Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Apolipoprotein E Receptor (apoER2) Is Involved for Thrombotic Complications in a Murine Model of Antiphospholipid Syndrome.

Penabad1,  Z. Romay, Shilagard1,  T., Vargas1,  G., Aguilar-Valenzuela1,  R., de Groot2,  P., Pierangeli1,  S.

Univ of TX Med Branch, Galveston, TX
University Hospital Utrecht, Utretch, The Netherlands

Background:

Antiphospholipid antibodies (aPL) recognize b2glycoprotein I(b2GPI)-bound to receptor(s) in target cells (i.e.: endothelial cells [EC], platelets, monocytes) and trigger a pro-coagulant/pro-inflammatory phenotype (i.e.: up-regulation of tissue factor [TF] that lead to thrombosis). The interaction of b2GPI with target cells may involve more than one protein. Previous publications suggest that b2GPI-aPL antibody complex binds to apoER2 in cell surface, inducing activation of platelets or EC. Moreover, it has been shown that a soluble binding domain I of apoER2 (sBDI) inhibits the binding of b2GPI to apoER2.

Objectives:: To determine whether apoER2 mediates pathogenic effects of murine and human aPL antibodies in vivo.

Methods:

Wild type (apoER2+/+) and apoER2-deficient (apoER2-/-) mice were injected twice with IgG purified from one patient with "primary" antiphospholipid syndrome (IgG-APS) or with control IgG (IgG-NHS) or with a murine monoclonal anti-b2GPI antibodies (named E7) or with control murine monoclonal antibody [1kMPOC-21(Sigma Aldrich)](MuMoAbC). Some wild type mice were also injected i.p. twice with 50 mg of soluble binding DI of apoER2 (sBD1), 30 minutes before each injection with aPL antibodies. Several procedures were done in treated and controls mice to study pathogenicity of aPL antibodies: a) dynamics of thrombus formation, b) TF activity in homogenates of carotid arteries and in peritoneal macrophages, and c) TF expression in macrophages using quantum dot nano crystals and two-photon excitation laser scanning microscopy.

Results:

Significantly larger thrombi and increased TF activity in carotid artery homogenates and in peritoneal macrophages was observed in apoER2+/+ mice treated with (IgG-APS or E7) when compared to controls. Importantly, apoER2-/-mice treated with murine or human aPL antibodies shown partial but significantly abrogation of thrombogenic effects compared with their counterparts injected with control antibodies. In addition, thrombogenic effects of IgG-APS were significantly abrogated in apoER2+/+ mice by sBD1, hence confirming the ApoER2 involvement in vivo.

Mice/treatmentThrombus size (mm2)TF activity carotids (pmol/mg · mL-1 protein)TF activity macrophages (pmol/mg·mL-1 protein)TF expression (AU)
apoER2+/+ IgG-APS*4094 ± 1037*21.4 ± 8.4*10.1 ± 1.2*11.9 ± 2.8
apoER2+/+ IgG-NHS287 ± 1105.8 ± 0.93.2 ± 0.83.2 ± 0.4
apoER2-/- IgG-APS**1675 ± 78114.6 ± 1.8**5.9 ± 1.54.8 ± 0.9
apoER2-/- IgG-NHS514 ± 1155.3 ± 1.72.7 ± 0.85.9 ± 0.9
apoER2+/+ IgG-APS + sBD1†665 ± 173†14.7 ± 1.6†4.4 ± 0.6†4.3 ± 0.9
apoER2+/+ IgG-NHS + sBD1486 ± 1644.5 ± 3.33.1 ± 2.53.2 ± 0.6
apoER2+/+/E7*2599 ± 766*70.3 ± 15.2*13.9 ± 2.8n/a
apoER2+/+ MuMoAbC827 ± 29413.5 ± 1.84.2 ± 1.7n/a
apoER2-/- E7**827 ± 294**24.3 ± 10.5**9 ± 0.6n/a
apoER2-/- MuMoAbC436 ± 12511.8 ± 2.54.3 ± 0.2n/a
(*) statistically significant different from their negative controls in apoER2+/+ mice.(**) statistically significant different from their negative controls and apoER2+/+ mice counterparts.(†) statistically significant different from apoER2+/+ mice treated with IgG

Conclusions:

Altogether these data show that apoER2 is a mediator of aPL thrombogenic effects in vivo. These data may have important implication in the design of new targeted treatments for APS.

To cite this abstract, please use the following information:
Penabad, Z. Romay, Shilagard, T., Vargas, G., Aguilar-Valenzuela, R., de Groot, P., Pierangeli, S.; Apolipoprotein E Receptor (apoER2) Is Involved for Thrombotic Complications in a Murine Model of Antiphospholipid Syndrome. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1360
DOI: 10.1002/art.29126

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