Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus.

Increased monocyte/macrophage (Mphi) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4(+) T cell subset. Furthermore, autoreactive murine CD4(+) T cells that kill syngeneic Mphi in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mphi apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mphi apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB x SWR (SNF(1)) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c x DBA1 (DBF(1)) non-lupus-prone mice. Lupus-prone mice SNF(1) mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs Id(LN)F(1), when compared with untreated SNF(1) mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF(1) lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF(1) mice developed significantly higher levels of anti-nucleosome and Id(LN)F(1) Abs but did not develop lupus nephritis. We propose that Mphi apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease.

The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.

Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.