BACKGROUND Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. METHODS We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. RESULTS Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A 2 receptor (PLA 2 R). Reactive serum specimens recognized recombinant PLA 2 R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA 2 R antibody. Anti-PLA 2 R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA 2 R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA 2 R. CONCLUSIONS A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA 2 R. PLA 2 R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA 2 R is a major antigen in this disease.

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M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

How dying cells alert the immune system to danger

Preeclampsia: an excessive maternal inflammatory response to pregnancy.

GLOMERULONEPHRITIS is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli1–4, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli5,6. We have used an animal model of acute mesangial proliferative glomerulonephritis7,8 to show that this disease is associated with increased production and activity of transforming growth factor β1 (TGF-βl)9, an inducer of extracellular matrix production10–17. Here we report that administration of anti-TGF-βl at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-βl in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.

Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1

The Uterine Spiral Arteries In Human Pregnancy: Facts and Controversies

A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats.

Experimental glomerulonephritis in rat induced by antibodies directed against tubular antigens .5. fixed glomerular antigens in pathogenesis of heterologous immune-complex glomerulonephritis

Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat.

Natural substrates for alkaline phosphatase (AP) are at present not identified despite extensive investigations Difficulties in imagining a possible physiological function involve its extremely high pH optimum for the usual exogenous substrates and its localization as an ecto-enzyme As endotoxin is a substance that contains phosphate groups and is usually present in the extracellular space, we studied whether AP is able to dephosphorylate this bacterial product at physiological pH levels We tested this in intestinal cryostat sections using histochemical methods with endotoxin from Escherichia coli and Salmonella minnesota R595 as substrate Results show that dephosphorylation of both preparations occurs at pH 75 by AP activity As phosphate residues in the lipid A moiety determine the toxicity of the molecule, we examined the effect of the AP inhibitor levamisole in vivo using a septicemia model in the rat The results show that inhibition of endogenous AP by levamisole significantly reduces survival of rats intraperitoneally injected with E coli bacteria, whereas this drug does not influence survival of rats receiving a sublethal dose of the gram-positive bacteria Staphylococcus aureus In view of the endotoxin-dephosphorylating properties of AP demonstrated in vitro, we propose a crucial role for this enzyme in host defense The effects of levamisole during gram-negative bacterial infections and the localization of AP as an ecto-enzyme in most organs as well as the induction of enzyme activity during inflammatory reactions and cholestasis is in accordance with such a protective role

Ww Bakker

Papers

A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats.

Experimental glomerulonephritis in rat induced by antibodies directed against tubular antigens .5. fixed glomerular antigens in pathogenesis of heterologous immune-complex glomerulonephritis

Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat.

Dephosphorylation of endotoxin by alkaline phosphatase in vivo.

A physiologic function for alkaline phosphatase: Endotoxin detoxification