title: Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-gamma and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis.
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Kwok-Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Trendell-Smith
authors.forename: Adrian
authors.initials: A
authors.lastname: Wu
authors.forename: Lina
authors.initials: L
authors.lastname: Tian
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Lam
authors.forename: Albert K
authors.initials: AK
authors.lastname: Chan
authors.forename: Chi-Kin
authors.initials: CK
authors.lastname: Lo
authors.forename: Stanley
authors.initials: S
authors.lastname: Chik
authors.forename: King-Hung
authors.initials: KH
authors.lastname: Ko
authors.forename: Christina K W
authors.initials: CK
authors.lastname: To
authors.forename: Siu-Kee
authors.initials: SK
authors.lastname: Kam
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Li
authors.forename: Cui-Hong
authors.initials: CH
authors.lastname: Yang
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
authors.forename: Mun-Hon
authors.initials: MH
authors.lastname: Ng
authors.forename: David I
authors.initials: DI
authors.lastname: Stott
authors.forename: G Gordon
authors.initials: GG
authors.lastname: MacPherson
authors.forename: Fang-Ping
authors.initials: FP
authors.lastname: Huang
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004198:Disease Susceptibility / Q000276:immunology; D004890:Erythema / Q000276:immunology / Q000473:pathology; D005145:Face; D005260:Female; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009336:Necrosis; D011507:Proteinuria / Q000276:immunology / Q000473:pathology; D012883:Skin Ulcer / Q000276:immunology / Q000473:pathology
chemical_list: D000974:Antibodies, Antinuclear; D016207:Cytokines; D004247:DNA