in Systemic Lupus Erythematosus Autoantibody Formation and Organ Damage Accelerated Macrophage Apoptosis Induces

Increased monocyte/macrophage (M (cid:1) ) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4 (cid:2) T cell subset. Furthermore, autoreactive murine CD4 (cid:2) T cells that kill syngeneic M (cid:1) in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased M (cid:1) apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased M (cid:1) apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB (cid:3) SWR (SNF 1 ) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c (cid:3) 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 M (cid:1) 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 Journal of Immunology, 2006, 176: 2095–2104.