title: OS069. Light, a TNF superfamily member, contributes to pathophysiology in a mouse model of preeclampsia.
abstract: BACKGROUND
  Preeclampsia (PE) is associated with alterations in the renin-angiotensin system due to the presence of autoantibodies that activate the major angiotensin receptor, AT1R. The resulting chronic activation of the AT1 receptor is believed to contribute to a pro-inflammatory state that is also characteristic of PE. Microarray analysis revealed a pronounced increase in the abundance of LIGHT, a potent member of the TNF superfamily that has emerged as a key factor mediating strong T-cell inflammatory responses and a contributor to autoimmune disease pathogenesis.
  
  
  OBJECTIVE
  The goal of research described here is to determine the contribution of LIGHT to the pathophysiology of PE.
  
  
  METHODS
  An ELISA, specific for LIGHT was used to validate the results of the initial microarray analysis. Infusion experiments were used to determine the effects of elevated LIGHT in pregnant and non-pregnant mice. An adoptive transfer model of PE in pregnant mice was used to determine if AT1R agonistic autoantibodies (AT1AA) stimulate LIGHT production. The potential contribution of increased LIGHT to clinical features of PE in pregnant mice was evaluated by the use of neutralizing antibodies directed to the LIGHT receptors, HVEM and LTβR.
  
  
  RESULTS
  The use of a LIGHT-specific ELISA showed that the cytokine was significantly increased in the circulation and placentas of women with PE. The infusion of recombinant LIGHT into pregnant mice induced major clinical features of PE, including hypertension and proteinuria. Such changes were not observed when LIGHT was infused into not non-pregnant mice. LIGHT was significantly elevated in a pregnant mouse model of PE based on the introduction of IgG from women with PE. In this autoantibody-injection model of PE, the use of neutralizing antibodies to the LIGHT receptors, HVEM and LTβR, blocked autoantibody-induced hypertension, proteinuria, elevated sFlt-1 production, impaired placental angiogenesis and endothelial dysfunction.
  
  
  CONCLUSIONS
  Overall, our studies show that LIGHT is significantly elevated in women with PE and that elevated LIGHT contributes to pathophysiology of PE in an antibody-injection model of PE in pregnant mice. LIGHT-induced pathophysiology can be abrogated by the use of neutralizing antibodies directed at its receptors, HVEM and LTβR. These results indicate that LIGHT may have a previously unrecognized role in the pathophysiology of PE and that its detrimental effects are pregnancy-dependent. These findings immediately suggest novel therapeutic possibilities.
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States.
authors.forename: R A
authors.initials: RA
authors.lastname: Irani
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Xia