Coagulopathy triggered autoimmunity: Experimental antiphospholipid syndrome in factor V Leiden mice

Aviva Katzav*, Nikolaos C. Grigoriadis, Tania Ebert, Olga Touloumi, Miri Blank, Chaim G. Pick, Yehuda Shoenfeld, Joab Chapman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 β2-glycoprotein I (β2-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 β2-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.

Original languageEnglish
Article number92
JournalBMC Medicine
Volume11
Issue number1
DOIs
StatePublished - 4 Apr 2013

Funding

FundersFunder number
Israel Science Foundation917/08

    Keywords

    • Antiphospholipid syndrome
    • Autoantibodies
    • Autoimmunity
    • Coagulopathy
    • Cognitive dysfunction
    • Experimental antiphospholipid syndrome
    • Factor V leiden
    • Hyperactivity
    • Neurodegeneration

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