Expression of glomerular heparan sulphate domains in murine and human lupus nephritis

Abstract

Background. Recently, we identified specific N-and 6-O-sulphated heparan sulphate (HS) domains on activated glomerular endothelial cells. In this study, we evaluated in lupus nephritis the expression of different HS domains on glomerular endothelium and in the glomerular basement membrane (GBM). Methods. The expression of specific glomerular HS domains and the presence of immunoglobulins (Ig) were determined by immunofluorescence staining of kidney sections of patients with nephritis due to systemic lupus erythematosus (SLE) and MRL/lpr lupus mice. The expression/presence of glomerular HS domains and Ig was also evaluated after eluting Ig from renal sections of lupus mice using two elution methods, and in renal sections of lupus mice treated with heparinoids. Results. Both MRL/lpr mice and patients with lupus nephritis showed a decreased expression of HS in the GBM. The expression of N-and 6-O-sulphated HS domains on glomerular endothelium was decreased in MRL/lpr mice, but increased in SLE patients. MRL/lpr mice had more extensive glomerular Ig deposits than SLE patients. After elution of Ig, the glomerular endothelial expression of N-and 6-O-sulphated HS domains in MRL/lpr mice was recovered and even increased above normal levels, while the expression of HS in the GBM was restored to normal levels. Treatment with heparinoids prevented Ig deposition and preserved the expression of glomerular HS domains at normal levels in lupus mice. Conclusion. The expression of specific HS domains on glomerular endothelium and in the GBM is changed during lupus nephritis due to masking by Ig deposits and induction of inflammatory N-and 6-O-sulphated HS domains.

Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

“…One may wonder why colocalization of chromatin or experimental anti‐dsDNA antibody probes with laminin was not found. This can be explained by the hypothesis that laminin within the electron‐dense deposits is masked by chromatin–immune complexes, and therefore not accessible to antilaminin antibodies, similar to the situation described for HS (45). Elution of chromatin–antibody complexes should lead to the reappearance of laminin, as we showed recently for glomerular HS in lupus‐prone mice and patients with SLE (45).…”

“…This can be explained by the hypothesis that laminin within the electron‐dense deposits is masked by chromatin–immune complexes, and therefore not accessible to antilaminin antibodies, similar to the situation described for HS (45). Elution of chromatin–antibody complexes should lead to the reappearance of laminin, as we showed recently for glomerular HS in lupus‐prone mice and patients with SLE (45). Recent findings with regard to the glomerular targeting of autoantibodies in lupus nephritis are graphically summarized in Figure 1.…”

“…On the other hand, the binding of antihistone antibodies (and in some cases antinucleosome antibodies) to the cationic histones would mask the positive charge, reducing deposition of nucleosome–immune complexes, as was indeed shown to be the case (44). This nucleosome‐mediated binding to the GBM was the reason that in both human and mouse lupus nephritis, staining with monoclonal anti‐HS antibodies revealed an almost complete absence of staining of HS in the GBM (45). We further showed that unmasking of HS by eluting the immune complexes from renal sections restored the staining of HS in the GBM (45).…”

“…This nucleosome‐mediated binding to the GBM was the reason that in both human and mouse lupus nephritis, staining with monoclonal anti‐HS antibodies revealed an almost complete absence of staining of HS in the GBM (45). We further showed that unmasking of HS by eluting the immune complexes from renal sections restored the staining of HS in the GBM (45).…”

Alteration of N‐glycosylation in the kidney in a mouse model of systemic lupus erythematosus: relative quantification of N‐glycans using an isotope‐tagging method

“…[13][14][15] A deficiency of a-mannosidase II (aM-II), which is associated with branching in N-glycans, has been found to induce human SLE-like glomerular nephritis in a mouse model. 16 Green et al reported that branching structures of N-glycan in mammals are involved in protection against immune responses in autoimmune disease pathogenesis.…”