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)

In 30 of 33 human systemic lupus erythematosus (SLE) sera and in 10 sera from MRL/l mice with spontaneous SLE, antibodies against heparan sulfate were detected. The anti-heparan sulfate titers showed a significant correlation with the anti-DNA antibody titers. By inhibition studies it was demonstrated that heparan sulfate could inhibit the binding of anti-DNA antibodies to DNA, whereas DNA could block the binding to heparan sulfate. That this reaction is due to crossreactivity of anti-DNA antibodies was further substantiated by the finding that two monoclonal anti-DNA antibodies also bound to heparan sulfate. Antibodies eluted from human and mouse kidneys with diffuse SLE glomerulonephritis showed a similar binding to DNA and heparan sulfate when these eluted antibodies were tested in vitro. Heparan sulfate is the major glycosaminoglycan constituent of the glomerular basement membrane. Our findings suggest that heparan sulfate might serve as a target antigen in vivo for cross-reactive anti-DNA antibodies.
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PMID:Cross-reactivity of human and murine anti-DNA antibodies with heparan sulfate. The major glycosaminoglycan in glomerular basement membranes. 294 Feb 65

Heparan sulphate-reactive antibodies in lupus sera have been suggested to be anti-DNA-DNA/histone immune complexes and to be associated with lupus nephritis. In this study, 23 anti-DNA-positive lupus sera including 13 active nephritis sera were tested for the presence of circulating anti-DNA-DNA/histone immune complexes by solid phase heparan sulphate-ELISA. Because of high background binding to protamine chloride-linked heparan sulphate plates, poly-L-lysine (PLL) was used as a linker and the remaining active sites of PLL were blocked with poly-L-glutamic acid. The ELISA was capable of detecting small amounts of anti-DNA IgG-DNA/histone immune complexes formed in vitro. However, only three active nephritis sera of the 23 sera tested showed significant binding to heparan sulphate plates. This binding was found to be non-specific, the result of high background binding of IgG to PLL. Anti-heparan sulphate ELISA using positively charged linkers detects non-specific binding when lupus sera are tested. Specific assays need to be developed for DNA/histone-related immune complexes present in lupus sera.
Lupus 1995 Feb
PMID:Heparan sulphate-ELISA gives false positive results for anti-DNA-DNA/histone immune complexes in sera of patients with SLE. 753 23

Markers of endothelial cell activation were measured in 28 patients presenting with various forms of limited or focal type cutaneous vasculitis. Plasma levels of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) and PAI-1 activity, fibrin plate, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and soluble thrombomodulin (sTM) were measured. In comparison with the control group (n = 20) there was a significant increase in t-PA:Ag, vWF:Ag and TF (P < 0.05, Mann-Whitney U-test) in the cutaneous vasculitis group. This study confirms that measurable degrees of endothelial activation occur in cutaneous vasculitis. Cutaneous vasculitis includes a diverse group of clinical conditions, which are associated with inflammatory changes in cutaneous blood vessels with local fibrin deposition. The aetiology and pathogenesis of the majority of these entities remain unknown. Causative mediators are thought to include immune complexes, anti-endothelial cell antibodies, cytotoxic lymphocytes and viruses. Histologically, immune complexes and complement are frequently detected on the vessel wall, and serologically anti-endothelial antibodies are often detected in patients with vasculitis and in systemic lupus erythematosus (SLE) which correlate with the severity of cutaneous vasculitis, arthritis and nephritis. Lymphocyte-mediated toxicity to endothelial cells has been reported in a small number of patients with giant cell arteritis and Takayasu's arteritis. The vascular endothelium plays a central part in the control of haemostasis. Under physiological conditions endothelial cells present an anticoagulant surface to blood constituents, partially due to surface expression of heparan sulphate and thrombomodulin (TM). Heparan sulphate binds antithrombin III (ATIII), thereby accelerating inactivation of intrinsic coagulation enzymes. Thrombomodulin is an endothelial cell surface glycoprotein which promotes anticoagulation by forming a complex with thrombin which then activates protein C. Activated protein C together with a cofactor, protein S, inactivates FVa and FVIIIa. von Willebrand factor (vWF) is synthesized by endothelial cells, stored in Weibel-Palade bodies and released into the circulation upon endothelial stimulation. vWF mediates the binding of platelets to the subendothelium and is the carrier molecule for FVIIIC. The endothelium controls fibrinolysis by producing t-PA and its inhibitor PAI-1. Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF) activate endothelial cells, causing a shift from an antithrombotic to prothrombotic state, including expression of tissue factor, increased synthesis of PAI-1 and decreased expression of TM. Fibrin deposition and intravascular thrombosis are seen in cutaneous vasculitis syndromes, suggesting local endothelial cell activation. The aim of this pilot study was to assess whether perturbation of the endothelium in cutaneous vasculitis could be detected in the patients' plasma samples. If so, further studies to assess any correlation in levels of these markers with disease activity might prove useful in the future.
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PMID:Endothelial cell activation in cutaneous vasculitis. 868 65

Heparan sulfate proteoglycans (HSPGs) are components of the basement membrane of various tissues. They are composed of a core protein and of the negatively charged glycosaminoglycan side chain heparan sulfate, which is covalently bound to the core protein. We previously found that in both human and murine lupus nephritis, heparan sulfate staining in the basement membrane of the glomerulus is almost completely absent, and that there was an inverse correlation between heparan sulfate staining and glomerular immunoglobulin deposits. As immunoglobulin deposits are also present in the skin of systemic lupus erythematosus patients, we investigated the heparan sulfate staining pattern in the basement membrane of the dermal-epidermal junction. furthermore, we studied whether there was a correlation between heparan sulfate staining and deposition of immunoglobulin in the basement membrane of this junction, and between heparan sulfate staining and the presence of anti-DNA antibodies in the serum. Biopsies of non-lesional skin of 21 systemic lupus erythematosus patients (15 anti-DNA positive and 6 anti-DNA negative patients at the time of biopsy) were stained for the HSPG-core protein (mAb JM-72), highly sulfated stretches within heparan sulfate (JM-13), the low sulfated regions of heparan sulfate (mAb JM-403) and for immunoglobulin depositions. Abnormal and discontinuous staining of the low sulfated parts of heparan sulfate using mAb JM-403 in the basement membrane was found in skin biopsies of 4 out of 15 systemic lupus erythematosus patients with anti-DNA antibodies. In contrast, all specimens of anti-DNA negative patients showed normal continuous staining. Staining with JM-13 and JM-72 showed normal linear staining in both groups. The decreased heparan sulfate staining was correlated significantly with the presence of immunoglobulin deposits in the basement membrane. The subgroup could not be identified by its clinical picture. Our results suggest similar but not identical pathways in systemic lupus erythematosus nephritis and skin of systemic lupus erythematosus patients.
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PMID:Decreased staining of heparan sulfate in non-lesional skin of a subgroup of patients with systemic lupus erythematosus. 977 46

Beta2-glycoprotein I (beta2GPI) is a cofactor for anti-phospholipid (aPL) binding to cardiolipin (CL)-coated plates. Beta2GPI is also able to bind to endothelial cell (EC) membranes as supported by in-vivo as well as by in-vitro studies. The PL-binding site in the fifth domain of the molecule is involved in the adhesion to endothelium. Actually, specific mutations in this molecular portion abolish endothelium binding and a synthetic peptide spanning the sequence Glu274-Cys288 of the CL-binding site displays comparable adhesion to EC monolayers. Heparan sulphate appears to be one of the anionic EC membrane structures with which cationic beta2GPI interacts, as supported by studies with heparitinase-treated EC. Beta2GPI binding to EC might be related to its activity as endothelial growth factor or as a lipid-carrying glycoprotein. Adhesion of beta2GPI to endothelial membranes offers suitable epitopes for circulating aPL that, once bound, can induce cell activation
Lupus 1998
PMID:Beta2-glycoprotein I as a 'cofactor' for anti-phospholipid reactivity with endothelial cells. 981 72

Chromatin is an important autoantigen in the pathogenesis of systemic lupus erythematosus (SLE) as an immunogen and as a part of nephritogenic immune complexes. Earlier studies focused on clearance of DNA. However, DNA released into the circulation from dying cells is found associated with histones in nucleosomes. The liver is the major organ involved in clearance of chromatin from the circulation of mice. Heparan sulphate proteoglycans (HSPG) have been implicated in the clearance of various charged molecules. Receptor-mediated clearance of ssDNA by the liver has also been reported. Because chromatin contains positively charged histones in addition to DNA, we wished to determine if HSPG and/or DNA receptors are involved in chromatin clearance. The rate of clearance of H1-stripped chromatin from the bloodstream of C57Bl/10 mice was markedly decreased by prior treatment of mice with Heparinase I. Clearance was also inhibited by heparin, heparan sulphate, and DNA, but not by colominic acid. DNA was the most effective inhibitor of clearance and released chromatin from sites of clearance. Depletion of Kupffer cells and splenic macrophages using liposome-encapsulated Clodronate (dichloromethylene bisphosphonate) markedly inhibited chromatin clearance. These data suggest that chromatin clearance is mediated by charge interactions with cell surface HSPG and by DNA receptors. Clearance and degradation of chromatin require functional macrophages in the liver and spleen.
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PMID:Chromatin clearance in C57Bl/10 mice: interaction with heparan sulphate proteoglycans and receptors on Kupffer cells. 1044 77

Heparan sulfate (HS) is the anionic polysaccharide side chain of HS proteoglycans (HSPGs) present in basement membranes, in extracellular matrix, and on cell surfaces. Recently, agrin was identified as a major HSPG present in the glomerular basement membrane (GBM). An increased permeability of the GBM for proteins after digestion of HS by heparitinase or after antibody binding to HS demonstrated the importance of HS for the permselective properties of the GBM. With recently developed antibodies directed against the GBM HSPG (agrin) core protein and the HS side chain, we demonstrated a decrease in HS staining in the GBM in different human proteinuric glomerulopathies, such as systemic lupus erythematosus (SLE), minimal change disease, membranous glomerulonephritis, and diabetic nephropathy, whereas the staining of the agrin core protein remained unaltered. This suggested changes in the HS side chains of HSPG in proteinuric glomerular diseases. To gain more insight into the mechanisms responsible for this observation, we studied GBM HS(PG) expression in experimental models of proteinuria. Similar HS changes were found in murine lupus nephritis, adriamycin nephropathy, and active Heymann nephritis. In these models, an inverse correlation was found between HS staining in the GBM and proteinuria. From these investigations, four new and different mechanisms have emerged. First, in lupus nephritis, HS was found to be masked by nucleosomes complexed to antinuclear autoantibodies. This masking was due to the binding of cationic moieties on the N-terminal parts of the core histones to anionic determinants in HS. Second, in adriamycin nephropathy, glomerular HS was depolymerized by reactive oxygen species (ROS), mainly hydroxyl radicals, which could be prevented by scavengers both in vitro (exposure of HS to ROS) and in vivo. Third, in vivo renal perfusion of purified elastase led to a decrease of HS in the GBM caused by proteolytic cleavage of the agrin core protein near the attachment sites of HS by the HS-bound enzyme. Fourth, in streptozotocin-induced diabetic nephropathy and during culture of glomerular cells under high glucose conditions, evidence was obtained that hyperglycemia led to a down-regulation of HS synthesis, accompanied by a reduction in the degree of HS sulfation.
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PMID:Glomerular heparan sulfate alterations: mechanisms and relevance for proteinuria. 1065 15

Urinary glycosaminoglycans (GAG) and heparan sulfate (HS) are considered to be markers of early renal involvement. This study was undertaken to demonstrate their excretion patterns in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) with and without arthritis. Serum creatinine and urinary GAG, HS, microalbumin, and creatinine measurements were made in 51 biopsy-proven lupus nephritis (LN) cases, 12 RA patients, and 21 healthy controls. Urinary GAG and HS levels were higher in the LN and RA groups than in controls. Heparan sulfate excretions and SLE disease activity index (SLEDAI) scores were no different between SLE patients with classes 1 and 2 (group A) and those with classes 3, 4, and 5 (group B) renal involvement. However, GAG and microalbumin excretions were significantly high in the latter. There were no differences in GAG and HS excretions between normoalbuminuric, microalbuminuric, and macroproteinuric SLE patients or between those with and without arthritis. In conclusion, urinary GAG and HS, being unrelated to the presence of arthritis, are independent markers of LN. Extrarenal causes or subclinical renal involvement may be responsible in RA due to their increased excretion in these patients.
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PMID:Increased excretions of glycosaminoglycans and heparan sulfate in lupus nephritis and rheumatoid arthritis. 1450 13

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