Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

4. The Pathogenic Mechanisms for Antiphospholipid Antibodies (aPL)-Mediated Pregnancy Loss

Nicoletta Di Simone  and Silvia D’Ippolito 


Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore Rome, Largo Agostino Gemelli 8, Rome, 00168, Italy

Nicoletta Di Simone (Corresponding author)


Silvia D’Ippolito




4.1 Introduction

The revised Sapporo criteria established that pregnancy morbidity in antiphospholipid syndrome (APS) encloses ≥3 consecutive and spontaneous early miscarriages before 10 weeks of gestation, at least one unexplained fetal death after the 10th week of gestation of a morphologically normal fetus, and a premature birth before the 34th week of gestation of a normal neonate due to eclampsia or severe preeclampsia or placental insufficiency [1].

During the years several researchers tried to find an etiopathogenic explanation for pregnancy morbidity in APS. The results underlined the heterogeneity of the pathogenic mechanisms involved in antiphospholipid antibody (aPL)-mediated fetal loss, all taking place within the placenta [15]. Actually, intraplacental thrombotic phenomena, a direct aPL-mediated placental damage, and inflammatory processes involving the complement cascade are considered the most important mechanisms underlying miscarriages in APS [35]. It is now well accepted that these mechanisms are not mutually exclusive and may play a role together or in different combination at different times of the pregnancy. Such a variety in the aPL-mediated action fits well with the heterogeneity of the clinical manifestations of the obstetric APS, spanning from early to late miscarriages or preeclampsia [6].

4.2 The Human Implantation and Placentation

Human implantation and placentation represent a complex process based on subsequent steps. In particular, trophoblast cells play a key role in placental development. After implantation, they differentiate into villous and extravillous trophoblast cells (VTC and EVTC, respectively) [6]. VTC support the maternal-fetal exchange of nutrients and the endocrine functions of the placenta. EVTC invade the maternal endometrium and, through the formation of cellular plugs, gradually erode local spiral arteries to provide access to the maternal blood. The invasive nature of EVTC is dependent on the activity of matrix metalloproteases (MMPs) [78], proteolytic enzyme degrading the extracellular matrix (ECM), and on the secretion of a number of molecules such as heparin-binding epidermal growth factor (HB-EGF), a strong mitogenic molecule expressed in VTC and EVTC, able to stimulate trophoblast differentiation, invasive phenotype, and motility [912].

During the early phase of pregnancy, also the endometrium of the uterus undergoes profound changes and transforms into decidua, a newly formed tissue that plays a critical role for successful embryo implantation and regular fetal growth. The decidua provides a physical anchorage for the implanted embryo tightly attached to the maternal tissue through anchoring villi which float in the intervillous space, surrounded by an outer layer of trophoblast cells. An important feature of the decidual tissue in the early phase of pregnancy is represented by the active angiogenic differentiation of endometrial endothelial cells (HEECs) and the vascular remodeling of the spiral arteries [13]. In particular decidualizing endometrial cells produce critical angiogenic molecules, such as vascular endothelial growth factor (VEGF) able to promote the angiogenic differentiation of HEECs [1416]. These changes facilitate a regular supply of maternal blood to the developing placenta at an optimal flow rate necessary for the adequate delivery of nutrients to the developing embryo [1316]. Noteworthy, VTC exposed to maternal blood circulating in the intervillous space and EVTC present in human decidua, being of fetal origin, represent a real challenge for the maternal immune system. As a result, a vigorous response may be mounted against paternal antigens expressed on trophoblasts leading to potential deleterious effects on fetal survival [17]. Trophoblast invasion of decidua results in recruitment and activation of leukocytes and precursors of endothelial cells and in the release of various cytokines, chemokines, and growth factors that promote tissue remodeling [31718]. There is evidence for a dynamic balance between proinflammatory and anti-inflammatory mediators in normal pregnancy [31720].

Embryo implantation is, therefore, strictly based on trophoblast invasion and endometrial decidualization both associated with an inflammatory process and a highly regulated maternal immune response which rather than having deleterious effects help to promote fetal survival and allow normal progression of pregnancy [31719].

4.3 aPL and Intraplacental Thrombotic Phenomena

In line with the thrombogenic effect of aPL, intraplacental thrombotic phenomena and the subsequent impaired maternal-fetal blood exchange were initially suggested as the main pathogenic mechanism underlying the poor obstetric outcome [2122]. Accordingly placental thrombosis and infarction were reported. It was suggested that such an effect might be due to the in vitro ability of aPL, mainly anti-ß2 glycoprotein 1 antibodies (anti-ß2GP1), to induce a procoagulant state via disruption of annexin A5 shield on trophoblast and endothelial cell monolayers. These findings were supported by the observation of reduced annexin A5 expression in placentas from aPL-positive women compared to those lacking the autoantibodies [2324]. However further histological studies revealed that neither thrombosis nor infarction is common in the placentas of patients with APS [2526]. Specifically, the prevalence of intervillous thrombosis in women with aPL was similar to that found in aPL-negative pregnancies. Moreover, due to the presence of trophoblast plugs in the uterine spiral arteries, significant maternal blood flow does not occur in the intervillous space until the end of the first trimester, suggesting that placental thrombosis and infarction are unlikely causes of embryonic or early fetal loss in APS patients.

4.4 aPL and Direct Placental Damage

Besides thrombosis, several evidence indicated that alternative aPL-mediated pathogenic mechanisms directly affect placental tissue. The observation of β2GPI reactivity with trophoblast cell membranes, human stromal decidual cells, and HEECs suggested the placental tropism of anti-β2GPI antibodies [152728]. β2GPI has been shown to bind to target cells through the phospholipid-binding site in the fifth domain of the molecule [41928]. Accordingly polyclonal IgG antibodies from APS patients and human IgM monoclonal antibodies with anti-β2GPI activity can react in vitro with β2GPI both at the fetal side of human placenta (i.e., on trophoblast cells) and at the maternal one (i.e., on stromal decidual cells and HEECs) [152728]. Subsequent studies demonstrated that, after reacting with target cells, aPL are able to:

·               Inhibit trophoblast differentiation, as shown by the reduced secretion of human chorionic gonadotrophin (hCG) [2829].

·               Impair EVTC invasiveness in an in vitro Matrigel assay. This effect is well correlated with a significant inhibition of expression/activity of MMPs [2829] and of HB-EGF production [30].

·               Induce trophoblast injury and apoptosis [31].

·               Be endocytosed into the human syncytiotrophoblast in a ß2GPI-dependent process, disrupting the normal apoptotic turnover and to induce the extrusion of necrotic trophoblast debris which are able to activate the maternal endothelium [32].

·               Induce a proinflammatory phenotype in stromal decidual cells [27].

·               Block endometrial angiogenesis both in vitro and in vivo, by inhibiting the HEECs angiogenic differentiation and the production of specific factors upregulated during angiogenesis, such as VEGF [15].

As a whole, all of these aPL-mediated effects might contribute to a final functional cellular damage resulting in a defective placentation and eventually in the poor obstetric outcome. Furthermore these findings suggest that APS-associated pregnancy complications can be mediated by several distinct pathogenic events not necessarily related to the procoagulant action of aPL [3419].

The above results suggest β2GPI-dependent aPL as the main pathogenic autoantibodies in obstetric APS. Accordingly, it has been hypothesized that most of these potentially pathogenic autoantibodies should be absorbed at the placental level (where β2GPI is expressed) and should not be transferred to the fetus. This mechanism would explain why thrombotic events are rarely reported in babies born to aPL-positive mothers, in spite of the high thrombophilic profile of neonates.

4.5 aPL and Inflammation-Mediated Damage

Acute inflammatory events can be responsible for a negative pregnancy outcome via the activity of proinflammatory mediators, such as complement, tumor necrosis factor-α [TNF-α], and chemokines that have been shown to have a role in animal models of aPL-induced fetal loss [341920]. Evidence from experimental animal models confirmed the ability of human IgG with aPL activity, passively infused after implantation (10 mg/mouse per injection), to induce fetal resorption and growth retardation. The decidual immunohistochemical and histological demonstration of human IgG and mouse complement deposition, neutrophil infiltration, and local TNF-α secretion suggested a placental inflammatory damage [3335]. The involvement of the complement system, in particular the cleaved product C5a, was supported by the observation that complement-deficient animal models are protected from pregnancy complications [203639]. In another experimental model of fetal loss, mice deficient in chemokine-binding protein D6, a placental scavenger receptor which controls local inflammation by degrading the majority of inflammatory chemokines, are more susceptible to fetal loss when passively infused with a small amount of human aPL IgG than wild-type mice or mice infused with normal IgG [40]. Further in vitro studies reported the ability of aPL to directly induce human first trimester trophoblasts to generate a potent proinflammatory and potentially damaging cytokine, interleukin-1ß (IL-1ß). This is possible via the aPL-mediated activation of the uric acid response which in turn activates the inflammasome, a protein complex containing the Nod-like receptor and the apoptosis-associated speck-like protein (Nalp3/ASC) able to facilitate pro-IL-1ß processing in the trophoblast [41].

Altogether, these findings suggest that a local acute inflammatory response might have a role in experimental aPL-mediated fetal loss.

In spite of the experimental results, the role of inflammation in determining APS pregnancy complications still remains a debated issue. In APS placentas a strong infiltration of complement components, as well as histopathological findings of deciduitis and villous infiltration, has been found more frequently compared to normal controls [4245]. On the contrary, further ex vivo examinations of APS placentas and subsequent in vivo studies, using another model of fetal resorption and growth retardation, injected with small amount of human aPL IgG (10–50 μg/mouse) before implantation, failed to show any sign of acute placental inflammatory events and complement deposition [46]. These discrepancies in the results might be due to the different experimental models used and to the fact that experimental observations are often restricted to a given period of the pregnancy, that is, when the investigation is performed or at the time of autoantibody passive infusion. For the same reason, histological examination of human term placentae may show only the resulting damage without providing any insight on the events taking place at the beginning of the aPL-mediated insult.

4.6 Conclusions and Implications from a Practical Point of View

Taken together, the above reported findings suggest that numerous, heterogeneous and complex events underlie pregnancy complications in APS patients. However several aspects with regard to the events that break out the aPL activity and precipitate the different clinical manifestations of obstetric APS are still debated and need further investigation. Nevertheless, it is nowadays well established the ability of aPL to directly target both the invading trophoblasts and the maternal decidua/endometrial endothelial cells in the human placenta and, then, to induce a negative effect on placentation not necessarily related to prothrombotic or inflammatory events.

From a practical point of view, the knowledge of the aPL-mediated placental action has allowed important therapeutical implications. In clinical practice, several strategies have been proposed to improve the pregnancy outcome, including combinations of aspirin and unfractionated (UFH) or low molecular weight (LMWH) heparin [4749]. Treatment with heparin is mainly based on the initial assumption that thrombotic events played the major role in APS pregnancy morbidity [4647]. However the evidence of alternative mechanisms of aPL-induced placental damage and the success of treatment with heparin on the pregnancy outcome suggested additional mechanisms of action for the drug [5051]. Actually it has been demonstrated the ability of LMWH to prevent the aPLs binding to trophoblast cells and to restore in vitro placental invasiveness and differentiation [49]. Accordingly, heparin has been shown to prevent the binding of β2GPI to negatively charged phospholipids (PL), which in turn prevents the deposition of the anti-β2GPI in tissues. Subsequent studies reported the ability of heparin to block the aPL-mediated inhibition of HEEC angiogenic differentiation [52]. As a whole, these results suggest that heparin, by interfering with the aPL binding, is able to prevent the aPL pathogenic action not only on the fetal side of the placenta (trophoblast cells) but also on the maternal one (HEECs).

In addition, other researchers, in line with the aPL/complement-mediated pathogenic action, demonstrated that the protective effect of heparin in the mouse model is linked to its anticomplement activity [50].

The likelihood of a good pregnancy outcome in women with APS is around 75–80 % under correct management. Unfortunately, a significant proportion of women, about 20–21 %, does not respond to the standard treatment and still suffer from miscarriages and adverse pregnancy events [5354]. The role of glucocorticoids remains still worthy of further assessment. The addition of 40–60 mg of prednisolone to aspirin alone or associated to heparin during gestation has shown no clear benefits in APS pregnant women in spite of important side effects, such as preterm delivery because of premature rupture of membranes or preeclampsia [5557]. By contrast, a recent study by Brahman et al. seems to suggest that the addition of low-dose prednisolone (10 mg) from the time of positive pregnancy test up to 14 weeks of gestation may be effective in increasing live birth rate [58]. The addition of intravenous immunoglobulin (IVIg) has not been shown to be superior to heparin and aspirin in unselected patients, while it seems to be efficacious in obstetric APS patients selected for poor prognosis or autoimmune phenomena [59].

A possible explanation for the high proportion of refractory APS might be that not all the mechanisms underlying aPL-mediated pregnancy complications have been clarified. Novel alternative therapies are urgently needed [60]. Given the evidence that β2GPI and the related autoantibodies play a central role in aPL-mediated obstetric manifestations, new molecules able to interfere with β2GPI expression at the placental level have been recently investigated. This is the case of a synthetic peptide, TIFI, sharing structural similarity with the PL-binding site of β2GPI. Through this similarity, TIFI can compete with the β2GPI PL-binding site and displace the molecule from the cell surface, ultimately inhibiting the aPL reaction with the target tissues [61]. Accordingly, this peptide is able to prevent aPL-mediated thrombosis in vivo and to inhibit the in vitro binding of β2GPI to human endothelial cells, murine monocytes, trophoblast cells, and HEECs [466162]. Furthermore, when passively infused in naïve pregnant mice, TIFI prevents the aPL-mediated fetal loss [46]. As a whole, these results show how molecules, possibly disrupting the β2GPI placental expression, can inhibit the binding of β2GPI-dependent aPL and, in turn, the aPL-mediated placental damage. At the same time, these results lead to investigate a further and more specific therapeutical approach able to abrogate the aPL pathogenic effects. Indeed, the observation that mice lacking β2GPI show a compromised early pregnancy suggested that functional β2GPI is necessary for optimal implantation and placental morphogenesis [63]. This has led researchers to conceive novel and promising biological therapies useful for refractory APS patients and based on the use of immunomodulatory drugs [64] or a monoclonal antibody which are able to prevent the aPL-mediated activation of the complement and the procoagulant and pro-abortive effects, without interfering with the expression of the placental β2GPI [6566].



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