title: Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Denny
authors.forename: Parthapratim
authors.initials: P
authors.lastname: Chandaroy
authors.forename: Paul D
authors.initials: PD
authors.lastname: Killen
authors.forename: Roberto
authors.initials: R
authors.lastname: Caricchio
authors.forename: Emily E
authors.initials: EE
authors.lastname: Lewis
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Richardson
authors.forename: Kyung-Dall
authors.initials: KD
authors.lastname: Lee
authors.forename: Jerrie
authors.initials: J
authors.lastname: Gavalchin
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D007668:Kidney / Q000473:pathology; D008081:Liposomes; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D051379:Mice; D013154:Spleen / Q000473:pathology
chemical_list: D001323:Autoantibodies; D008081:Liposomes