Mouse monoclonal autoantibodies penetrate mouse macrophage cells and stimulate NF-kappaB activation and TNF-alpha release.

Autoantibodies against double-stranded DNA (dsDNA) are found in the serum of systemic lupus erythematosus (SLE) patients. However, the mechanism by which anti-dsDNA antibodies (Abs) contribute to the pathogenesis of SLE is not yet fully understood. In this study, we investigated four anti-dsDNA mouse monoclonal autoantibodies that share positively charged amino acids (including arginines) in their complementarity determining regions for their ability to penetrate RAW264.7 macrophage cells, activate NF-kappaB and stimulate TNF-alpha production. All four antibodies penetrated into macrophage cells and increased the level of extracellular TNF-alpha; two also activated NF-kappaB. The fact that two of four cell-penetrating anti-dsDNA mAbs induced both NF-kappaB activation and TNF-alpha production in macrophages suggests that at least some autoantibodies against dsDNA may play a role in the pathogenesis of SLE by penetrating into macrophage cells and nuclei, and subsequently inducing the pro-inflammatory cytokine, TNF-alpha, by binding to the NF-kappaB gene and stimulating its transcriptional activity.