title: Heparan sulfate staining of the glomerular basement membrane in relation to circulating anti-DNA and anti-heparan sulfate reactivity: a longitudinal study in NZB/W F1 mice.
abstract: 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 GBM 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 membrane and deposition of immunoglobulins (Ig). HS staining was significantly decreased in the glomerular capillary loops 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, P < 0.001), albuminuria (tau = -0.508, P < 0.001) and a decreased in anti-DNA levels measured in plasma (tau = 0.758, P < 0.005). Altered anti-HS reactivity in plasma did correlate with increased Ig deposition in the kidney (tau = 0.33, P < 0.05) but was not correlated with decreased staining of HS in the kidney. In conclusion, our study demonstrates that disappearance of staining of HS in the glomerular capillary loops is associated with albuminuria, increased Ig deposition in the glomerulus and decreased anti-DNA reactivity in plasma. Our findings are compatible with a model in which interaction ('masking') of HS with immune complexes consisting of anti-DNA antibodies and nucleosomes takes place.
authors.affiliation: Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (C.L.B.), Amsterdam, The Netherlands.
authors.forename: M N
authors.initials: MN
authors.lastname: Hylkema
authors.forename: M C
authors.initials: MC
authors.lastname: van Bruggen
authors.forename: R
authors.initials: R
authors.lastname: van de Lagemaat
authors.forename: K
authors.initials: K
authors.lastname: Kramers
authors.forename: J H
authors.initials: JH
authors.lastname: Berden
authors.forename: R J
authors.initials: RJ
authors.lastname: Smeenk
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D001485:Basement Membrane / Q000737:chemistry* / Q000276:immunology*; D004247:DNA / Q000276:immunology; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D006497:Heparan Sulfate / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D007136:Immunoglobulins / Q000276:immunology; D007668:Kidney / Q000276:immunology; D007678:Kidney Glomerulus / Q000033:anatomy & histology / Q000737:chemistry* / Q000276:immunology*; D008137:Longitudinal Studies; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB
chemical_list: D000974:Antibodies, Antinuclear; D004247:DNA; D006497:Heparan Sulfate; D007136:Immunoglobulins