In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: Proof of concept

Yiannis Ioannou, Z. Romay-Penabad, C. Pericleous, I. Giles, E. Papalardo, Gracie Vargas, T. Shilagard, D. S. Latchman, D. A. Isenberg, A. Rahman, S. Pierangeli

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Objectives: In the antiphospholipid syndrome (APS), the immunodominant epitope for the majority of circulating pathogenic antiphospholipid antibodies (aPLs) is the N-terminal domain I (DI) of β2- glycoprotein I. We have previously shown that recombinant DI inhibits the binding of aPLs in fluid phase to immobilized native antigen, and that this inhibition is greater with the DI(D8S/D9G) mutant and absent with the DI(R39S) mutant. Hence, we hypothesized that DI and DI(D8S/D9G) would inhibit aPL-induced pathogenicity in vivo. Methods: C57BL/6 mice (n = 5, each group) were injected with purified IgG derived from APS patients (IgG-APS, 500 μg) or IgG from normal healthy serum (IgG-NHS) and either recombinant DI, DI(R39S), DI(D8S/ D9G), or an irrelevant control peptide (at 10-40 μg). Outcome variables measured were femoral vein thrombus dynamics in treated and control groups following standardized vessel injury, expression of vascular cell adhesion molecule-1 (VCAM-1) on the aortic endothelial surface, and tissue factor (TF) activity in murine macrophages. Results: IgG-APS significantly increased thrombus size as compared with IgG-NHS. The IgG-APS thrombus enhancement effect was abolished in mice pretreated with recombinant DI (P ≤ 0.0001) and DI(D8S/D9G) (P ≤ 0.0001), but not in those treated with DI(R39S) or control peptide. This inhibitory effect by DI was dose-dependent, and at lower doses DI(D8S/ D9G) was a more potent inhibitor of thrombosis than wild-type DI (P ≤ 0.01). DI also inhibited IgG-APS induction of VCAM-1 on the aortic endothelial surface and TF production by murine macrophages. Conclusion: Our findings in this proof-of-concept study support the development of recombinant DI or the novel variant DI(D8S/D9G) as a potential future therapeutic agent for APS.

Original languageEnglish (US)
Pages (from-to)833-842
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume7
Issue number5
DOIs
StatePublished - 2009

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Keywords

  • β-glycoprotein I
  • Antiphospholipid antibodies
  • Antiphospholipid syndrome
  • thrombosis
  • Tissue factor
  • Vascular cell adhesion molecule-1

ASJC Scopus subject areas

  • Hematology

Cite this

Ioannou, Y., Romay-Penabad, Z., Pericleous, C., Giles, I., Papalardo, E., Vargas, G., Shilagard, T., Latchman, D. S., Isenberg, D. A., Rahman, A., & Pierangeli, S. (2009). In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: Proof of concept. Journal of Thrombosis and Haemostasis, 7(5), 833-842. https://doi.org/10.1111/j.1538-7836.2009.03316.x