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Recurrent spontaneous abortion (RSA) is serious health problem affecting 2–5% of reproducing couples …


Biology Articles » Reproductive Biology » 1-alpha,25-dihydroxy-vitamin-D3 asnew immunotherapy in treatment ofrecurrent spontaneous abortion » Mechanisms of recurrent spontaneousabortion

Mechanisms of recurrent spontaneousabortion
- 1-alpha,25-dihydroxy-vitamin-D3 asnew immunotherapy in treatment ofrecurrent spontaneous abortion

In most mammals, cells of the syncytotrophoblast are totally MHC I and II negative, but the underlying cytotrophoblasts are weakly MHC I positive [1]. Extravillous cytotrophoblasts express a kind of MHC class I molecules, so-called HLA-G and its expression is limited to the placenta and the epithelial cells of the thymus [2]. The HLA-G positive placental cells play important immunoregulatory role, as they are much less sensitive to NK cell mediated lysis. In addition, HLA-G may confuse, trap or defuse the T cell receptor (TCR) complex. As none of the forms of trophoblast carries class II MHC molecules they cannot stimulate T helper cells directly to begin immunological reactions. Consequently, without any Class I or II MHC molecules, the villous trophoblast cells cannot function as the targets for MHC directed cytotoxic T cells [2,3].

Cytokines are seen to have a complex role in post-implantation pregnancy. In normal pregnancy, trophoblastic cells are resistant to lysis by cytotoxic T lymphocytes, NK cells and antibody dependent cytotoxicity [3]. The lymphokines, which can activate NK cells into LAK cells, include TNF-α, IL-2, IFN-, IL-12 and IL-18. Another cytokines have been shown to prevent LAK cell activation and abortion. These include IL-3, GM-CSF, CSF- 1, IL-10 and TGF-β produced by CD8+ cells expressing progesterone receptors [3,4]. TGF-β has been shown to be a competitive antagonist of IL-2, where IL-2 induces the activation of NK cells and the secretion of TNF from these cells [4,5].

T helper type 1 (Th1) cells produce abortogenic cytokines such as IL-2 and INF-γ which are seen to cause abortion in mice; T helper type 2 (Th2) cells however produce IL-3, IL-4 and IL-10 which promote antibody formation, put off inflammation and NK cell activation [6–8]. The NK derived INF-γ may activate the macrophages of the feto-maternal interface or other TNF-α secreting cells whereas Th2 cells would suppress this activation [4,5,8].

Some authors represent opinion that the major inhibitor of the abortogenic reaction of the NK cells is seen to be the trophoblast dependent natural suppressor (NS) cell. During pregnancy, there are an increased number of NK cells in the decidua and these cells account for about 40% of the decidua lymphocytes. These cells are uniquely CD56+CD16) and are seen to produce suppressor factors and Th2 cytokines. It is possible that these NK cells are NS cells, which are responsible for maintenance of the fetal allograft and initiating the appropriate immune response [6,7,9].

The CD8+ T cells with the αβ-TCR appear to be the more protective T cell subset. Production of IL- 4 and IL-7 by the trophoblast would be expected to deviate T cell differentiation along the Th2 pathway whatever the TCR phenotype and along with the trophoblast cell derived factors, such as GMCSF, may boost NS cell activity. Independently, IL-10 and IL-4 may inhibit NK cell activation into LAKs [8,10]. In these processes, maybe the most important mechanism is extrathymic lymphocyte maturation pathway. In pregnancy, the site of extrathymic lymphocyte maturation is decidua [5,6,10].

The basis for pregnancy failure is thus centered on the activation of the NK cell into a LAK cell. Some of the data obtained from studies of RSA seem to suggest that abortion occurs due to failure of the activation of NS cells. These cells carry the γδ-TCR rather than the αβ-TCR that requires HLAA, B and C for efficient recognition and binding [11]. As well as showing a deficiency in CD56+CD16) cells, women experiencing RSA show an increased level of the CD56+CD16+ NK activated cells in the decidua and blood [2,3].

The cytokines TNF-α and IFN-γ play an important role in abortions, as their administration increases the abortion rate and specific antagonists decrease the abortion rate. It has been proposed that macrophage derived TNF-α stimulates NK cells to produce IFN-γ, which further activates the macrophages, as occurs in the early defense response to infectious agents. There are other potential sources of TNF-α and IFN-γ, and systemic Th1 type responses may cause abortions via augmenting levels of such cytokines; IL-2 may also cause abortions by contributing to NK macrophage activation at the feto-maternal interface. TNF-α is thought to be part of the mechanism, which brings about pregnancy loss through its effects on the placenta. In women experiencing RSA, circulating IFN-γ promote mechanisms of MHC class I and II molecules expression. Consequently, MHC expressing cells become apparently target cells. In addition, IFN-γ stimulated macrophages produce TNF-α.This in effect would cause the recognition of the induced MHC expression and thus rejection of the fetal allograft by the maternal immune system would result [4–6]. Maternal recognition of the conceptus as foreign is seen by some as the primary or possibly the only step in preventing its rejection. In animal models, TNF-α and IFN-γ coadministration aborted >80% of the embryos, whether or not NK cells or macrophages had been depleted or estradiol and progesterone was injected to correct potential reduction in ovarian function by cytokines. Some authors have shown that the embryos die from ischemia due to activation of vascular endothelial cell procoagulant, which causes thrombosis and inflammation [6,8,9]. This appears similar to the mechanism whereby TNF-α causes ischemic necrosis of nonantigenic tumors [12].


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