ReviewComplement activation in anti-phospholipid syndrome: A clue for an inflammatory process?
Introduction
Anti-phospholipid syndrome (APS) is a clinical disorder, characterised by recurrent thrombosis, fetal losses and circulating anti-phospholipid antibodies (aPL), reacting to PL-binding plasma proteins (namely β2glycoprotein I [β2GPI] and prothrombin) [1].
It is widely accepted that β2GPI-dependent aPL play a pathogenic role. In fact, several in vivo studies showed a direct effect of these autoantibodies in inducing fetal loss [2], [3], [4], [5], endothelial activation [6] and in enhancing the pro-coagulant effect of a trigger factor [6], [7], [8].
The thrombophilic state in APS has been associated with a vasculopathy rather than with a true inflammatory vasculitic process. Actually, even the recent classification criteria state that inflammatory signs should be absent in the thrombotic manifestations of APS [9]. Such a statement is apparently in clash with the evidence that aPL, and in particular anti-β2GPI antibodies, are able to induce an inflammatory phenotype in both monocytes and endothelial cells (EC) in in vitro experimental models [10]. Actually these cell types may up-regulate the synthesis and secretion of pro-inflammatory cytokines, chemokines and adhesion molecules (ADM) when incubated in the presence of β2GPI-dependent aPL [11], [12], [13], [14], [15]. Animals deficient for ADMs or treated with anti-VCAM-1 blocking antibodies were shown to be protected from the thrombogenic effect of human aPL IgG and VCAM-1 up-regulation was shown in the endothelium of carotid arteries in animals injected with human aPL IgG fractions (rev. in ref. [40]). As a whole these findings do suggest that an endothelial pro-inflammatory phenotype may be present also in in vivo APS animal models.
The obstetrical counterpart of APS is represented by the occurrence of pregnancy losses and pregnancy complications such as early pre-eclampsia. Both histopathological studies and experimental evidence of a direct effect of aPL on placental tissues strongly suggest that thrombotic phenomena alone cannot explain the obstetrical manifestations of the syndrome [16], [17]. A local inflammatory process has been suggested to play a role in inducing a defective placentation as a cause of the recurrent fetal losses associated to aPL. Actually local Tumor Necrosis Factor alpha (TNFα) production, neutrophil recruitment and complement activation/deposition have been described in experimental animal models of aPL-mediated fetal loss [18], [19], [20], [21]. In line with these experimental findings, histological evaluation of terminal placental tissues of APS women reported an increased infiltration of monocyte-macrophage lineage cells [22].
Section snippets
Potential role of complement in vascular thrombosis
Particular attention has been paid on the endothelial perturbation mediated by β2GPI-dependent aPL in APS pathogenesis [10], [23]. In this regard, it is important to underline the close relationship between the complement system and endothelial functions [24]. In fact, EC could synthesize different complement proteins, such as C3 and C4 and late components in response to pro-inflammatory cytokines [25], [26], [27]. In addition, complement system – through membrane attack complex activation –
APS thrombosis and complement
Notwithstanding, the mechanisms of pro-coagulant effects of anti-PL are not fully understood. In fact, a complex interaction between these autoantibodies, EC, platelets and leukocytes has been suggested to eventually trigger the coagulation process in combination with a second hit [10], [23]. In this “scenario” the complement system has been recently reported to play a role in mediating the aPL-induced clotting in experimental animal models.
In order to reproduce the thrombosis occurring in APS
APS recurrent fetal loss and complement
As mentioned before, complement activation has been suggested to play a pathogenic role also in aPL-associated pregnancy loss.
Several studies showed that passive transfer of human aPL IgG in pregnant mice can cause fetal loss and growth retardation [2], [3], [4], [5]. Although some experimental models highlight the role of thrombosis in the pathogenesis of fetal loss in APS, histological findings on the placenta tissues suggest that pro-inflammatory elements can co-operate to tissue damage [22]
Case report
In spite of the experimental evidence there is scarce information on complement activation in the course of APS. Plasma hypocomplementemia was originally reported in a small series of patients with Central Nervous System (CNS) involvement and low plasma complement levels were also described in APS patients by some groups [42], [43], [44], [45]. In addition, a relationship between anti-cardiolipin antibodies and null alleles of C4 was also reported [46].
However, no clear correlation between
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Cited by (76)
Histopathology in the placentae of women with antiphospholipid antibodies: A systematic review of the literature
2015, Autoimmunity ReviewsCitation Excerpt :The majority of studies reported here performed tests for lupus anticoagulant and/or anticardiolipin antibodies. Only six studies tested for the third clinically relevant aPL, anti-β2GPI antibodies [58,67,73,74,99,113]. One noteworthy group of control women met the clinical criteria of the APS but did not have lupus anticoagulant or anticardiolipin antibodies, and were referred to as having antiphospholipid-like syndrome [64].
Antiphospholipid Antibody Syndrome
2014, Obstetrics and Gynecology Clinics of North AmericaThe role of complement in the antiphospholipid syndrome: A novel mechanism for pregnancy morbidity
2012, Seminars in Arthritis and RheumatismPregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome
2012, Journal of AutoimmunityCitation Excerpt :Human placentas have been also studied for clarifying the role of complement, in terms of both deposition and activation. Although case reports failed to show any complement deposition in abortive material from APS patients [74], prospective studies did find complement deposition and activation [75,76]. However, this finding was not exclusive of abortive specimen, but was found in APS placentas at term as well.