Hylkema M N, van Bruggen M C, van de Lagemaat R, Kramers K, Berden J H, Smeenk R J
Department of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (C.L.B.), Amsterdam, The Netherlands.
J Autoimmun. 1996 Feb;9(1):41-50. doi: 10.1006/jaut.1996.0006.
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.
血清抗体与硫酸乙酰肝素（HS）的反应性已被证明与人类和小鼠的狼疮性肾炎有关，尽管这种关联的病因学意义尚不清楚。我们实验室最近的研究表明，这些抗体与HS的结合可能由含组蛋白的免疫复合物介导。在人类狼疮性肾炎中，我们发现肾小球基底膜（GBM）中的HS染色明显减少。本研究的目的是阐明实验性系统性红斑狼疮（SLE）中蛋白尿、GBM中HS染色以及血浆中抗DNA和抗HS反应性之间的相关性。因此，我们研究了NZB/W F1小鼠在肾小球疾病不同阶段的情况，并将它们与年龄匹配的无蛋白尿的对照NZB/W F1小鼠进行比较。在纵向收集的血浆样本中测量抗DNA和抗HS反应性，并将其与蛋白尿的发作、肾小球基底膜中HS的染色以及免疫球蛋白（Ig）的沉积相关联。与年龄匹配的对照小鼠相比，蛋白尿持续时间延长的小鼠肾小球毛细血管袢中的HS染色显著降低（P = 0.0013）。这种HS染色的降低与毛细血管袢中Ig沉积的增加（tau = -0.42，P < 0.001）、蛋白尿（tau = -0.508，P < 0.001）以及血浆中抗DNA水平的降低（tau = 0.758，P < 0.005）相关。血浆中抗HS反应性的改变确实与肾脏中Ig沉积的增加相关（tau = 0.33，P < 0.05），但与肾脏中HS染色的降低无关。总之，我们的研究表明，肾小球毛细血管袢中HS染色的消失与蛋白尿、肾小球中Ig沉积的增加以及血浆中抗DNA反应性的降低有关。我们的发现与HS与由抗DNA抗体和核小体组成的免疫复合物发生相互作用（“掩盖”）的模型一致。
