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Rheumatology Advance Access originally published online on September 5, 2007
Rheumatology 2007 46(10):1517-1519; doi:10.1093/rheumatology/kem219
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Recurrent spontaneous abortions in antiphospholipid syndrome: natural killer cells—an additional mechanism in a multi factorial process

H. J. A. Carp and Y. Shoenfeld1,*

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer & Tel Aviv University, Israel and 1Department of Internal Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University.

Correspondence to: Y. Shoenfeld, MD FRCP, Department of Internal Medicine B, Sheba Medical Center, Tel Hashomer, 52621, Israel. E-mail: shoenfel{at}post.tau.ac.il

In this issue, Perricone et al. have shown that patients with antiphospholipid syndrome (APS) and recurrent spontaneous abortions (RSA) have higher levels of natural killer (NK) cells than those with APS and no RSA. NK cells have long been suspected to cause RSA since Aoki's original report [1] showing that increased numbers of NK cells in the peripheral blood of women with RSA predict the likelihood of another miscarriage. NK cells are the only lymphocytes found in the endometrium in pregnancy, and are able to induce apoptosis in the trophoblast if cytokine activated. There have even been attempts to reduce NK cell levels with intravenous immunoglobulin (IVIg) [2] or immunization with paternal leucocytes (PLI) [3], to prevent subsequent miscarriages. There are two questions: what are the roles of NK cells, and whether NK cells explain part of the mechanism of action of antiphospholipid (aPL) antibodies?

NK cells have been found in increased numbers in the peripheral blood [4] and placental bed biopsies in RSA [5], and their killing activity has been shown to be increased [1, 3]. NK cells can attack the trophoblast by inducing apoptosis [6]. They represent an innate mechanism of cell-mediated immunity which is not dependent on the recognition of specific foreign antigens. Certain cytokines such as tumour necrosis factor (TNF)-{alpha} are able to activate the NK cells [7]. There may also be numerous other cytokines whose role has not yet been fully elucidated. It is difficult to assess the role of TNF-{alpha} in pregnancy as the cytokine is secreted locally. However, pro-inflammatory cytokines have been said to be increased in RSA. Most studies have been carried out in the murine model of pregnancy loss, and the results have been assumed to be relevant to human pregnancy. However, two confounding factors in human pregnancy, embryonic chromosomal aberrations and aPL cannot be excluded from the murine studies. NK cells physiologically accumulate in the human deciduae in the first trimester of pregnancy and regress towards the myometrium at the end of the first trimester and at the beginning of the second trimester. Hence, it is questionable whether these cells are pathological in nature. Their role has been reported to be immunosurveillance, but these cells may also mediate the angiogenesis necessary for continuation of the pregnancy [8] or mediate the remodelling of the spiral arteries to uteroplacental arteries [9]. The question arises as to why these cells may become activated and possibly attack the trophoblast. In human RSA, 30% of miscarriages are due to chromosomal aberrations in the embryo such as trisomy 16 or triploidy which are incompatible with life [10]. In the presence of chromosomal aberrations, embryonic demise leads to lack of an embryonic circulation to the trophoblast, and a fall in hCG levels and subsequent progesterone levels. The hCG is intimately related to IL-6, a prothrombotic cytokine [11], and progesterone inhibits NK numbers and killing activity [12]. In these circumstances, lack of progesterone may allow activation of the NK cells. Therefore, the killing activity of the NK cells may be part of the mechanism of abortion rather than its cause. If aPls are also present they may be epiphenomena rather than the cause.

The aPl antibodies are known to cause pregnancy loss directly as injection of serum from mice with a high titre of aPL to naive mice induces resorbtion of pregnancies in the recipient [13], and active immunization with human pathogenic monoclonal anticardiolipin antibody induces the clinical manifestations of APS in BALB/c mice [14]. The mechanism is mainly assumed to be thrombosis in decidual vessels, as thrombosis can explain most of the internal medical ramifications of the condition. However, placental histology shows most of the antibody to be concentrated in the cytotrophoblast. The pathological features of aPL on the trophoblast include: decreased vasculosyncitial membranes, increased syncytial knots, substantially more fibrosis, hypovascular villi and infarcts than in women without APS [15]. Although the changes in syncytial membranes may be secondary to thrombosis, thrombosis could also be secondary to placental damage which allows free transplacental passage of maternal aPL. APS has also been shown to lead to pregnancy loss by other mechanisms, such as inhibiting placental human chorionic gonadotrophin (hCG) secretion [16], complement activation [17] and cytokine imbalance, all of which may be responsible for some of aPL's actions. A full list of possible mechanisms of the action of aPL are shown in Table 1. Cytokine imbalances are particularly relevant as cytokines may affect the activation or inhibition of NK cells. Administration of IL-3 prevents fetal loss in experimental APS [18], the balance of pro–inflammatory and anti-inflammatory cytokines may be altered in APS [19] and TNF-{alpha} levels have been found to be significantly higher in patients with APS than healthy controls [20], and has been reported to be a critical effector in APS [21]. Chromosomal aberrations in the embryo may also confound the results of studies on aPL in pregnancy as 30% [22, 23] of miscarriages are due to chromosomal aberrations in APS. No studies on APS have corrected for chromosomal aberrations. Additionally, the cause of APS has been reported to be due to molecular mimicry between phospholipids, ß2-glycoprotein 1 (ß2GP1) and infectious organisms [24]. Infections are also accompanied by the release of pro–inflammatory and prothrombotic cytokines.


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  		TABLE 1. Possible mechanisms whereby aPL may cause pregnancy loss

 
Live birth rates of 80% have been described in cases of APS without treatment [25]. Hence, it is necessary to question again whether treatment is always necessary in APS or to lower NK cells. It is generally an accepted practice that aPL should be treated, and a combination of low-dose aspirin and heparin or low-molecular dose heparins are the treatment of choice [26]. However, the role of aspirin has been challenged as a meta-analysis of three trials has not shown any evidence of effect [25]. Heparins also have anti-inflammatory effects in addition to the anticoagulant effects. Heparin increases serum TNF binding protein, thus protecting against systemic harmful manifestations [27]. Low-molecular weight heparins inhibit TNF-{alpha} production [28]. Thrombosis results in an inflammatory response in the vein wall. Both heparin and low-molecular weight heparins limit the anti-inflammatory response [29] including neutrophil extravasation and decreasing vein wall permeability. Therefore, the effect of heparins in preventing Recurrent Pregnacy Loss (RPL) in APS may be due to the anti-inflammatory and cytokine modulating effects rather than the anticoagulant actions. It would be interesting to see whether as a result of Perricone et al.'s paper, the effect of heparins on NK cells could be assessed. However, heparins do not lower the incidence of obstetric complications such as pre-eclampsia, pre-term labour and Intra Uterine Growth Retardation IUGR[V1] in APS [30]. However, IVIg does seem to lower the incidence of these complications in APS [31].

IVIg has numerous actions which have been described elsewhere [32], these include lowering NK numbers and activity [2]. IVIg also mediates cytokine balance [33, 34]. IVIg has been used to prevent further miscarriages in women with unexplained RSA. Although two meta-analyses have not shown IVIg to be effective [35, 36], none of the trials correct for chromosomal aberrations, thus confounding the results. When IVIg is used on selective populations such as those with high numbers of miscarriages (five or more), where the chance of chromosomal aberrations is less [22], or raised NK levels, the improvement in the live birth rate has been significant [37, 38]. However, it is doubtful if reduction of NK levels is always warranted as NK cells may be required for their possible physiological role in pregnancy.

In conclusion, there is still much work to be done in defining the physiological role of NK cells, and their possible deleterious effect in pregnancy. Additionally, the role of aPL requires much clarification. It has been recommended that the abortus should be karyotyped in RSA [39], in order to determine in whom the cause is due to a chromosomal disorder, and in whom the cause is maternal in origin. Only then will it be possible to determine who actually requires treatment.

The authors have declared no conflicts of interest.

Notes

*Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmunity Diseases, Tel-Aviv University, Israel Back

References

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Accepted 10 July 2007


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