivity and reproductive failure have also been associated with autoantibody abnormalities, especially antiphospholipid autoantibodies. Because the correlation between LA and autoantibody positivity has remained controversial, we retroactively investigated 326 sera of patients with reproductive failure for correlation between lupus anticoagulant and 15 autoantibodies separately for IgG, IgM, and IgA isotypes. LA by TTI and APTT correlated significantly (p less than 0.0001). Among 18 antiphospholipid isotypes, 6 (33%) correlated significantly with TTI, 5 (28%) with APTT, and 3 (17%) both with TTI and APTT. Among 15 isotypes to histone subfractions, 4 (27%) correlated significantly to TTI, 3 (20%) to APTT, and 2 (13%) to both LA assay methods. Of 12 isotypes to antipolynucleotide antibodies, 2 (17%) correlated significantly to TTI, 1 (8%) to APTT, and none to both assay methods. The correlation between LA and autoantibodies was less striking among LA-positive than LA-negative sera. LA by both TTI and APTT was primarily found to correlate with IgG and IgA autoantibodies. This occurs in decreasing frequency to phospholipids, histones, and polynucleotides. At abnormal levels of LA (by either method) the correlation with autoantibody levels is less pronounced and appears closer with IgM autoantibodies to histones and polynucleotides than antibodies to phospholipids. We conclude that the correlation between LA and autoantibodies, especially antiphospholipid antibodies, is less pronounced than often reported in the literature. Patients suspected to suffer from reproductive failure due to abnormal autoimmunity have to be screened not only with LA and/or selected antiphospholipid autoantibodies, but with a more comprehensive autoantibody profile.
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PMID:The correlation between lupus anticoagulant and autoantibodies. 173 35

Systemic lupus erythematosus (SLE) and other autoimmune diseases are characterized by immune responses to intracellular, highly conserved antigens such as DNA and histone. In this study, peripheral blood lymphocytes (PBL) from a patient with histone autoantibodies were used to prepare IgM human-human hybridoma cell lines. Indirect immunofluorescence (IIF) was used to identify monoclonal antibodies that bound to cytoskeletal and other cytoplasmic constituents. These supernatants did not bind double-stranded or single-stranded DNA. However, immunoblotting revealed that 7/20 hybridomas selected for their binding to cytoskeletal components produced antibodies that also bound mammalian and avian histones. When peptide fragments of histone were used in immunoblotting experiments, it was found that the monoclonal antibodies bound to the carboxyl terminus of H1, a region previously shown to bind autoantibodies from sera of patients with SLE and drug-induced lupus (DIL). When the amino acid sequences of histones and cytoskeletal components were compared using the Swiss-Prot protein data bank, it was confirmed that there are eight regions of similarity. While the significance of polyreactive human monoclonal antibodies to cytoskeletal components and histones is not understood at present, it is possible that the human histone antibodies represent polyreactive antibodies that arise through the mechanism of molecular mimicry.
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PMID:Human monoclonal antibodies demonstrate polyreactivity for histones and the cytoskeleton. 177 13

Increasing evidence suggests that autoantibodies in the rheumatic diseases are a consequence of immune selection by self-material, but the nature of the in vivo immunogen is unknown. Insight into this problem may be obtained by measuring autoantibody binding to various forms of a target antigen. Antihistone antibodies arising as a side effect of therapy with various drugs offer an opportunity to explore this premise because many forms of histone have been characterized and adapted to ELISA formats. Two patterns of antibody reactivity were observed. All 21 patients with symptomatic procainamide-induced lupus and 7 of 12 patients with quinidine-induced lupus had IgG antibodies reacting predominantly with the (H2A-H2B)-DNA complex and with chromatin. In contrast, antibodies in 19 of 24 patients taking procainamide without accompanying lupus-like symptoms did not show any pattern. The second pattern was observed in 18/19 chlorpromazine-treated patients and 14/17 patients with hydralazine-induced lupus in which IgM antibodies displayed more reactivity with DNA-free histones than with the corresponding histone-DNA complexes and almost no binding to H1-stripped chromatin. Absorption studies were entirely consistent with these results. Thus, the two patterns of reactivity with nucleosomal components reflect the molecular substructure of chromatin, suggesting that two processes underlie antihistone antibody induction by drugs. In one, IgG autoantibodies appear to be elicited by chromatin, whereas in the other, autoimmune tolerance to native chromatin appears largely intact, and IgM antibodies may be driven by DNA-free histone.
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PMID:Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. 186 77

As autoantibodies are thought to participate in the pathogenesis of renal inflammation in systemic lupus erythematosis (SLE) we investigated associations between serological markers of disease activity in SLE and the activity of renal histopathological lesions in thirty-five patients with lupus nephritis (LN). We found the following prevalence of serum auto-antibodies in LN: IgG antinuclear antibodies (ANA) 100%, IgM ANA 69%, IgA ANA 60%, IgG anti-dsDNA 60%, IgM anti-dsDNA 71%, IgA anti-dsDNA 60%, anti-RNP 20%, anti-Sm 14%, anti-SSA 31%, anti-SSB 14%, anti-histone 37%, anti-cardiolipin 80% and antibody to ribosomal protein (anti-P) 6%. No correlation was found between serological parameters and the WHO-classification of biopsies. The activity-index of histological lesion, assessed according to the NIH-renal histology scoring system, correlated with IgM ANA and IgM anti-dsDNA titers. Of all the specific features of histological renal inflammation, glomerular proliferation showed the best overall correlation with serological parameters of disease activity. Anticardiolipin antibodies were correlated with overall disease activity, but not with renal histological activity. Thus, serological markers of disease activity did not adequately reflect the amount of renal inflammation in LN and cannot replace renal biopsy as a diagnostic tool.
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PMID:Relation between serological data at the time of biopsy and renal histology in lupus nephritis. 194 73

This study presents 8 dogs of German Shepherd breed (6 males, 2 females, 2-5 years of age at onset of the disease) with a lupus like syndrome characterized by febrile polyarthritis, wasting, nephropathy, cutaneous lesions and high positive titres of ANA (antinuclear antibodies) of speckled type. The serum autoantibodies were further characterized by double immunodiffusion against ENA (extractable nuclear antigen), ELISA for Histone antibodies (Histon fraction H-24A and H-3S), indirect IF on rat-liver sections, non treated and RNase/DNase digested sections for DNP/RNP antibodies, and smears of a hemoflagellate C. luciliae for antibodies vs doubbel strained DNA, (dsDNA). Thus, the high ANA titres in these dogs represent varying types of autoantibodies against nucleoproteins of both DNA and RNA nature, associated histone antigens and non-histone antibodies (RNA and Sm) as well. Rheumatoid Factor titres in serum from these dogs were low or negative. Immunoglobulin deposits at dermo-epidermal junctions were demonstrated in some of the dogs with hyperkeratotic skin lesions. High concentration of serum-IgG was a constant finding in combination with anemia and in most cases leukopenia probably related to the chronic inflammatory process in these animals. Autoimmune hemolytic anemia (AIHA) or thrombocytopenia was not detected in these dogs.
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PMID:Serum auto antibodies and clinical/pathological features in German shepherd dogs with a lupuslike syndrome. 195 Aug 49

Abnormal autoantibodies have recently been implicated in pregnancy wastage. The normal autoantibody profile of pregnancy has so far, however, not been established. We investigated the effect of pregnancy on autoantibody production prospectively and longitudinally. Forty-three healthy pregnant women were compared with 50 nonpregnant healthy controls matched for age, race, and various obstetric and medical indices. All sera were tested for total immunoglobulin (Ig) levels; IgG, IgM, and IgA isotypes of autoantibodies to six phospholipids; total histone and four histone subfractions; and four polynucleotides. Plasma samples were evaluated for the presence of lupus anticoagulant. Total IgG decreased significantly in pregnant patients. The majority of autoantibody levels in pregnant women were within normal nonpregnant ranges. Only a few autoantibodies were increased in early pregnancy, including IgG antiphosphatidylinositol and H 2B, IgM antiphosphatidylinositol and phosphatidic acid, and IgA antiphosphatidylinositol and H 4. Most autoantibodies, although increased at term, were still within the normal nonpregnant range. Normalizing the data for expanded plasma volume did not significantly alter these results. Adjustment regression analysis excluded age, race, and various medical and obstetric indicators as confounding variables for autoantibody levels. The expected and observed prevalence of positive autoantibody levels in pregnant women was not significantly different from that of nonpregnant controls. None of the pregnant women demonstrated positive lupus anticoagulant. We conclude that in normal pregnancy between 16 weeks' gestation and term, autoantibody levels are largely within the normal range. Alterations occur, if at all, at the time of delivery.
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PMID:The prevalence of autoantibodies and lupus anticoagulant in healthy pregnant women. 210 7

IgG immunoglobulin preparations have been increasingly utilized to treat a variety of diseases. Since disease response to this form of therapy in patients with abnormal autoimmune function is often evaluated through the subsequent investigation of autoantibody levels, it is possible that autoantibody positivities reflect autoantibody reactivity of circulating immunoglobulin preparations and not of the patient's inherent B-cell activity. We therefore investigated three commercially available IgG immunoglobulin preparations separately for IgG, IgM and IgA autoantibody reactivity to six phospholipid antigens, total histone and four histone subfractions, and four polynucleotides. Universally, all three preparations demonstrated considerable IgG antiphospholipid and antihistone reactivity at dilutions of up to 1:10(3) but not antipolynucleotide reactivity. Although no IgM reactivity was detected in any of the preparations, in all three preparations surprising IgA reactivity, especially with antihistone specificity, was detected. No autoantibody reactivity was detected at dilutions compatible with physiologic conditions in vivo. Identical observations were made for lupus anticoagulant reactivity, which was evaluated by activated partial thromboplastin time (APTT) and tissue thromboplastin inhibition (TTI). Since autoantibody reactivities and prolonged APTT assays are observed only at pharmacologic dilution levels, it is unlikely that the administration of IgG immunoglobulin preparation will affect the evaluation of autoantibody levels in patients undergoing such treatment.
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PMID:Commercial IgG immunoglobulin preparations exhibit IgG and IgA autoantibody reactivity at pharmacologic but not at physiologic concentrations. 212 97

Autoantibodies to the non-histone nucleoprotein antigens SS-A/Ro, SS-B/La, and RNP are highly associated with photosensitive cutaneous lupus erythematosus (LE). In order to better understand the potential mechanisms of ultraviolet (UV) light on photosensitivity in patients with cutaneous LE, we designed immunopathologic in vitro and in vivo experiments to evaluate the effects of UV on the binding of such autoantibodies to the surface of human keratinocytes, one major target of immunologic damage in photosensitive LE. Short-term 2% paraformaldehyde fixation of suspensions of cultured human keratinocytes previously incubated with monospecific antiserum probes enabled the detection of ENA expression on the cell surface by flow-cytometry analysis. UVB light (280-320 nm) induced the binding of monospecific antibody probes for SS-A/Ro and SS-B/La on keratinocytes in a dose-dependent pattern with maximal induction observed at the dose of 200 mJ/cm2 UVB. Binding of SS-A/Ro, SS-B/La, and RNP antibody was augmented strongly, but binding of anti-Sm was very weak. In contrast, UVA (320-400 nm) light had no effect on the induction of binding of these antibody probes. Identical results were seen by standard immunofluorescence techniques. Hydroxyurea-treated keratinocytes showed similar induction of those antigens by UVB irradiation, which suggested that ENA expression on cultured keratinocytes by UVB were cell-cycle independent. Tunicamycin, an inhibitor of glycosylation of proteins, reduced UVB light effect on the SS-A/Ro and SS-B/La antigen's expression. These in vitro FACS analyses revealed that ENA augmentation on the keratinocyte cell surface was dose dependent, UVB dependent, glycosylation dependent, and cell-cycle independent. In vivo ENA augmentation on the keratinocyte surface was examined in suction blister epidermal roofs. Specific antibody probes for SS-A/Ro, SS-B/La, RNP, and Sm bound to human keratinocytes in intact suction blister epidermis following UVL irradiation in vivo. Using three different protocols, we have demonstrated that antibodies to SS-A/Ro, SS-B/La, and U1RNP bind to UVL-irradiated human keratinocytes. We speculate that this antibody binding is an important inducer of antibody dependent keratinocyte damage in photosensitive cutaneous lupus.
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PMID:Binding of antibodies to the extractable nuclear antigens SS-A/Ro and SS-B/La is induced on the surface of human keratinocytes by ultraviolet light (UVL): implications for the pathogenesis of photosensitive cutaneous lupus. 187 59

In spite of intensive endeavours, attempts to identify nephritogenic antigens in cases of immune complex glomerulonephritis have not yielded convincing results. Cationic antigens can have high affinity for the glomerular basement membrane and are prime candidates as nephritogens. They can be expected to play a role in post-infectious and in autoimmune glomerular disease. Histones show great promise in the latter case: we are able to demonstrate (1) a high affinity for the glomerular basement membrane and (2) their ability to promote glomerular deposition of anionic antigens as an additional target. Histones were detectable in glomerular deposits in two murine models of glomerulonephritis: the spontaneous lupus-like disease of NZB/W F1 mice and in graft-versus-host disease. We propose that histones may be responsible for the induction of glomerulonephritis in lupus-like syndromes, as well as other types of autoimmune renal disease. As an analogue, histone-like proteins from micro-organisms may also be responsible for glomerular disease in post-infectious nephritis.
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PMID:The role of cationic proteins in the pathogenesis of immune complex glomerulonephritis. 215 42


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