title: LPS-induced murine abortions require C5 but not C3, and are prevented by upregulating expression of the CD200 tolerance signaling molecule.
abstract: OBJECTIVE
  Lipopolysaccharide (LPS) acts via tlr4 to promote Th1 cytokine secretion and abortions. LPS is an essential co-factor in spontaneous abortion in the CBA x DBA/2 model and in stress-triggered abortions. In the CBA x DBA/2 model, C3a, C5a, and fgl2 prothrombinase participate in triggering inflammation that terminates embryo viability. As fgl2 prothrombinase (via thrombin) can generate C5a, it was predicted that LPS-driven abortions (which require fgl2) would be independent of C3. CD200Fc can prevent abortions in the CBA x DBA/2 model, but an action through Fc could not be excluded.
  
  
  METHODS
  C3(-/-) and C5(-/-) knock-out mice on a B6 background were syngeneically mated and Salmonella enteritidis LPS was administered i.p. on day 6.5 or pregnancy along with 2 mg progesterone in sesame oil s.c. The total number of implants and the number of resorbing embryos were counted on day 13.5 of pregnancy. CD200-rtTA double transgenic homozygous males (B6 background) mated with B6(+/+) females were similarly treated. To up-regulate CD200 expression in embryonic trophoblasts, doxycycline was added to the drinking water from the time of mating.
  
  
  RESULTS
  The LPS boosted the abortion rate from 15.5% (control) to 42.0% in C3(-/-) mice (chi(2) = 9.28, P < 0.005). In C5(-/-) mice, there was no increase in abortion rate with LPS compared to progesterone-treated controls (22.8%versus 26.3%, P = NS). LPS-treated transgenic mice given LPS + progesterone had a 42.5% abortion rate, but when the mice were given doxycycline to induce expression of CD200 by the embryo, the abortion rate was only 8.3% (chi(2) = 14.40, P < 0.005, Fisher's exact test P = 0.00007).
  
  
  CONCLUSIONS
  C5, but not C3, appears necessary for LPS-driven abortions. Up-regulation of CD200 can prevent LPS-driven abortions, possibly by altering dendritic cells to promote Treg cell development or by a direct suppressive action on macrophages and mast cells that also express CD200 receptors.
authors.affiliation: Toronto General Research Institute & CIHR Group on Cellular and Molecular Mechanisms of Organ Injury, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Katharina
authors.initials: K
authors.lastname: Foerster
authors.forename: Justin
authors.initials: J
authors.lastname: Manuel
authors.forename: Hector
authors.initials: H
authors.lastname: Molina
authors.forename: Gary A
authors.initials: GA
authors.lastname: Levy
authors.forename: Reginald M
authors.initials: RM
authors.lastname: Gorczynski
authors.forename: David A
authors.initials: DA
authors.lastname: Clark
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015926:Complement C3a / Q000172:deficiency / Q000276:immunology*; D015936:Complement C5a / Q000172:deficiency / Q000276:immunology*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000276:immunology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C490637:Fgl2 protein, mouse; D008070:Lipopolysaccharides; D011374:Progesterone; D015926:Complement C3a; D015936:Complement C5a; D005340:Fibrinogen; C042739:antigens, CD200