... LAMBERT P. VAN DEN HEUVEL, JACQUES H. VEERKAMP, JAAP VAN DEN BORN, LEO AH MONNENS and JO HM B... more ... LAMBERT P. VAN DEN HEUVEL, JACQUES H. VEERKAMP, JAAP VAN DEN BORN, LEO AH MONNENS and JO HM BERDEN. ... used: GBM, glomerular basement membrane; HSPG, heparan sulphate proteoglycan; TBM, tubular basement membrane; elisa, enzyme-linked ...
The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus ... more 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.
Page 1. Comparison of Methods for Measurement of Na /Li Countertransport Across the Erythrocyte M... more Page 1. Comparison of Methods for Measurement of Na /Li Countertransport Across the Erythrocyte Membrane To the Editor: About 30% of patients with insulin-dependent diabetes mellitus develop diabetic nephropathy. Since ...
Antibodies against heparan sulfate (HS) were detected in sera from patients with active systemic ... more Antibodies against heparan sulfate (HS) were detected in sera from patients with active systemic lupus erythematosus (SLE) and in sera from MRL/l mice with a spontaneous SLE-like disease. By inhibition studies it was shown that this reactivity towards HS was due to cross-reactivity of anti-DNA antibodies. Immunoglobulin eluted from human and mouse kidneys with diffuse proliferative SLE glomerulonephritis also bound to HS. This crossreaction of anti-DNA antibodies was further substantiated by the finding that 17 out of 42 anti-DNA monoclonal antibodies (mAb) also bound to HS, 11 out of 17 HS positive mAb bound to heparan sulfate proteoglycan (HSPG) purified from human glomerular basement membranes (GBM) and 7 out of 42 bound directly to isolated human GBM-loops. The binding to HS, HSPG, and GBM could be inhibited in a dose-dependent manner by DNA. In a retrospective analysis of sera from 10 SLE patients, in which 6-16 serum samples per patient were studied, we found in all 5 episodes of onset or exacerbation of a SLE nephritis an anti-HS activity in the serum, prior to onset of the nephritis. In 4 episodes of onset or exacerbation of non-renal manifestations, anti-HS activity was only found in the serum during one episode. Based on these studies we postulate that binding of anti-DNA antibodies to HS within the GBM may be an important immunopathological event in the development of SLE nephritis.
Arthritis & rheumatology (Hoboken, N.J.), Jan 11, 2015
Objective - Circulating chromatin-containing apoptotic material and/or neutrophil extracellular t... more Objective - Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed as an important driving force for the anti-chromatin autoimmune response in patients with systemic lupus erythematosus (SLE). We aimed to determine the exact nature of microparticles that circulate in SLE patients, and assess their effects on the immune system. Methods - We analyzed microparticles isolated from plasma of patients with SLE, rheumatoid arthritis (RA) or systemic sclerosis (SSc), and healthy subjects, and determined their effects on blood-derived DCs and neutrophils. Results - In SLE patients, we identified microparticles highly positive for annexin V and apoptosis-modified chromatin, not present in healthy subjects or RA and SSc patients. These microparticles were mostly CD31(+) /CD45(-) (endothelial), partially CD45(+) /CD66b(+) (granulocyte), and negative for B and T cell markers. Microparticles isolated from plasma of SLE patients increase...
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1997
To investigate whether albuminuria in streptozotocin-induced diabetes mellitus in the rat is a sy... more To investigate whether albuminuria in streptozotocin-induced diabetes mellitus in the rat is a symptom of a more generalized vessel wall permeability, and whether changes in vessel wall heparan sulfate (HS) are associated with alterations in vessel wall permeability. The transcapillary escape rate of albumin (TERalb) was calculated from the disappearance rate from the circulation of i.v. injected radiolabeled albumin, together with the regional clearance of albumin (RCalb) in several tissues using a double isotope technique. These measurements were performed in seven rats one year after diabetes induction and in seven sex- and age-matched control rats. To evaluate the association between vessel wall HS and the transcapillary passage of albumin, we determined the content of basement membrane HS in tissue homogenates of heart, liver, kidneys, and lungs with a sensitive inhibition-ELISA using a monoclonal antibody (JM-403), which specifically recognizes basement membrane HS. Diabetic r...
Mycophenolate mofetil (MMF) is the morpholin- oethyb ester of mycophenolic acid, which is its act... more Mycophenolate mofetil (MMF) is the morpholin- oethyb ester of mycophenolic acid, which is its active metab- olite. MMF is effective in prolonging survival of albografts and xenografts. However, little is known about the effects and the main mechanism of action of MMF in autoimmune diseases. In this study, the effect of MMF on the spontaneous disease progression in the MRL/Ipr
Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimen... more Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibi...
Virchows Archiv. B, Cell pathology including molecular pathology, 1993
Heparins blunt the development of glomerulosclerosis in several disease models in the rat and thi... more Heparins blunt the development of glomerulosclerosis in several disease models in the rat and this protective effect may be related to suppression of glomerular cell proliferation. In this study the direct effect of heparins on another key event in glomerulosclerosis, extracellular matrix (ECM) deposition, was examined. Standard heparin (hep) and non-anticoagulant N-desulfated acetylated heparin (DSA-hep) significantly reduced the fibronectin content in the conditioned media of subconfluent, confluent, and supraconfluent rat glomerular mesangial cells (MCs) in culture, as assessed by a sandwich ELISA technique. Both heparins significantly increased the amount of cell-associated fibronectin in sparse and subconfluent MCs. DSA-hep, but not hep, increased the fibronectin content of ECM formed by confluent and supraconfluent MCs. Using 3H-proline pulse-labeling, Hep and DSA-hep were found to significantly decrease cell-associated collagen in subconfluent but not in confluent MCs. No eff...
... LAMBERT P. VAN DEN HEUVEL, JACQUES H. VEERKAMP, JAAP VAN DEN BORN, LEO AH MONNENS and JO HM B... more ... LAMBERT P. VAN DEN HEUVEL, JACQUES H. VEERKAMP, JAAP VAN DEN BORN, LEO AH MONNENS and JO HM BERDEN. ... used: GBM, glomerular basement membrane; HSPG, heparan sulphate proteoglycan; TBM, tubular basement membrane; elisa, enzyme-linked ...
The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus ... more 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.
Page 1. Comparison of Methods for Measurement of Na /Li Countertransport Across the Erythrocyte M... more Page 1. Comparison of Methods for Measurement of Na /Li Countertransport Across the Erythrocyte Membrane To the Editor: About 30% of patients with insulin-dependent diabetes mellitus develop diabetic nephropathy. Since ...
Antibodies against heparan sulfate (HS) were detected in sera from patients with active systemic ... more Antibodies against heparan sulfate (HS) were detected in sera from patients with active systemic lupus erythematosus (SLE) and in sera from MRL/l mice with a spontaneous SLE-like disease. By inhibition studies it was shown that this reactivity towards HS was due to cross-reactivity of anti-DNA antibodies. Immunoglobulin eluted from human and mouse kidneys with diffuse proliferative SLE glomerulonephritis also bound to HS. This crossreaction of anti-DNA antibodies was further substantiated by the finding that 17 out of 42 anti-DNA monoclonal antibodies (mAb) also bound to HS, 11 out of 17 HS positive mAb bound to heparan sulfate proteoglycan (HSPG) purified from human glomerular basement membranes (GBM) and 7 out of 42 bound directly to isolated human GBM-loops. The binding to HS, HSPG, and GBM could be inhibited in a dose-dependent manner by DNA. In a retrospective analysis of sera from 10 SLE patients, in which 6-16 serum samples per patient were studied, we found in all 5 episodes of onset or exacerbation of a SLE nephritis an anti-HS activity in the serum, prior to onset of the nephritis. In 4 episodes of onset or exacerbation of non-renal manifestations, anti-HS activity was only found in the serum during one episode. Based on these studies we postulate that binding of anti-DNA antibodies to HS within the GBM may be an important immunopathological event in the development of SLE nephritis.
Arthritis & rheumatology (Hoboken, N.J.), Jan 11, 2015
Objective - Circulating chromatin-containing apoptotic material and/or neutrophil extracellular t... more Objective - Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed as an important driving force for the anti-chromatin autoimmune response in patients with systemic lupus erythematosus (SLE). We aimed to determine the exact nature of microparticles that circulate in SLE patients, and assess their effects on the immune system. Methods - We analyzed microparticles isolated from plasma of patients with SLE, rheumatoid arthritis (RA) or systemic sclerosis (SSc), and healthy subjects, and determined their effects on blood-derived DCs and neutrophils. Results - In SLE patients, we identified microparticles highly positive for annexin V and apoptosis-modified chromatin, not present in healthy subjects or RA and SSc patients. These microparticles were mostly CD31(+) /CD45(-) (endothelial), partially CD45(+) /CD66b(+) (granulocyte), and negative for B and T cell markers. Microparticles isolated from plasma of SLE patients increase...
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1997
To investigate whether albuminuria in streptozotocin-induced diabetes mellitus in the rat is a sy... more To investigate whether albuminuria in streptozotocin-induced diabetes mellitus in the rat is a symptom of a more generalized vessel wall permeability, and whether changes in vessel wall heparan sulfate (HS) are associated with alterations in vessel wall permeability. The transcapillary escape rate of albumin (TERalb) was calculated from the disappearance rate from the circulation of i.v. injected radiolabeled albumin, together with the regional clearance of albumin (RCalb) in several tissues using a double isotope technique. These measurements were performed in seven rats one year after diabetes induction and in seven sex- and age-matched control rats. To evaluate the association between vessel wall HS and the transcapillary passage of albumin, we determined the content of basement membrane HS in tissue homogenates of heart, liver, kidneys, and lungs with a sensitive inhibition-ELISA using a monoclonal antibody (JM-403), which specifically recognizes basement membrane HS. Diabetic r...
Mycophenolate mofetil (MMF) is the morpholin- oethyb ester of mycophenolic acid, which is its act... more Mycophenolate mofetil (MMF) is the morpholin- oethyb ester of mycophenolic acid, which is its active metab- olite. MMF is effective in prolonging survival of albografts and xenografts. However, little is known about the effects and the main mechanism of action of MMF in autoimmune diseases. In this study, the effect of MMF on the spontaneous disease progression in the MRL/Ipr
Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimen... more Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibi...
Virchows Archiv. B, Cell pathology including molecular pathology, 1993
Heparins blunt the development of glomerulosclerosis in several disease models in the rat and thi... more Heparins blunt the development of glomerulosclerosis in several disease models in the rat and this protective effect may be related to suppression of glomerular cell proliferation. In this study the direct effect of heparins on another key event in glomerulosclerosis, extracellular matrix (ECM) deposition, was examined. Standard heparin (hep) and non-anticoagulant N-desulfated acetylated heparin (DSA-hep) significantly reduced the fibronectin content in the conditioned media of subconfluent, confluent, and supraconfluent rat glomerular mesangial cells (MCs) in culture, as assessed by a sandwich ELISA technique. Both heparins significantly increased the amount of cell-associated fibronectin in sparse and subconfluent MCs. DSA-hep, but not hep, increased the fibronectin content of ECM formed by confluent and supraconfluent MCs. Using 3H-proline pulse-labeling, Hep and DSA-hep were found to significantly decrease cell-associated collagen in subconfluent but not in confluent MCs. No eff...
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