Treatment with a Laminin-Derived Peptide Suppresses Lupus Nephritis

Abstract

The role of DNA as the target for pathogenic lupus autoantibodies in systemic lupus erythematosus is equivocal and renal damage may be due to cross-reactivity of lupus Abs with glomerular components. We have previously shown that lupus autoantibodies bind to the laminin component of the extracellular matrix. In the present work, we have analyzed the fine specificity of the interaction of pathogenic murine lupus autoantibodies with this molecule and the effect of inhibiting their binding to laminin during the course of the disease. We have found that pathogenic murine lupus autoantibodies react with a 21-mer peptide located in the globular part of the α-chain of laminin. Immunization of young lupus-prone mice with this peptide accelerated renal disease. Analysis of transgenic, congenic, and RAG-1−/− mice confirmed the importance of this epitope in the pathogenesis of lupus renal disease. We have synthesized a panel of peptides that cross-react with the anti-laminin Abs and have found that the binding of lupus autoantibodies to the extracellular matrix could be inhibited in vitro by some of these competitive peptides. Treatment of MRL/lpr/lpr mice with these peptides prevented Ab deposition in the kidneys, ameliorated renal disease, and prolonged survival of the peptide-treated mice. We suggest that laminin components can serve as the target for lupus Abs. The interaction with these Ags can explain both the tissue distribution and the immunopathological findings in lupus. Moreover, inhibition of autoantibody binding to the extracellular matrix can lead to suppression of disease.

Nephritogenic Lupus Antibodies Recognize Glomerular Basement Membrane-Associated Chromatin Fragments Released from Apoptotic Intraglomerular Cells

“…Sera from individual B/W mice were obtained at the age of 11,17,21,30, and 33 weeks. The sera were stored at Ϫ20°C until used.…”

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

“…These immune complexes were observed as electron-dense structures in GBMs and the mesangial matrix, and bound IgG was confined to electron-dense structures in both murine (12,14) and human (13) lupus nephritis. In vivo bound IgG was not observed in regular glomerular structures (15), although anti-DNA antibodies have been shown to cross-react in vitro with other glomerular antigens (16)(17)(18)(19). It is unclear whether antibodies form complexes with chromatin in circulation or in situ in glomeruli.…”

Identification of New Pathogenic Players in Lupus: Autoantibody-Secreting Cells Are Present in Nephritic Kidneys of (NZBxNZW)F1 Mice

“…Recent studies suggest that autoantibodies rather react with apoptotic chromatin fragments deposited in the glomeruli of nephritic NZB/W mice and lupus patients, this apoptotic material resulting from a reduced fragmentation and clearance of chromatin (11)(12)(13). Another possible pathway involves cross-reactions of lupus anti-DNA/nucleosome autoantibodies with glomerular constituents, such as a-actinin, laminin, mesangial cells, or mesangial matrix structures (14)(15)(16). It has also been proposed that already formed circulating immune complexes bind to components of the skin and glomerular basement membrane (GBM).…”