Pathogenesis of antiphospholipid syndrome: understanding the antibodies

• Published in: Nature reviews. Rheumatology Vol. 7; no. 6; pp. 330 - 339
• Main Authors: Meroni, Pier Luigi, Borghi, M. Orietta, Raschi, Elena, Tedesco, Francesco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2011; Nature Publishing Group
• Subjects: 692/420/2780; 692/53/2421; 692/699/1670/122/1928; Antibodies; Antibodies, Antiphospholipid - immunology; Anticoagulants; Antigens; Antiphospholipid antibodies; Antiphospholipid syndrome; Antiphospholipid Syndrome - etiology; Antiphospholipid Syndrome - immunology; Blood clot; Blood clots; Development and progression; Diagnosis; Female; Humans; Immune response; Medicine; Medicine & Public Health; Pathogenesis; Physiological aspects; Pregnancy; Pregnancy Complications - etiology; Pregnancy Complications - immunology; review-article; Rheumatology; Risk factors; Thrombosis; Italy
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/nrrheum.2011.52

Pathogenic autoantibodies trigger thromboses in antiphospholipid syndrome (APS), through several mechanisms that favor blood clotting and act in concert with inflammatory events. APS-associated fetal loss, however, is not fully explained by thrombogenic mechanisms, and other, direct actions of the autoantibodies are proposed. This Review summarizes the autoantibody-mediated pathways in APS, with a focus on the causes of pregnancy complications.
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. β
2
glycoprotein I (β
2
GPI)-dependent aPL, the most important subset of these antibodies, mediate several—not necessarily alternative—thrombogenic mechanisms, mainly on the basis of their reactivity with β
2
GPI 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. β
2
GPI-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
β
2
glycoprotein I (β
2
GPI)-dependent autoantibodies seem to be the main pathogenic subpopulation of aPL
More information about the epitope specificity of anti-β
2
GPI aPL, as well as about the tissue expression of the target molecule, might help to better understand the pathogenesis of APS