C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies

A. L. Carrera-Marín, Z. Romay-Penabad, E. Papalardo, E. Reyes-Maldonado, E. García-Latorre, Gracie Vargas, T. Shilagard, S. Pierangeli

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6-/-) mice. Methods: C6-/- mice or the wild-type C3H/HeJ (C6+/+) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. Results: Thrombus sizes were significantly larger in C6+/+ treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6+/+ mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6-/- mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6+/+ counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6-/- mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6 +/+) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-β2glycoprotein I (aβ2GPI) antibodies. Conclusions: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.

Original languageEnglish (US)
Pages (from-to)1497-1505
Number of pages9
JournalLupus
Volume21
Issue number14
DOIs
StatePublished - Dec 2012

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Antiphospholipid Antibodies
Antiphospholipid Syndrome
Thrombophilia
Knockout Mice
Immunoglobulin G
Immunoglobulin M
Thrombosis
Thromboplastin
Complement Membrane Attack Complex
Serum
Immunoglobulins
Complement C6
Femoral Vein
Complement Activation
Peritoneal Macrophages
Carotid Arteries
Up-Regulation

Keywords

  • Anticardiolipin antibodies
  • antiphospholipid syndrome
  • complement activation
  • lupus anticoagulant
  • thrombosis

ASJC Scopus subject areas

  • Rheumatology

Cite this

Carrera-Marín, A. L., Romay-Penabad, Z., Papalardo, E., Reyes-Maldonado, E., García-Latorre, E., Vargas, G., ... Pierangeli, S. (2012). C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. Lupus, 21(14), 1497-1505. https://doi.org/10.1177/0961203312458839

C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. / Carrera-Marín, A. L.; Romay-Penabad, Z.; Papalardo, E.; Reyes-Maldonado, E.; García-Latorre, E.; Vargas, Gracie; Shilagard, T.; Pierangeli, S.

In: Lupus, Vol. 21, No. 14, 12.2012, p. 1497-1505.

Research output: Contribution to journalArticle

Carrera-Marín, AL, Romay-Penabad, Z, Papalardo, E, Reyes-Maldonado, E, García-Latorre, E, Vargas, G, Shilagard, T & Pierangeli, S 2012, 'C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies', Lupus, vol. 21, no. 14, pp. 1497-1505. https://doi.org/10.1177/0961203312458839
Carrera-Marín AL, Romay-Penabad Z, Papalardo E, Reyes-Maldonado E, García-Latorre E, Vargas G et al. C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. Lupus. 2012 Dec;21(14):1497-1505. https://doi.org/10.1177/0961203312458839
Carrera-Marín, A. L. ; Romay-Penabad, Z. ; Papalardo, E. ; Reyes-Maldonado, E. ; García-Latorre, E. ; Vargas, Gracie ; Shilagard, T. ; Pierangeli, S. / C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies. In: Lupus. 2012 ; Vol. 21, No. 14. pp. 1497-1505.
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abstract = "Background: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6-/-) mice. Methods: C6-/- mice or the wild-type C3H/HeJ (C6+/+) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. Results: Thrombus sizes were significantly larger in C6+/+ treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6+/+ mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6-/- mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6+/+ counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6-/- mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6 +/+) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-β2glycoprotein I (aβ2GPI) antibodies. Conclusions: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.",
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AU - Carrera-Marín, A. L.

AU - Romay-Penabad, Z.

AU - Papalardo, E.

AU - Reyes-Maldonado, E.

AU - García-Latorre, E.

AU - Vargas, Gracie

AU - Shilagard, T.

AU - Pierangeli, S.

PY - 2012/12

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N2 - Background: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6-/-) mice. Methods: C6-/- mice or the wild-type C3H/HeJ (C6+/+) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. Results: Thrombus sizes were significantly larger in C6+/+ treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6+/+ mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6-/- mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6+/+ counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6-/- mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6 +/+) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-β2glycoprotein I (aβ2GPI) antibodies. Conclusions: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.

AB - Background: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6-/-) mice. Methods: C6-/- mice or the wild-type C3H/HeJ (C6+/+) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. Results: Thrombus sizes were significantly larger in C6+/+ treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6+/+ mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6-/- mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6+/+ counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6-/- mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6 +/+) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-β2glycoprotein I (aβ2GPI) antibodies. Conclusions: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.

KW - Anticardiolipin antibodies

KW - antiphospholipid syndrome

KW - complement activation

KW - lupus anticoagulant

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