Certain Autoantibodies to Phosphatidylethanolamine (aPE) Recognize Factor XI and Prekallikrein Independently or in Addition to the Kininogens

Sugi, Toshitaka; McIntyre, John A.

doi:10.1006/jaut.2001.0543

Cited by 43 publications

(27 citation statements)

References 36 publications

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“…Thus, the decreased levels of PE in Sphk1 -/-Sphk2 +/-uteri could be the result of the block of substrate flux through the sphingolipid metabolic pathway. PE is a major component of both the outer and inner leaflets of cell plasma membranes and makes a complex with several plasma proteins, such as high-molecular weight kininogen, low-molecular weight kininogen, and proteins in complex with high-molecular weight kininogen, factor XI, or prekallikrein (40,41). Kininogen and its metabolites are abundantly expressed in the female reproductive system (42)(43)(44)(45).…”

Section: Figure 10mentioning

confidence: 99%

“…Kininogen and its metabolites are abundantly expressed in the female reproductive system (42)(43)(44)(45). Furthermore, in antiphospholipid syndrome, which is clinically characterized by systemic thrombosis and recurrent pregnancy loss, anti-PE antibody recognizes the PE-binding proteins (40,41). Kininogen and prekallikrein/kallikrein were found to be expressed in the endothelial cells of the placental villous capillaries, suggesting their importance in the vasculature of fetomaternal interface (45).…”

Section: Figure 10mentioning

confidence: 99%

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Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

Mizugishi

Li²,

Olivera³

et al. 2007

J. Clin. Invest.

137

119

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Uterine decidualization, a process that occurs in response to embryo implantation, is critical for embryonic survival and thus is a key event for successful pregnancy. Here we show that the sphingolipid metabolic pathway is highly activated in the deciduum during pregnancy and disturbance of the pathway by disruption of sphingosine kinase (Sphk) genes causes defective decidualization with severely compromised uterine blood vessels, leading to early pregnancy loss. Sphk-deficient female mice (Sphk1 -/-Sphk2 +/-) exhibited both an enormous accumulation of dihydrosphingosine and sphingosine and a reduction in phosphatidylethanolamine levels in pregnant uteri. These mice also revealed increased cell death in decidual cells, decreased cell proliferation in undifferentiated stromal cells, and massive breakage of decidual blood vessels, leading to uterine hemorrhage and early embryonic lethality. Thus, sphingolipid metabolism regulates proper uterine decidualization and blood vessel stability. Our findings also suggest that disturbance in sphingolipid metabolism may be considered as a cause of pregnancy loss in humans. IntroductionEmbryonic implantation is a complex series of processes that establishes the connection between maternal and embryonic tissues and requires an intricate program of uterine preparation (1, 2). Very soon after implantation, which occurs in the mouse on day 4.5 postcoitum (pc) (day 0.5 - vaginal plug), endometrial stromal cells surrounding implanting blastocysts undergo dramatic transformation (decidualization), during which they proliferate and differentiate into decidual cells. Decidualization begins in the stromal region immediately surrounding the embryo (antimesometrial site). Next to the implanting blastocyst, thin, dense, avascular cell layers, called the primary decidual zone, are formed. Adjacent to the primary decidual zone, the broad secondary decidual zone is fully developed by day 6.5 pc, and is characterized by terminally differentiated decidual polyploidy with acquisition of large mono- or binucleated cells (3). The decidua provides a vascular network for nutrition and gas exchange for the developing embryo before a functional placenta is established (4). It also acts as a barrier to uncontrolled trophoblast proliferation.The sphingolipid metabolic pathway produces bioactive signaling metabolites as well as complex lipids that are utilized in membrane organization and structure. A very prominent signaling lipid is sphingosine-1-phosphate (S1P), which enhances cell survival and growth (5-8). Recent studies have demonstrated its physiologic importance in the development of the vascular and nervous system (9-12), the heart (13), and the immune system (14-16) by signaling through a family of G protein-coupled receptors designated S1P 1-5 . In contrast, 2 precursors of S1P,

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Section: Figure 10mentioning

confidence: 99%

Section: Figure 10mentioning

confidence: 99%

Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

Mizugishi

Li²,

Olivera³

et al. 2007

J. Clin. Invest.

137

119

View full text Add to dashboard Cite

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“…The basis of this conflict has been the dependence on plasma proteins of certain aPEs. In view of this and to avoid missing such aPEs, Sugi et al [19,20,25] recommended the addition of adult bovine serum or plasma, both of which are considered better sources of these plasma proteins than fetal calf serum and both of which provide optimal detection of aPEs. In contrast, other investigators have reported that the reactivity of aPEs decreased considerably using adult bovine serum compared with newborn or fetal calf serum [21, 22, 24•].…”

Section: Antiphosphatidylethanolamine Antibody Detection Methodsmentioning

confidence: 99%

“…However, Sugi and McIntyre [19] claimed that PE could bind HKs and that formation of the HK-PE complex could induce conformational changes in HKs, revealing some antigenic epitopes recognizable by certain aPEs. Other plasma proteins have been proposed as targets of aPE, which is the case for factor XI and prekallikrein [20]. However, these data come from few sera and few studies.…”

Section: Antigen Specificities Of Antiphosphatidylethanolamine Antibomentioning

confidence: 97%

Is Testing for Antiphosphatidylethanolamine Antibodies Clinically Useful?

Sanmarco

2010

Curr Rheumatol Rep

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One of the most intriguing characteristics of the antiphospholipid syndrome (APS) is that diagnosis requires the combined presence of clinical abnormalities (thrombosis and/or miscarriages) and at least one of the following antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, or anti–β2-glycoprotein I. Clinicians occasionally have difficulty making this diagnosis in patients with a clinical picture of APS but without any of the previously mentioned antiphospholipid antibodies. Such a status has been defined as "seronegative APS." Under these conditions, antiphosphatidylethanolamine antibodies deserve particular attention, as they have been described as being associated with the main clinical events of APS. Thus, this review focuses on issues related to the characteristics of antiphosphatidylethanolamine antibodies, including the nature of antigen targets and their role in homeostasis, the methodologic problems encountered in their detection, and their clinical associations.

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“…Phosphatidylethanolamine is a zwitterionic phospholipid normally present in the outer leaflet of cell membranes, and it plays a role in reactions of protein C pathway. Antibodies can react with the complexes of aPE with high and low molecular weight kininogens (HMWK, LMWK), factor XI and prekallikrein (Sugi & McIntyre, 2001). There were some studies conducted that show aPE as the only antibody in a limited number of APS patients (Karmochkine et al, 1992).…”

Section: Non Classical Aplmentioning

confidence: 99%