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Pathogenesis of antiphospholipid syndrome: understanding the antibodies

Nature Reviews Rheumatology volume 7, pages 330–339 (2011)Cite this article

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Abstract

Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β2 glycoprotein I (β2GPI)-dependent aPL, the most important subset of these antibodies, mediate several—not necessarily alternative—thrombogenic mechanisms, mainly on the basis of their reactivity with β2GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β2GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.

Key Points

  • Antiphospholipid antibodies (aPL) are autoantibodies that are diagnostic of, and pathogenic in, antiphospholipid syndrome (APS)

  • aPL mediate several procoagulant mechanisms that can explain their thrombogenic effect in animal models, and their epidemiological association with APS in clinical studies

  • Whereas evidence shows that a second hit (usually an inflammatory event) is required for thrombus formation in APS, this requirement is less clear for fetal loss

  • In addition to placental thrombosis, other mechanisms for direct effects of aPL on placental tissues have been proposed

  • β2 glycoprotein I (β2GPI)-dependent autoantibodies seem to be the main pathogenic subpopulation of aPL

  • More information about the epitope specificity of anti-β2GPI aPL, as well as about the tissue expression of the target molecule, might help to better understand the pathogenesis of APS

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Figure 1: Pathogenic clotting mechanisms mediated by aPL.
Figure 2: Main effects of aPL on placenta.
Figure 3: Endothelial cell activation by anti-β2GPI autoantibodies.
Figure 4: aPL effects on trophoblasts.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Milan, Via della Pace 9, 20122, Milan, Italy

    Pier Luigi Meroni

  2. Immunological Research Laboratory, IRCCS Istituto Auxologico Italiano, Via G. Zucchi 18, Cusano Milanino, 20095, MI, Italy

    M. Orietta Borghi & Elena Raschi

  3. Department of Life Sciences, University of Trieste, Via Fleming 22, 34127, Trieste, Italy

    Francesco Tedesco

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Meroni, P., Borghi, M., Raschi, E. et al. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 7, 330–339 (2011). https://doi.org/10.1038/nrrheum.2011.52

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