ReviewAnti-phosphatidylethanolamine antibody, thromboembolic events and the antiphospholipid syndrome
Introduction
The antiphospholipid syndrome (APS) is a systemic thrombotic diathesis of young adults. The mechanisms by which antiphospholipid antibodies (aPL) cause thrombosis and obstetric morbidity are poorly understood, but probably include inhibition of natural anticoagulants, activation of platelets and endothelial cells, blocking of the fibrinolytic system, and triggering of the complement cascade [1]. A ‘second hit’, frequently linked to innate inflammatory responses, is probably necessary to initiate the thrombotic vasculopathy characteristic of APS [2].
It is well known that aPL from patients with APS preferentially target negatively charged phospholipids (PL) and/or their complex with plasma proteins such as β2-glycoprotein I (β2GPI) [3].
Binding of APS sera to zwitterionic compounds such as phosphatidylethanolamine (PE) was not recognized by the time aPL specificities were detailed by Gharavi et al. in 1987 [4]. PE, a neutral PL in the pH range 2 to 7, is the main lipid component of the microbial membranes, and it is largely found in mitochondria. The PE molecule consists of a combination of glycerol esterified with two fatty acids and phosphoric acid. The phosphate group (negatively charged) is bound to ethanolamine, an alcohol with a positive charge. These contrasting charges characterize PE as a typical zwitterionic PL. In biological membranes, PE seems to work as a “chaperone” to guide the folding of other membrane proteins; it also supports active transport by the lactose permease [5].
In Bacillus megaterium, PE is asymmetrically distributed in the cell membrane, with one-third in the outer leaflet and two-thirds in the inner leaflet. This asymmetric distribution of PE is usual in the structure of biological membranes [6]. PE structure and main location in a hypothetical lipid bilayer are shown in Fig. 1.
As PE molecules are mainly located in the inner leaflet of biological membranes [6], [7], their bioavailability as targets for aPE at the endothelial cell surface is an issue to be clarified; it is possible that a primary event in APS patients expose PE molecules in the outer part of the membrane, making possible for the antibody to bind. Recent experiments utilizing rat aortic arch showed high levels of PE distributed along the endothelial surfaces, where the luminal location of PE might relate to aPE autoimmunity and thrombotic risk [7].
In 2007, it was shown that human monocytes and platelets, when activated, generated four analogous PE lipids that contained 12 or 15-hydroxyeicosatetraenoic acid (HETE); these PE-esterified HETEs, within the immune cells, could be signaling the lipoxygenase cascade [8]. Whether such proinflammatory effects attributable to PE are playing a role in systemic disorders as APS is an open question.
Section snippets
Pathogenesis and laboratory aspects
Although still controversial, the interest for aPE antibodies dates back to 1989, when we described for the first time a case of primary APS whereby a lupus anticoagulant (LA) was accompanied only by an IgM aPE. The aPE ELISA results were confirmed by inhibition studies and affinity purification [9]. Six other patients with LA but no anticardiolipin (aCL), showed no binding to various negatively charged compounds or PE. However, the LA activity could be removed by hexagonal phase PE [10], a
aPE antibodies: uncommon clinical associations
aPL antibodies, including aPE, have been eventually reported in rather more unusual clinical situations. In a survey of sickle cell disease patients dated from 1993, 68% of the individuals were positive for aPL antibodies, with aPE being one of the most frequent among them. The presence of aPE antibodies in these patients is of interest, as the sickled red cell greatly exposes hexagonal PL along the membrane [27].
In 1995, aPE and LA were persistently detected in two patients with Mediterranean
aPE and pregnancy morbidity
The association of aPE antibodies with pregnancy morbidity has been a matter of interest in recent years. According to data from 1996, 17.3% of women with recurrent pregnancy loss had aCL antibodies, but another 10.1% were positive for another aPL antibody, including aPE [31]. A stronger association of aPE antibodies (as compared to antibodies to anionic PL) was demonstrated in women with early pregnancy loss, as reported in 1999 [32].
It is worth noting that aPE and anti-phosphatidylserine
aPE antibodies, thromboembolism and antiphospholipid syndrome
In 1992, aPE was reported as the sole aPL antibody in a patient with systemic lupus erythematosus (SLE) and pulmonary embolism [39]. In 1993, aPE was detected in patients with SLE and thrombosis in the absence of LA or aCL antibodies [40]. aPE antibodies contributed to the diagnosis of APS in another SLE survey, and their presence is associated particularly with valvulopathy and livedo reticularis [41].
In 2001, aPE was the most frequent serological finding (as compared to aCL and
Conclusion
After 23 years from the original description of aPE antibodies in a patient with primary APS [9], the role of these antibodies in individuals with unexplained thrombosis and pregnancy morbidity remains intriguing. While there is no robust evidence to propose the inclusion of aPE antibodies as criteria for APS as yet, one, at the same time, should not neglect the importance of testing for aPE in cases of “seronegative” APS, as recently suggested [59]. If patients with sole aPE antibodies and
Take-home messages
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Patients with classical anti-phospholipid syndrome (APS) usually show antibodies towards negatively charged phospholipids (PL) such as cardiolipin and phosphatidylserine. In solid assays, binding to neutral PL such as phosphatidylethanolamine (PE) in lamellar phase is less frequent. Interestingly, lupus anticoagulant activity (LA) can be inhibited by hexagonal phase PE. In another words, binding of anti-phospholipid antibodies to PE might vary according to the PE spatial structure in different
Acknowledgments
MLB is funded by the Louise Gergel Fellowship.
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Cited by (38)
Clinical performance of non-criteria antibodies to phospholipids in Chinese patients with antiphospholipid syndrome
2019, Clinica Chimica ActaCitation Excerpt :Over the past two decades, a number of home-made or commercial ELISA kits have been developed for detecting those non-criteria aPLs. Despite tremendous efforts has been made to elucidate their clinical relevance in APS, the results were inconsistent, especially regarding whether those aPLs could predict patients with at high risk of thrombosis or recurrent fetal loss [12–19]. A possible explanation for those discrepancies mentioned above is the differences in genetic/environmental factors.
The outcome of ELISA for antiphosphatidylethanolamine antibodies is dependent on the composition of phosphatidylethanolamine
2017, Journal of Immunological MethodsCitation Excerpt :These autoantibodies, including antiphosphatidylethanolamine (aPE), are being actively pursued in order to establish a complete diagnostic panel for APS patients. In a number of clinical studies, aPE antibodies are shown to positively correlate with symptoms of APS (McIntyre and Wagenknecht, 2000; Sher et al., 2000; Yetman and Kutteh, 1996; Matsubayashi et al., 2001; Sanmarco et al., 2007; Yamada et al., 2009; Gris et al., 2000; Balada et al., 2001; Gonzales-Portillo et al., 2001; Sanmarco et al., 2007; Karmochkine et al., 1992; Berard et al., 1996; Sugi et al., 1999; Boffa et al., 1996; Sugi et al., 2004; Staub et al., 2012). While different antiphospholipid autoantibodies can coexist in the same patient, aPE antibodies are sometimes the sole antibodies in patients with symptoms of APS, suggesting aPE may be an independent etiological entity (Karmochkine et al., 1992; Berard et al., 1996).
Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: A systematic review and meta-analysis
2014, Autoimmunity ReviewsCitation Excerpt :They include anti-β2 Glycoprotein I (β2GpI), identified in 1990, anti-prothrombin (aPT), anti-phosphatidyl serine (aPS) and anti-phosphatidyl ethanolamine (aPE) [9–14]. Patients with thrombosis may be positive for these antibodies, mainly in the absence of LA and aCL [15,16]. The clinical significance of their presence is still debated, as the clinical relevance of immunoglobulin (Ig) APL isotypes (IgG, IgM and IgA) [17].
Obstetric antiphospholipid syndrome: A recent classification for an old defined disorder
2014, Autoimmunity ReviewsCitation Excerpt :In addition to classical aPLs, increasing evidence demonstrates the presence of several autoantibodies shown to be directed to negatively charged PL other than cardiolipin, including phosphatidylethanolamine (aPE), to other PL-binding proteins (i.e. prothrombin (aPT) and/or phosphatidylserine–prothrombin complex, aPT/PS) or to interfere with the anticoagulant activity of annexin 5. All together these autoantibodies have been proposed to be relevant in obstetric APS, but controversial conclusions have been reported [62–66]. aPEs are directed against phosphatidylethanolamine, one of the main lipid components of the microbial membranes where it seems to work as a molecule involved in the folding of other membrane proteins [63].