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Biomedical subjects

M A Seelen

Publications and source records attributed to M A Seelen.

9 recordsLinked to original sources
PubMed2003

Complement and renal disease.

The complement system is involved in several aspects of renal disease, including primary renal diseases, dialysis and renal transplant rejection. Initially, a role for complement in renal disease was inferred solely from the deposition of complement components in affected kidneys and changes in complement levels in the circulation during active disease. Recent studies have shown how complement modulates the onset, development and the resolution of renal disease. Current research provides clues on the role of individual complement components and activation pathways as well as possible modes of complement regulation in the management of renal disease.

Animals↗
PubMed2003

Glomerular deposition of C1q and anti-C1q antibodies in mice following injection of antimouse C1q antibodies.

Anti-C1q autoantibodies are present in the serum of patients with different autoimmune diseases such as systemic lupus erythematosus (SLE). The occurrence of these autoantibodies correlates with renal involvement. In the present study we examined whether injection of rabbit antimouse C1q antibodies in mice leads to deposition in kidneys. Injection of healthy mice with a single dose of rabbit IgG antimouse C1q antibodies resulted in deposition of both C1q and IgG anti-C1q in glomeruli. The pattern of deposition observed in the glomeruli of mice injected with antimouse C1q antibodies both at 24 h and 2 weeks was both glomerular basement membrane (GBM)-associated and mesangial. Injection of control IgG did not have a detectable effect on circulating C1q levels, and no deposition of either C1q or rabbit IgG was seen at 24 h. The deposition of rabbit antimouse C1q and C1q in glomeruli resulted in complement activation, as assessed by C3 deposition, and influx of leucocytes associated with albuminuria in some, but not all mice. In none of the control mice was albuminuria observed. This report is the first to show that anti-C1q antibodies deposit in the healthy glomerulus together with autologous C1q. This deposition is stable for at least 2 weeks, causes complement activation, leucocyte influx and can lead to mild albuminuria.

Albuminuria↗
PubMed1996

[Hypertension caused by licorice consumption].

In a 38-year-old woman who was hospitalized because of hypertension and hypokalaemic alkalosis, the intake of liquorice (200 g per day) was proven to be the cause. A liquorice provocation test produced all the expected clinical and biochemical abnormalities. Some kinds of liquorice contain glycyrrhetic acid which inhibits the enzyme 11-beta-hydroxysteroid dehydrogenase (e.g. in the kidney) leading to decreased transformation of cortisol into cortisone. The mineralocorticoid action of cortisol causes a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, which in the patient described led to retention of water resulting in weight increase and hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Proteinase 3, the major autoantigen of Wegener's granulomatosis, enhances IL-8 production by endothelial cells in vitro.

Proteinase 3 is the major target antigen of antineutrophil cytoplasmic autoantibodies (ANCA) in Wegener's granulomatosis and is contained in the azurophilic granules of polymorphonuclear neutrophils, the dominant cell type in vascular lesions during the early stages of systemic vasculitis. This study questioned whether neutrophil lysosomal enzymes, once released at the site of inflammation, are able to potentiate the influx of additional neutrophils by enhancing the production of the chemotactic cytokine interleukin-8 (IL-8) by endothelial cells. Therefore, human umbilical vein endothelial cells in culture were incubated with varying concentrations of highly purified proteinase 3, human neutrophil elastase, and cathepsin G for different time periods. The supernatants were subsequently assessed for IL-8 antigen by using a sandwich ELISA. The presence of both proteinase 3 and elastase resulted in an increased production of IL-8, up to 15.6- and 4.2-fold, respectively, in a dose- and time-dependent fashion. Cathepsin G did not influence IL-8 production. Although the addition of an alpha 1-proteinase inhibitor completely abrogated elastase-mediated IL-8 production, it did not significantly influence the effect of proteinase 3. Both proteinase 3-and elastase-mediated production of IL-8 was inhibited by cycloheximide, indicating de novo synthesis. This was supported by the finding of increased IL-8 mRNA levels in proteinase 3-treated human umbilical vein endothelial cells by using Northern blot analysis. Taken together, the neutrophil lysosomal enzymes proteinase 3 and human neutrophil elastase may contribute to a self-perpetuating process of neutrophil recruitment in acute inflammation by increasing de novo synthesis of IL-8 by endothelial cells. The studies presented here also show that proteinase 3 mediates its effect independently of its enzymatic activity, indicating a hitherto unknown mode of action on endothelial cells.

Autoantigens↗
PubMed1995

The anti-lipid A monoclonal antibody E5 binds to rough gram-negative bacteria, fixes C3, and facilitates binding of bacterial immune complexes to both erythrocytes and monocytes.

Treatment of patients with septic shock using monoclonal antibodies (mAbs) to endotoxin is still controversial. Clinical trials of E5, one of the mAbs directed against the lipid A moiety of lipopolysaccharide (LPS), are currently in progress. The mechanisms of action of this, and other antibodies under clinical evaluation, are, however, poorly understood. In this study we examined in vitro the ways in which E5 interacted with Gram-negative bacteria, complement, erythrocytes and monocytes. By fluorescence-activated cell sorter (FACS) analysis we showed direct, dose-dependent binding of E5 to Escherichia coli (E. coli) and Salmonella minnesota (S. minnesota). Antibody binding to S. minnesota was enhanced by treatment with the beta-lactam antibiotic amoxycillin, but not by treatment with the aminoglycoside gentamicin. Immune complexes formed between E5 and both species of Gram-negative bacteria activated both classical and alternative complement pathways, but only in the case of S. minnesota did this facilitate binding to erythrocyte CR1 and monocyte CR3. Bacterial C3b and iC3b fixation by E5 was quantified using specific mAbs. These observations suggest that E5 may enhance bacterial clearance in several ways: (1) by facilitating direct complement fixation; (2) by facilitating the binding of opsonized bacteria to cells of the mononuclear phagocyte system; (3) by enabling bacteria to bind to erythrocyte CR1 (CD35), allowing safe carriage in the circulation to the fixed macrophages of the liver and spleen; (4) by acting synergistically with beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed1993

IFN-gamma mediates stimulation of complement C4 biosynthesis in human proximal tubular epithelial cells.

The liver has been presumed to be the main source of complement deposited in inflammatory lesions such as in glomerulonephritis. In a previous study, however, it was demonstrated that renal tubular cells synthesize C3 in vitro. Furthermore, it was shown by others that C4 gene transcripts were detectable in situ in renal tubular cells. Therefore studies were initiated to investigate the synthesis of C4 by proximal tubular epithelial cells (PTEC) in vitro. Biosynthetic labeling experiments showed de novo synthesis of C4 by PTEC. The synthesis of C4 by PTEC and its regulation by IFN-gamma was fully inhibitable by the addition of cycloheximide, indicating that protein synthesis is required for an increase in C4 secretion. Addition of increasing concentrations of IFN-gamma enhanced the production of C4 by PTEC in a dose dependent fashion, with a 2.5-fold maximum. Kinetic experiments demonstrated higher levels of C4 production when stimulated with IFN-gamma for up to 72 hours. The hemolytic activity of C4 present in culture supernatants of PTEC decreased during the culture period as assessed by hemolytic titration. Northern blot analysis showed no enhancement of C4 mRNA in IFN-gamma treated PTEC, indicating that IFN-gamma regulates C4 production at a post-transcriptional level. Antibody blocking experiments confirmed that regulation of C4 production was directly mediated by IFN-gamma. From this study it was concluded that renal cells are able to synthesize complement components that could possibly play a role in inflammatory responses evolving in the kidney.

Cells, Cultured↗