Decay-accelerating factor ameliorates systemic autoimmune disease in MRL/lpr mice via both complement-dependent and -independent mechanisms.
Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. Previous studies have established a significant protective activity of DAF in the MRL/lpr murine model of human systemic lupus erythematosus. To dissect the mechanism of protection by DAF in this disease model, we evaluated the effect of C3 gene ablation on disease development in MRL/lpr-Daf-1(-/-) mice. We found no significant difference in lymphadenopathy, splenomegaly, or anti-chromatin autoantibody titer between complement-sufficient and complement-deficient MRL/lpr-Daf-1(-/-) mice. On the other hand, complement deficiency strikingly reduced the incidence and severity of dermatitis in MRL/lpr-Daf-1(-/-) mice. To assess the contribution of DAF expression on lymphocytes versus local tissues in suppressing dermatitis, we generated BM chimeric mice between MRL/lpr-Daf-1(-/-) and MRL/lpr-Daf-1(+/+) mice. Compared with MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(-/-) controls, MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(+/+) chimeras developed significantly attenuated dermatitis, suggesting that the protective effect of DAF in suppressing dermatitis is primarily attributable to its local expression. We conclude that DAF works as a complement regulator in the skin to protect MRL/lpr mice from skin inflammation, whereas its inhibitory role in the induction phase of MRL/lpr autoimmunity is complement-independent. Together, these results reveal multiple mechanisms of action for DAF in ameliorating systemic autoimmunity.
Miwa
Takashi
T
Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, 1254 BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. song@spirit.gcrc.upenn.edu
Maldonado
Michael A
MA
Zhou
Lin
L
Yamada
Koei
K
Gilkeson
Gary S
GS
Eisenberg
Robert A
RA
Song
Wen-Chao
WC
D000818:Animals; D016026:Bone Marrow Transplantation; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003872:Dermatitis / Q000097:blood / Q000503:physiopathology; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009929:Organ Size; D015398:Signal Transduction / Q000502:physiology
D018958:CD55 Antigens; D003176:Complement C3; D007074:Immunoglobulin G; D007075:Immunoglobulin M