title: Coagulopathy triggered autoimmunity: experimental antiphospholipid syndrome in factor V Leiden mice.
abstract: BACKGROUND
  We investigated interactions between genetically and autoimmune-mediated coagulopathies by inducing experimental antiphospholipid syndrome (eAPS) in mice carrying the factor V Leiden (FVL) mutation.
  
  
  METHODS
  eAPS was induced in heterozygous and homozygous FVL transgenic mice (C57BL/6 background) by immunization with β(2)-glycoprotein I (β(2)-GPI). Autoantibody levels were measured at 1 and 5 months post-immunization. Mice were tested at 4 months post-immunization for behavior and cognitive function in the staircase, elevated plus-maze, and swim T-maze tests. Brains were removed and analyzed by immunohistochemistry for inflammatory markers and neurodegenerative processes.
  
  
  RESULTS
  A single immunization with β(2)-GPI induced significantly higher and longer-lasting immune responses, and this was dependent on the number of FVL alleles. At 1 and 5 months post-immunization, levels of antibodies rose from 1.17 ± 0.07 to 1.62 ± 0.17 (optical density units; ODU) in homozygous FVL mice, compared with stable levels of 0.59 ± 0.17 and 0.48 ± 0.16 ODU in heterozygous FVL mice and a drop from 1.62 ± 0.21 to 0.61 ± 0.13 ODU in wild-type mice. Behavioral and cognitive clinical features of eAPS were also correlated with FVL allele load, as assessed by the elevated plus-maze (altered anxiety), staircase (hyperactivity and higher exploration), and swim T-maze (impaired learning) tests. Histological studies identified significant neurodegenerative changes in both grey and white matter in the eAPS-FVL brains. In spite of the potential interaction of two prothrombotic disease states, there were no ischemic lesions seen in this group.
  
  
  CONCLUSIONS
  The results indicate that genetically mediated coagulopathies increase the risk of developing coagulation-targeted autoimmune responses, and suggest the importance of antibody-mediated neurodegenerative processes in the brain in APS.
authors.affiliation: Department of Neurology and Sagol Center for Neurosciences, Sheba Medical Center, Tel-Hashomer, 2 Sheba Rd, Ramat Gan 52621, Israel. avivakatzav@gmail.com
authors.forename: Aviva
authors.initials: A
authors.lastname: Katzav
authors.forename: Nikolaos C
authors.initials: NC
authors.lastname: Grigoriadis
authors.forename: Tania
authors.initials: T
authors.lastname: Ebert
authors.forename: Olga
authors.initials: O
authors.lastname: Touloumi
authors.forename: Miri
authors.initials: M
authors.lastname: Blank
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
mesh_terms: D000818:Animals; D016736:Antiphospholipid Syndrome / Q000473:pathology*; D001323:Autoantibodies / Q000097:blood; D025861:Blood Coagulation Disorders, Inherited / Q000150:complications*; D001921:Brain / Q000473:pathology; D060825:Cognitive Dysfunction / Q000139:chemically induced*; D004195:Disease Models, Animal; D005165:Factor V / Q000235:genetics*; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D001323:Autoantibodies; C095381:factor V Leiden; D005165:Factor V