Anti-DNA antibodies can bind to the glomerulus via two distinct mechanisms

Abstract

It is generally assumed that antibodies to double stranded DNA (anti-DNA) play a pivotal role in the pathogenesis of SLE nephritis. Recently, we reported that anti-DNA antibodies can bind to heparan sulphate proteoglycan (HSPG), a constituent of the glomerular basement membrane (GBM), via histones and DNA. We postulated that these histone/DNA/anti-DNA complexes can bind via their histone part to the glomerulus in vivo. To test this hypothesis we performed in vitro binding studies with isolated GBM loops and renal perfusion studies in the rat using histones, DNA and an anti-DNA monoclonal antibody (mAb) with high avidity for dsDNA. A strong granular binding of anti-DNA mAb to isolated GBM loops occurred via histones and DNA and a moderate granular binding was found via DNA alone. Anti-DNA mAb alone did not bind to the GBM loops. After perfusion of histones, DNA and immediately thereafter anti-DNA, we found with immunoelectron microscopy (IEM) a strong binding to endothelial cells in the glomerulus and to a lesser extent in the GBM. When the anti-DNA mAb was injected i.v. one hour after perfusion of histones and DNA, we observed a strong fine granular binding to the capillary wall by immunofluorescence (IF) in a membranous pattern along with some minor mesangial deposits. After perfusion of DNA alone followed by anti-DNA mAb, binding in the glomerulus was less than with histones and DNA, and was more restricted to the mesangium. No direct binding to the glomerulus was observed after perfusion with anti-DNA mAb alone, histones and anti-DNA mAb, or histones, DNA and a control mAb.(ABSTRACT TRUNCATED AT 250 WORDS)

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis

“…We assumed that the histones in the complex were responsible for the binding to HS, since histones, which are highly positively charged molecules, have a high affinity for the GBM [19]. In a recent study, we showed that if we perfused histones, DNA and anti-DNA into a rat kidney, we could demonstrate localization of anti-DNA in the GBM, while perfusion of anti-DNA alone did not lead to binding [20].…”

No evidence for an independent role of anti-heparan sulphate reactivity apart from anti-DNA in lupus nephritis

“…The observation that anti-HS reactivity seems to be mediated by anti-DNA reactivity is not very surprising, since we have already demonstrated that anti-DNA/hi.stone/DNA complexes can bind to HS via histone molecule(s) [11,17]. Still, the Farr assay, which has been used to measure anti-DNA reactivity, has in general been considered to be highly specific for the measurement o\' high-avidity anti-dsDNA antibodies [10,27].…”

Anti-DNA antibody derived from a systemic lupus erythematosus (SLE) patient forms histone–DNA–anti-DNA complexes that bind to rat glomeruli in vivo

“…We and others showed that histones, which are highly positively charged DNA binding proteins, can mediate the deposition of DNA and DNA-anti-DNA IC [8][9][10]. Histones were also demonstrated in glomerular immune deposits in lupus patients and lupus-prone mice [11,12].…”