Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains.
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.
Ma
Liang
L
Department of Pathology, University of Hong Kong, Hong Kong, China.
Chan
Kwok-Wah
KW
Trendell-Smith
Nigel J
NJ
Wu
Adrian
A
Tian
Lina
L
Lam
Audrey C
AC
Chan
Albert K
AK
Lo
Chi-Kin
CK
Chik
Stanley
S
Ko
King-Hung
KH
To
Christina K W
CK
Kam
Siu-Kee
SK
Li
Xiao-Song
XS
Yang
Cui-Hong
CH
Leung
Suet Yi
SY
Ng
Mun-Hon
MH
Stott
David I
DI
MacPherson
G Gordon
GG
Huang
Fang-Ping
FP
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
D000974:Antibodies, Antinuclear; D016207:Cytokines; D004247:DNA