PATHOPHYSIOLOGY OF LUPUS NEPHRITIS:THE ROLE OF NUCLEOSOMES

Lupus nephritis is regarded as an immune complex mediated disease. Since anti-DNA antibodies are present in the circulation and in diseased glomeruli of patients with lupus nephritis, these antibodies have been assigned a pivotal role in the initiation of lupus nephritis. It remains however unclear how these antibodies become localized in the glomerulus. Contrary td the classical concept of glomerular deposition of DNA/anti-DNA complexes, it has been suggested that anti-DNA antibodies can interact with intrinsic glomerular antigens. Some anti-DNA antibodies can cross-react with heparan sulphate (HS), which is such an intrinsic constituent of the glomerular basement membrane (GBM). Serum HS reactivity coincides with the occurrence of lupus nephritis. It was found that this HS reactivity was exhibited by anti-DNA antibodies complexed to nucleosomes and not by the antibody itself. Nucleosomes are DNA/histone complexes, present in the nucleus, which are released by dying cells. The histone part of the nucleosome is responsible for the binding to the GBM. Recently, it has become clear that also anti-nucleosome antibodies can bind to HS in the GBM via nucleosomes. These nucleosome-containing immune complexes exhibit anti-DNA reactivity in ELISA and Farr assay. It is now thought that nucleosomes released by dying cells bind to anti-DNA or anti-nucleosome antibodies in the circulation, giving rise to nephritogenic immune complexes. Alternatively, nucleosomes may bind to the GBM and serve then as planted antigen for subsequent binding of antibodies via an in situ mechanism. Binding of antibodies via both mechanisms leads to complement activation and damage of the GBM. The recent finding of histones and DNA in glomerular depositions in lupus nephritis is in line with this hypothesis

Heparan sulfate staining of the glomerular basement membrane in relation to circulating anti-RNA and anti-heparan sulfate reactivity:A longitudinal study in NZB/W F1 mice

Reactivity of serum antibodies with heparan sulfate (HS) has been associated with human and murine lupus nephritis, although the aetiological significance of this association is not clear. Recent work from our laboratories showed that binding of these antibodies to HS could be mediated by histone containing immune complexes. In human lupus nephritis we found a strong decrease in HS staining in the glomerular basement membrane (GBM). The aim of this study was to elucidate the correlation in experimental systemic lupus erythematosus (SLE) between albuminuria, staining of HS in the GEM and anti-DNA and anti-HS reactivity in plasma. We therefore studied NZB/W F1 mice during different stages of glomerular disease and compared them with age matched control NZB/W F1 mice without albuminuria. Anti-DNA and anti-HS reactivity were measured in longitudinally collected plasma samples and correlated with the onset of albuminuria, staining of HS in the glomerular basement HS staining was of mice with prolonged proteinuria in comparison with age matched control mice (P=0.0013). This decreased HS staining was correlated with increased Ig deposition in the capillary loops (tau=-0.42,

HIGHER ANTI-HEPARAN SULFATE REACTIVITY DURING SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE) DISEASE EXACERBATIONS WITH RENAL MANIFESTATIONS - A LONG-TERM PROSPECTIVE ANALYSIS

Cross-reactive antibodies against heparan sulphate (HS) have been suggested to play a role in initiating renal disease in SLE. Recently, we found that HS-reactivity is mediated by anti-DNA antibodies complexed with DNA and histones. To evaluate the clinical significance of anti-HS reactivity, we studied prospectively a cohort of 72 consecutive SLE patients, of whom 22 experienced 40 exacerbations. In 20 of these exacerbations renal symptoms were present. In these 20 exacerbations significantly higher anti-DNA (median 1:160) and anti-HS (median 1:30) titres were detected compared with exacerbations without renal manifestations (median 1:60 for anti-DNA and negative for anti-HS). There were no correlations with other symptoms of SLE. Anti-HS titres showed a significant correlation with anti-DNA antibody titres (r(s) = 0-57, P <0.05). Anti-HS without anti-DNA reactivity was never detected. Some SLE patients showed a high anti-DNA titre without anti-HS reactivity, suggesting that not all anti-DNA antibodies are able to bind to histone/DNA complexes and thus to exhibit anti-HS reactivity. Our findings indicate that anti-HS reactivity is correlated with renal disease in SLE