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    War and Peace at The Feto-Placental Front Line: Recurrent Spontaneous Abortion

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    Ayu Wedhani Spc
    1) Recurrent spontaneous abortion (RSA) is defined as two or more consecutive miscarriages and can be caused by immune mediated pathways like an imbalance of Th1/Th2 cytokines leading to increased natural killer (NK) cells. 2) NK cells play a key role in both immunological infertility and RSA. Increased NK cells in the blood predict future miscarriages and high NK cells are considered a cause and prognostic factor. 3) Antiphospholipid antibodies (APL) are associated with RSA and the risk of loss increases after 10 weeks of pregnancy. APL and NK cells may both contribute to pregnancy losses through several mechanisms like thrombosis, inhibition of hormones, and increased inflammation.

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    War and Peace at The Feto-Placental Front Line: Recurrent Spontaneous Abortion

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    Ayu Wedhani Spc
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    1) Recurrent spontaneous abortion (RSA) is defined as two or more consecutive miscarriages and can be caused by immune mediated pathways like an imbalance of Th1/Th2 cytokines leading to increased natural killer (NK) cells. 2) NK cells play a key role in both immunological infertility and RSA. Increased NK cells in the blood predict future miscarriages and high NK cells are considered a cause and prognostic factor. 3) Antiphospholipid antibodies (APL) are associated with RSA and the risk of loss increases after 10 weeks of pregnancy. APL and NK cells may both contribute to pregnancy losses through several mechanisms like thrombosis, inhibition of hormones, and increased inflammation.

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    1) Recurrent spontaneous abortion (RSA) is defined as two or more consecutive miscarriages and can be caused by immune mediated pathways like an imbalance of Th1/Th2 cytokines leading to increased natural killer (NK) cells. 2) NK cells play a key role in both immunological infertility and RSA. Increased NK cells in the blood predict future miscarriages and high NK cells are considered a cause and prognostic factor. 3) Antiphospholipid antibodies (APL) are associated with RSA and the risk of loss increases after 10 weeks of pregnancy. APL and NK cells may both contribute to pregnancy losses through several mechanisms like thrombosis, inhibition of hormones, and increased inflammation.

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    17 views2 pages

    War and Peace at The Feto-Placental Front Line: Recurrent Spontaneous Abortion

    Uploaded by

    Ayu Wedhani Spc
    1) Recurrent spontaneous abortion (RSA) is defined as two or more consecutive miscarriages and can be caused by immune mediated pathways like an imbalance of Th1/Th2 cytokines leading to increased natural killer (NK) cells. 2) NK cells play a key role in both immunological infertility and RSA. Increased NK cells in the blood predict future miscarriages and high NK cells are considered a cause and prognostic factor. 3) Antiphospholipid antibodies (APL) are associated with RSA and the risk of loss increases after 10 weeks of pregnancy. APL and NK cells may both contribute to pregnancy losses through several mechanisms like thrombosis, inhibition of hormones, and increased inflammation.

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    of 2

    IMAJ VOL 16 october 2014

    War and Peace at the Feto-Placental Front Line:


    Recurrent Spontaneous Abortion
    Caterina De Carolis MD1, Carlo Perricone MD2 and Roberto Perricone MD3
    1

    Department of Gynaecology and Obstetrics II, San Giovanni-Addolorata Hospital, Rome, Italy
    Reumatology Unit, Department of Medicine, Sapienza University of Rome, Rome, Italy
    3
    Rheumatology, Allergology and Clinical Immunology, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy
    2

    Key words: recurrent spontaneous abortion (RSA) antiphospholipid


    syndrome (APS), natural killer cells (NK), thyroid, cytokines

    IMAJ 2014; 16: 667668

    I basic features of the fetal-maternal communication system

    mplantation is an event depending on several steps. The

    of human pregnancy comprise two arms (placental and paracrine). The villous trophoblasts are the fetal tissue of the anatomic interface of the placental arm, while the fetal membranes
    are the fetal tissues of the anatomic interface of the paracrine
    arm of this system. A communication link is established by
    way of the placental arm: maternal blood directly bathes the
    villous trophoblasts; fetal blood is contained in fetal capillaries
    that traverse the intravillous space. At every step, there is a
    continuous embryo-uterus interaction. The discovery of the
    implantation window and emergence of the concept of uterine
    receptivity led to the intriguing idea that cytokines could be
    central to such a process [1].
    During apposition/adhesion, the induction of adhesion
    molecules and the proper ligands are critical steps. Hence, it
    is essential that the expression of receptors/ligands at the cell
    surface of the embryo and uterus coincide. Interleukins (IL) are
    involved and hormonal regulation plays a major role in both the
    uterus and the embryo. Adhesion molecules are also modulated.
    Subsequently, invasion-penetration occurs, and at this step several enzymes are involved, especially matrix metalloproteases,
    counterbalanced by their inhibitors. In normal pregnancy, the
    maternal immunological response against trophoblast antigens,
    concomitant with a transient depression of maternal cell-mediated immunity to protect semi-allogenic embryo from rejection,
    is the predominant mechanism for a high live birth rate.
    Recurrent spontaneous abortion (RSA) is defined as two
    or more consecutive spontaneous abortions, a heterogeneous
    condition (with numerous causes and clinical presentations)
    that may occur at any stage of pregnancy [2]. Mechanisms of
    RSA involve immune mediated pathways including the presence of a predominant T helper (Th)1-type immunity during

    pregnancy, a decrease in T regulatory cells and an increase in


    natural killer (NK) cells. These phenomena can occur locally (at
    the site of implantation) and are often reflected in the peripheral
    blood. The interaction between human leukocyte antigen molecules regulate NK cells activity at the maternal-fetal interface.
    Two main populations have been suggested, NK1 and NK2.
    The peripheral NK cells (PNKs) cytokine repertoire comprises
    mainly type 1 cytokines, such as interferon-gamma (IFN) and
    tumor necrosis factor-alpha (TNF), although proper stimuli
    can induce production of type 2 cytokines such as IL-4, IL-5
    and IL-13 [3]. Even more intriguing, NK cells have long been
    suspected as the cause of RSA since the original report by Aoki
    and colleagues [4]. In RSA, increased numbers and killing activity of NK cells in the peripheral blood predict the likelihood of
    another miscarriage and are considered a causal and prognostic
    factor for infertility, and miscarriage. Thus, NK cells may also
    play a key role in immunological infertility and in RSA if the
    concentrations are too high. In RSA, the creation of an imbalance in Th1-Th2 response, resulting in a prevalent Th1 cytokine
    environment in the periphery, may lead to NK cell activation
    and proliferation, which could result in migration of cytotoxic
    NK cells into the uterus and, in turn, contribute to mechanisms
    involved in miscarriage [5]. Alternatively, the local endometrial
    immune assessment may be disrupted at various levels, causing
    defects in homing of the proper NK population to the uterus,
    local production of cytokines and hormones such as IL-15 and
    prolactin, and impairment of more downstream events such as
    production of immunoregulatory factors by uterine NK cells.
    Disruption at any of these levels may alter the ability of the uterine NK cell population to perform its normal functions and may
    result in an unsuccessful pregnancy [6].

    NK and antiphospholipid antibodies (APL)


    APL are found in approximately 517% of the general population but are more frequent in patients with RSA [3]. An
    increased number of NK cells correlate with reduced gestational age at abortion in patients with APS-RSA. NK cells
    might precipitate damage initiated by aPL or they might cause
    pathology in RSA independent of aPL, contributing to RSA
    667

    IMAJ VOL 16 october 2014

    668

    in patients with APS. APS is an autoimmune disease characterized by the presence of one or more laboratory findings of
    APL and at least one clinical manifestation in addition to deep
    venous and/or arterial thrombosis and/or pregnancy disease
    comprising RSA, with or without thrombocytopenia The association between APS and RSA is well known, such that RSA
    represents one of the clinical diagnostic criteria for APS.
    The risk of pregnancy loss in women with APS is higher
    from the 10th gestational week (GW) onward (fetal period).
    The Sapporo criteria and the revised criteria for APS underline this situation by considering only patients with one or
    more unexplained fetal loss (of a morphologically normal
    fetus) beyond the 10th GW, or three or more unexplained
    consecutive spontaneous abortions before the 10th GW.
    A number of controversies plague the current understanding of APS and RSA; thus several authors have reviewed the
    role of APS and specifically of APL in RSA and stressed the
    existence of different subclasses of clinical subsets of RSA in
    APS patients. Indeed, intrinsic to the definition of APS is a
    dichotomy regarding patients who have multiple (> 3) abortions within the first 10 GWs and those who have at least one
    abortion beyond the 10th GW.
    Striking evidence of how NK cells behave as pathogenic
    effectors in RSA comes from a recent study that suggested the
    possible role of NK cells in the pathogenesis of abortive events
    in a subpopulation of APS-RSA patients, previously explained in
    terms of autoimmune specific reactions (APL-mediated).
    aPL may cause pregnancy loss via many mechanisms such
    as thrombosis in decidual vessels, platelet activation, increased
    expression of adhesion molecules on endometrial cells, and
    inhibition of anticoagulants. Furthermore, aPL inhibit human
    chorionic gonadotropin secretion by trophoblast cells, prevent
    the metalloprotease urokinase from binding to receptors on
    the trophoblast and inhibit prostaglandin synthesis by decidual
    cells (decidualization), activated placental complement NK
    cells, and increase of TNF, IL-1b and IL-6 [7].

    thyronine and thyroxine act on migration and proliferation of


    dendritic cells, NK cells and T cells. Previous studies suggested
    that the measure of peripheral blood NK cell percentage was a
    reliable predictor of pregnancy outcome in women with infertility and RSA rather than the measure of NK cell activity. All
    these data support the recommendation of assessing peripheral
    blood NK cell percentage in the context of female reproductive
    failure since it may enhance treatment outcome by delineating
    the underlying etiology [10].

    NK, thyroid and aPL


    Anti-thyroid antibodies and aPL are associated with reduced
    fertility, miscarriage and preterm delivery, but the precise
    mechanisms by which thyroid antibodies as well as those
    against other tissues are suppressed during pregnancy and
    often exacerbate after delivery remain obscure. Presumably, the
    rapid reduction in immune suppressor functions after delivery leads to the reestablishment and/or exacerbation of these
    conditions. Subclinical hypothyroidism of the mother may
    impair the course of pregnancy and may disturb the normal
    development of the fetus [8,9]. It usually originates from an
    underlying autoimmunity, the most common cause of thyroid
    dysfunction in pregnancy. Thyroid-stimulating hormone may
    act as a direct stimulator of the immune response, and triiodo-

    4. Aoki K, Kajiura S, Matsumoto Y, et al. 1995. Preconceptional natural-killercell activity as a predictor of miscarriage. Lancet 1995; 345: 1340-2.

    Conclusions

    The interactions between NK cell and other autoimmune factors, such as aPS and thyroid, may be associated with impaired
    pregnancy, and the modulation in the number of circulating
    NK cells is most likely a primary event rather than an active
    inflammation/drug administration consequence during an
    inflammatory/autoimmune process. Thus, NK cells are key
    players in the pathogenesis of RSA. The role of NK cells at
    different anatomic sites as well as the role of genetic factors,
    especially in terms of response to different stimuli from the
    local microenvironment to which NK cells home and become
    activated, should be further investigated.
    Correspondence
    Dr. C. De Carolis
    Gynaecology and Obstetrics II, Azienda Ospedaliera San GiovanniAddolorata, Via dell Amba Aradam 9, 00184 Rome, Italy
    Phone: (39-067) 705-5657
    email: [email protected]

    References
    1. Wilczynski JR (2005) Th1/Th2 cytokines balance yin and yang of reproductive
    immunology [Review]. Eur J Obstet Gynecol Reprod Biol 2005; 122: 136-43.
    2. Practice Committee of the American Society for Reproductive Medicine.
    Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
    Fertil Steril 2012; 98: 1103-11.
    3. Perricone C, De Carolis C, Giacomelli R, et al. High levels of NK cells in the
    peripheral blood of patients affected with anti-phospholipid syndrome and
    recurrent spontaneous abortion: a potential new hypothesis. Rheumatology
    (Oxford) 2007; 46: 1574-8.

    5. Carp HJ, Shoenfeld Y. Recurrent spontaneous abortions in antiphospholipid


    syndrome: natural killer cells an additional mechanism in a multi factorial
    process. Rheumatology (Oxford) 2007; 46: 1517-19.
    6. Perricone R, Di Muzio G, Perricone C, et al. High levels of peripheral blood NK
    cells in women suffering from recurrent spontaneous abortion are reverted from
    high-dose intravenous immunoglobulins. Am J Reprod Immunol 2006; 55: 232-9.
    7. Galarza-Maldonado C, Kourilovitch MR, Prez-Fernndez OM, et al. Obstetric
    antiphospholipid syndrome [Review]. Autoimmun Rev 2012; 11 (4): 288-95.
    8. Carvalheiras G, Faria R, Braga J, Vasconcelos C. Fetal outcome in autoimmune
    diseases [Review]. Autoimmun Rev 2012; 11 (6-7): A520-30.
    9. De Carolis C, Greco E, Guarino MD, et al. Anti-thyroid antibodies and
    antiphospholipid syndrome: evidence of reduced fecundity and poor pregnancy
    outcome in recurrent spontaneous aborters. Am J Reprod Immunol 2004; 52: 263-6.
    10. Twig G, Shina A, Amital H, Shoenfeld Y. Pathogenesis of infertility and
    recurrent pregnancy loss in thyroid autoimmunity. J Autoimm 2012; 38: 275-81.

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