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)

Formation of anti-nuclear autoantibodies is a cardinal characteristic of systemic lupus erythematosus (SLE). In recent years the nucleosome has been identified as the major autoantigen, since nucleosome specific T cells have been identified, which also drive the formation of anti-dsDNA and anti-histone antibodies. Nucleosome specific autoantibodies are present in a large majority of SLE patients and lupus mice. Nucleosomes are formed during apoptosis by organized cleavage of chromatin. These nucleosomes together with other lupus autoantigens cluster in apoptotic bodies at the surface of apoptotic cells. Systemic release of these autoantigens is normally prevented by swift removal of apoptotic cels. However, if the rate of apoptosis overflows the removal capacity and/or the cleaning machinery is reduced, nucleosomes are released. Furthermore, during apoptosis autoantigens can be modified, which makes them more immunogenic. Nucleosomes also play a pivotal role in the evolution of tissue lesions, especially glomerulonephritis. In lupus nephritis nucleosomes, anti-nucleosome autoantibodies and nucleosome/Ig complexes have been identified in the glomerular immune deposits. Via their cationic histone part nucleosomes can bind to heparan sulfate, a strong anionic constituent of the glomerular basement membrane.
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PMID:Lupus nephritis: a nucleosome waste disposal defect? 1251 68

The formation of autoantibodies against chromatin is the main feature of systemic lupus erythematosis (SLE), an autoimmune disease, which is T-cell dependent and autoantigen-driven. Historically, antibodies against dsDNA, one of the components of chromatin, are considered as a hallmark of SLE. However, dsDNA is poorly immunogenic. Nucleosome-specific T helper cells have been identified. These T cells propagate not only nucleosome-specific antibodies, but also anti-dsDNA antibodies. Nucleosomes are formed during apoptosis by cleavage of chromatin, and evidence of disturbed apoptosis has been found especially in certain murine models of lupus. In addition to an increased rate of apoptosis, autoimmunity against chromatin might also result from an impaired phagocytosis of apoptotic material, for which strong evidence has been provided by studies in certain knock-out mice (C1q, SAP, Dnase I). The induction of an immune response to nucleosomes could be enhanced by modifications of histones or DNA during apoptosis, altered presentation by antigen presenting cells or a viral infection. The release of nucleosomes and the formation of anti-chromatin autoantibodies result in formation of complexes, which bind to the glomerular basement membrane via heparan sulfate. This deposition incites glomerulonephritis, the most serious manifestation of SLE.
Lupus 2002
PMID:Triggers for anti-chromatin autoantibody production in SLE. 1252 51

Venous thromboembolism is a common and potentially fatal disease. If properly used, anticoagulation therapy is effective in preventing recurrence of venous thromboembolism and in improving survival. Symptomatic patients with an objective diagnosis of acute deep vein thrombosis (DVT) or pulmonary embolism (PE) should receive immediate systemic heparin anticoagulation at dosages sufficient to rapidly prolong the activated partial thromboplastin time into the laboratory-specific therapeutic range; this range corresponds to a plasma heparin concentration of 0.2 to 0.4 IU/ml (as measured by protamine sulfate titration), or 0.3 to 0.7 anti-Xa IU/ml. An oral vitamin K antagonist (e.g. warfarin) should be started within 24 hours after starting heparin; the starting dose should be the estimated patient-specific daily dose with no loading dose. Heparin and warfarin anticoagulation should be overlapped for at least 4 to 5 days and until the international normalized ratio (INR) is within the therapeutic range (2.0 to 3.0) on 2 measurements made at least 24 hours apart. The duration of warfarin anticoagulation should be individualized based on the respective risks of venous thromboembolism recurrence and anticoagulant-related bleeding. In general, warfarin should be continued for at least 3 months, and longer for patients with recurrent or idiopathic venous thromboembolism, malignant neoplasm, neurologic disease with extremity paresis, obesity, or laboratory evidence of a lupus anticoagulant/anticardiolipin antibody, homozygous carrier or combined heterozygous carrier for the factor V R506Q (Leiden) and prothrombin G20210A mutations, and possibly deficiency of either antithrombin, protein C, or protein S. Low molecular weight heparin (LMWH) is effective and well tolerated as acute therapy for patients with DVT or stable PE, and does not require laboratory monitoring or dose adjustment. Outpatient LMWH therapy is also well tolerated and cost effective for most patients with DVT, and possibly for selected patients with PE.
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PMID:Current management of acute symptomatic deep vein thrombosis. 1472 51

We describe the safety and efficacy of long-term immunoadsorbent plasmapheresis (IAPP) with dextran sulfate-cellulose bead columns in antiphospholipid syndrome (APS). IAPP was administered to a 38-year old male Japanese patient with APS with Budd-Chiari syndrome (BCS), who had presented with refractory lower leg skin ulcers and arterial and venous thromboses including BCS. After hepatic vein transluminal angioplasty was performed, the combination of corticosteroid, aspirin and IAPP was administered because of an underlying bleeding tendency related to liver dysfunction. From February 1994 to February 2003, a total of 228 procedures were performed. No further thrombosis-related symptoms or bleeding have occurred for more than nine years, suggesting that IAPP with dextran sulfate cellulose columns is safe and effective for APS in preventing additional thrombotic events. This IAPP supplements anticoagulation, antiplatelet, corticosteroid and immunosuppressant therapies.
Lupus 2004
PMID:Long-term efficacy of immunoadsorbent plasmapheresis in a patient with Budd-Chiari syndrome due to antiphospholipid syndrome: case report with nine-year follow-up. 1499 8

Disturbances of the embryo-maternal interaction, i.e. impaired implantation, are seen in only a minor fraction of couples. These malfunctions become evident as recurrent spontaneous abortions (RSA), or repetitive implantation failure (RIF) in cases with IVF or ICSI procedures. The antiphospholipid syndrome (APL) is the only consensus-defined syndrome associated with RSA (anticardiolipin antibodies and/or lupus anticoagulant plus clinical symptoms). Since antiphospholipid antibodies directly interfere with hemostasis (increased coagulation), heparin is an established treatment option in these cases resulting in unequivocal benefits. There is no defined antibody syndrome in RIF even if it may be assumed that it exists. Conclusive evidence for a benefit of heparin (and aspirin) in this situation is lacking as well. However, the majority of investigations including our own experience indicate that anticoagulation may be useful. Besides the extensively studied anticardiolipin antibodies, other - by far less thoroughly investigated - antiphospholid antibodies have been described. So far it is unclear if heparin may exert positive effects in women carrying these antibodies. Autoreactive immune processes may also become apparent by the emergence of further antibodies, such as antinuclear (ANA), thyreoglobulin (TGA) and thyreoperoxidase antibodies (TPO) etc. However, there is no established definition of a syndrome associated with these antibodies, TGA and TPO probably being the most relevant. - Most studies in this area including our own experience indicate that heparin may be a useful. The detection or autoantibodies per se is probably not of pathophysiological relevance if there is no ongoing pathological activation of the immune system. However, an acute autoimmune response associated with irregular antibodies may represent the pathophysiological basis of a reproductive autoimmune failure syndrome. In these cases, immune-equilibrating interventions appear to be more appropriate than heparin therapy. - Coagulation disorders, namely thrombophilia, are a frequent cause of RSA and probably RIF as well, the most relevant being antithrombin deficiency, Factor V Leiden and prothrombin mutations. Deficiencies of protein S, protein C and factor XII and XIII are of minor importance. There is a varying degree of evidence for a benefit of heparin/aspirin in these syndromes. Heparin not only reduces the abortion rate but also lowers the risk for developmental retardation, premature birth and preeclampsia. - The effects of heparin are not restricted to anticoagulation. It is directly or indirectly (e.g. via heparan sulfate proteoglycans or heparin-binding EGF) involved in the adhesion of the blastocyst to the endometrial epithelium and the subsequent invasion. Actually, prolonged heparin treatment (14 days) resulted in an increased pregnancy rate in our patient population. Shorter courses of heparin where not effective.
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PMID:Effectivity of heparin in assisted reproduction. 1521 Apr 1

There is no serologic test that reliably measures disease activity in systemic lupus erythematosus (SLE). The 'gold standard' is the anti-dsDNA antibody test, which has been used as a marker of disease activity by clinicians in SLE for over 35 years. Anti-dsDNA antibodies perform best in those with lupus nephritis, specifically in the presence of a proliferative lesion [World Health Organization (WHO) class III or IV] on renal biopsy. In one recent meta-analysis, the mean positive likelihood ratio of anti-dsDNA antibodies as a marker of disease activity in SLE was 4.14, implying the overall predictive effect was small. More recently autoantibody assays have been developed that show greater promise in gauging SLE disease activity, specifically anti-nucleosome and anti-C1q antibodies (especially with renal disease activity). Other tests thought previously to be lacking in specificity that refinements in ELISA technology now render possibly useful include anti-heparan sulfate, anti-ssDNA and anti-Scl-70 autoantibodies. Other tests that as yet have not been shown to be as reliable (and therefore are not as useful in clinical practice for serial determination to measure disease activity) include other anti-extractable nuclear antibodies (anti-Ro, La, Sm, RNP), anti-cardiolipin antibodies, and anti-nuclear cytoplasmic antibodies (ANCA). New technologies using proteomic determinations show promise as aids in the search for more reliable and feasible autoantibody determinations of disease activity in SLE.
Lupus 2004
PMID:Predictive value of autoantibodies for activity of systemic lupus erythematosus. 1523 Feb 81

Systemic lupus erythematosus (SLE) is characterized by the development of a large array of autoantibodies that primarily are directed against the whole chromatin (antinucleosome) and its individual components, dsDNA and histones. Apoptotic defects and impaired removal of apoptotic cells could contribute to an overload of autoantigens (and in particular of nucleosomes) in circulation or in target tissues that could become available to initiate an autoimmune response. In susceptible individuals, this can lead to autoantibody-mediated tissue damage. In addition to intrinsic or secondary apoptosis/apoptotic cell removal defects, certain apoptotic stimuli (eg, UV, viruses) could lead to posttranscriptional modifications that generate autoantigen cryptic fragments for which cells of the immune system have not been tolerized. Besides their role as a major immunogen in lupus, nucleosomes participate in antibody-mediated renal pathogenicity and act as a bridging molecule that recognizes heparin sulfate/collagen V components of the glomerular basement membrane. New tools that were developed to detect antinucleosome antibodies in the serum of patients (by ELISA) have shown the specificity and the high sensitivity of antinucleosome antibody reactivity in SLE. In particular, antinucleosome could be a useful marker of patients who have SLE and lack anti-dsDNA antibodies, a prognosis marker for imminent relapse, and a diagnosis marker of lupus nephritis.
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PMID:Nucleosomes in the pathogenesis of systemic lupus erythematosus. 1526 40

Histological studies suggest that the basement membrane zone (BMZ) is the main target of tissue pathology in cutaneous lupus erythematosus (LE). The BMZ is characteristically thickened and is the site of deposition of autoantibodies in LE. Alteration of some (BMZ) macromolecules is implicated in the pathology of several bullous skin diseases. A major component of BMZ is heparan sulphate proteoglycan (HSPG) which was found reduced in the skin of some patients with systemic lupus erythematosus (SLE) and in the kidney of mice with lupus nephritis. Similar to the skin, amnion is derived from the ectodermal germ layer during embryogenesis and expression of BMZ components of amniochorion was not previously studied in SLE. The aim of the present study was to investigate the expression of major BMZ macromolecules in the skin, kidney and amnioplacentae obtained from patients with SLE and compare these findings with organ biopsies from unaffected individuals. In addition, determining whether the differences in composition and distribution of BMZ macromolecules in these organs correlate with certain patterns of deposition of immunoreactants could contribute to our understanding of the mechanism of deposition of immunoreactants in SLE. In some patients with SLE, reduced expression of HSPG in nonlesional skin was reported previously. These changes of heparan sulphate might be important in the pathogenesis of LE. Therefore, the aims of this study are to confirm the previous finding and to compare HSPG expression between lesional and nonlesional LE skin. The unique features of each BMZ could contribute to the deposition or binding of positively charged immune complexes and explain the different patterns of immunofluorescence. Frozen sections of skin, kidney and amniochorion obtained from patients with SLE were investigated by indirect immunofluorescence technique using monoclonal antibodies (Moab) to determine the expression of major components of the BMZ. Heparan sulfate expression is reduced in the skin and, to a lesser extent, in the kidney in patients with SLE. There was no correlation between the kidney and skin heparan sulfate expression within the same patient. The BMZ composition in amniochorionic membrane ofplacentae from women with SLE was normal. Heparan sulfate may be one of the major targets for immunoglobulin deposition in the skin of patients with SLE. The processes of immunoglobulin deposition in SLE may be more complex in that there was no correlation between heparan sulfate expression in the skin and kidney of the same patient.
Lupus 2004
PMID:The basement membrane zone in patients with systemic lupus erythematosus: immunofluorescence studies in the skin, kidney and amniochorion. 1546 89

Sulfatide, ceramide galactosyl-3'-sulfate, is mainly present in nervous tissue, kidney, testis, red blood cells, platelets and granulocyte. Antibodies to sulfatide are present in many patients with demyelinating peripheral neuropathy, HIV infection and systemic lupus erythematosus and may account for some of the clinical manifestations. To evaluate the effect of such antibodies, we have constructed a phage-display antibody fragment library from the lymphocytes of patients with systemic lupus erythematosus. Sulfatide-reactive phage were selected by absorption and elution on sulfatide liposomes and soluble single chain variable fragment (ScFv) were isolated from individual colonies and tested in an ELISA assay for binding to bovine brain sulfatide. Five ScFv clones that bound sulfatide were isolated. Two of the clones, PH5 and PA38, bound sulfatide but not phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin or ceramide. These two clones also bound sulfatide from human red blood cells. The DNA encoding the fragments was sequenced, revealing predicted polypeptides of 19 kDa for PH5 containing only variable heavy (VH) sequences, and 31 kDa for PA38, with both VH and variable light (VL) sequences. Although they had similar antigen specificities, the VH domains of the two clones were derived from different heavy-chain families. The clustered mutational patterns in the complementarity-determining region (CDR) of the heavy chains in both clones suggest that the V-domains are the products of antigen-driven B cell clonal maturation leading to the development of sulfatide-binding specificity. These results show the presence of sulfatide-specific antibodies in lupus patients, and allow us to test the possibility that the interaction of the antibodies with sulfatide may contribute to some of the symptoms. In addition, the antibodies provide useful reagents to test the role of sulfatide in pathophysiological processes.
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PMID:Characterization of autoantibodies against sulfatide from a V-gene phage-display library derived from patients with systemic lupus erythematosus. 1562 18

Spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by a constellation of behavioral deficits, including blunted responsiveness to sucrose. Although autoimmunity-induced damage of limbic areas is proposed to underlie this deficit, the systemic nature of the disease precludes inference of a causal relationship between CNS damage and functional loss. Based on the stimulatory effects of d-amphetamine sulfate (AMPH) on sucrose intake, the present study pharmacologically probes the functional status of central dopaminergic circuits involved in control of behavioral reward. The response rates were compared between diseased MRL-lpr mice and congenic MRL +/+ controls tested in the sucrose preference paradigm. Neuronal loss was assessed by Fluoro Jade B (FJB) staining of nucleus accumbens and the CA2/CA3 region. While control mice significantly increased intake of sucrose solutions 60 min after administration of AMPH (i.p., 0.5 mg/kg), the intake in drugged MRL-lpr mice was comparable to those given saline injection. Increased FJB staining was detected in the nucleus accumbens and hippocampus of diseased mice, and AMPH treatment neither altered this nor other measures of organ pathology. The results obtained are consistent with previously observed changes in the mesolimbic dopamine system of MRL-lpr mice and suggest that the lesion in the nucleus accumbens and deficits in dopamine release underlie impaired responsiveness to palatable stimulation during the progress of systemic autoimmune disease. As such, they point to a neurotransmitter-specific regional brain damage which may account for depressive behaviors in neuropsychiatric lupus erythematosus.
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PMID:Impaired response to amphetamine and neuronal degeneration in the nucleus accumbens of autoimmune MRL-lpr mice. 1618 44


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