Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of β2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis

Charis Pericleous, Patricia Ruiz-Limón, Zurina Romay-Penabad, Ana Carrera Marín, Acely Garza-Garcia, Lucy Murfitt, Paul C. Driscoll, David S. Latchman, David A. Isenberg, Ian Giles, Yiannis Ioannou, Anisur Rahman, Silvia S. Pierangeli

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Objective. IgG aPL against domain I of β2-glycoprotein I (β2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS. Methods. Two polyclonal IgG fractions were isolated from serum of a patient with APS, both with high aPL activity but differing in aDI activity (aDI-rich and aDI-poor). These IgG fractions were tested for their pathogenic ability in an in vivo mouse model of thrombosis. Male CD1 mice were injected intraperitoneally with either aDIrich or aDI-poor IgG; as a control, IgG isolated from healthy serum was used. A pinch injury was applied to the right femoral vein and thrombus dynamics and tissue factor activity in isolated tissue were evaluated. Results. Both aDI-rich and aDI-poor IgG retained aCL and anti-β2GPI activity, while only aDI-rich IgG displayed high aDI activity, as defined by our in-house cut-offs for positivity in each assay. aDI-rich IgG induced significantly larger thrombi in vivo compared with aDI-poor IgG (P<0.0001). Similarly, aDI-rich IgG significantly enhanced the procoagulant activity of carotid artery endothelium and peritoneal macrophages isolated from experimental animals (P<0.01). Conclusion. These data directly demonstrate that the ability to cause thrombosis in vivo is concentrated in the aDI fraction of aPL.

Original languageEnglish (US)
Pages (from-to)722-727
Number of pages6
JournalRheumatology (United Kingdom)
Volume54
Issue number4
DOIs
StatePublished - Dec 11 2014

Keywords

  • Anti-phospholipid antibodies
  • Anti-phospholipid syndrome
  • Domain i
  • Mouse model
  • Venous thrombosis
  • β2-glycoprotein i

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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    Pericleous, C., Ruiz-Limón, P., Romay-Penabad, Z., Carrera Marín, A., Garza-Garcia, A., Murfitt, L., Driscoll, P. C., Latchman, D. S., Isenberg, D. A., Giles, I., Ioannou, Y., Rahman, A., & Pierangeli, S. S. (2014). Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of β2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis. Rheumatology (United Kingdom), 54(4), 722-727. https://doi.org/10.1093/rheumatology/keu360