A quiet and silentconceptual revolution is taking place in reproductive immunology. The ‘riddle of the fetal allograft’ was viewed by many, and still is by most, as resulting most probably from an altered, T cell-mediated, maternal immune response which permits tolerance to the paternally inherited histocompatibilty antigens of the conceptus. Thus, the ideas inherited from the Sir Peter Medawar citation classic [1] have set the scene in reproductive immunology for the past half-century.

Medawar's hypothesis, and most of the ensuing research, is dominated by a classical view of the immune system and as soon as the T cell/B cell dichotomy became apparent, the field began searching for mechanisms that explained how maternal T cells were tolerized/anergised/inactivated. Although placental and decidual suppressor factors have been studied extensively in this respect, T cell-mediated rejection of the fetal allograft was not demonstrated until the late 1990s, when Mellor and colleagues demonstrated elegantly that inactivation of indoleamine 2,3-dioxygenase leads to (CD4) mediated rejection of allogeneic fetuses, but was not harmful in the case of syngeneic pregnancies [2].

T cell anergy, partial clonal deletion and suppression have all been demonstrated in pregnancy [3], but the ‘tolerance’ paradigm was challenged by data obtained in a murine spontaneous abortion model (the CBA × DBA/2 system) which led Wegmann to ask whether ‘Fetal protection against abortion: is it immuno suppression or immuno stimulation?’[4]. This was the initial enunciation of the immunotrophism concept. Surprisingly, natural killer (NK) cells appeared to be the causative effector cells in the CBAx DBA/2 spontaneous abortion system [5,6], and to be the main lymphocytic cells which control local interleukin (IL)-10 production [7]; however, a T cell bias was still evident in the second Wegmann paradigm, the ‘pregnancy as a Th2 phenomenon’ hypothesis [8]. Loke suggested, as early as 1989 [9], that one should pay more attention to the innate immune system and to the ‘missing self’ theory of Karre [10]. In a prophetic paper, Loke also wrote that uterine NK cells ‘may have a role in the control of implantation and the transformation of the uterine vasculature by trophoblast on which the blood supply to the fetoplacental unit depends’[11].

Although no effect was seen after neutralizing IL-10 in non-abortion-prone murine mating combinations [12], the data obtained in the abortion-prone CBA × DBA/2 model [12] and other systems suggested that cytokines can play a vital role in fetal allograft survival and so fuelled the Th1/Th2 hypothesis. However, despite challenges regarding this hypothesis from both outside the field of reproductive immunology (e.g. ‘Th1/Th2 subsets, paradigms lost?’ as written by Kelso in 1995 [13]) and within the field in relation to human pregnancy [14], the Th1/Th2 paradigm quickly reigned supreme even for human pregnancy [15]. Since its enunciation, the model has been very useful for explaining recurrent spontaneous abortion, as well as materno–fetal tolerance, and it has certainly generated many interesting studies.

However, disturbing facts regarding the hypothesis have emerged. First, studies in NK cell-depleted and NK cell knockout mice have shown that NK cells are necessary for successful murine pregnancy and, even more surprisingly, a ‘bad guy’, gamma interferon, was proved to be pivotal in remodelling local arterial vasculature during pregnancy [16,17].

Secondly, not only did the profiles of newly identified cytokines fail to fit the Th1/Th2 scheme but, surprisingly, more IL-18 (and interferon gamma inducer) was found in the IL-12-containing decidua and placenta of the non-aborting murine CBA × BALB/c mating combination than in the abortion-prone CBA × DBA/2 one [18,19]. In the immediate post-implantation period, the uterus was found to be filled with activated, IL-18-secreting NK cells. Thirdly, looking at the situation from the opposite angle, a quadruple Th2 knockout mouse was found to have normal reproductive performance [20]. Together these data severely challenge the Th1/Th2 paradigm, as did another set of results obtained in early pregnancy: indeed, we had known for a long time that implantation is characterized by an inflammation-like reaction [21] whose impairment surprisingly prevents implantation [22]. In this vein, leukemia inhibitory factor (LIF), IL-1, IL-11, etc., which are inflammatory cytokines, are mandatory for successful implantation. Furthermore, we have observed in humans that an absence of IL-12 + IL-18 correlates with female sterility [23].

Recent data from Croy [24] (and B. A. Croy, personal communication) confirm that (uterine) NK cells need to be present, be expanded in numbers by IL-15, and be activated by a T cell-dependent signal in order for successful implantation/pregnancy to occur.

The data in the present issue of this journal by Sacks et al. [25] go one step further by showing that the innate immune system is systemically primed during a normal pregnancy. This result is very important because:

  • (a) 
    As far as leucocyte alloimmunization immunotherapy (IT) is concerned, the present ‘theory’ − after trophoblast leukocytre cross-reactive antigen, HLA homologues, adaptation of immunotrophisms, etc. − has been adapted to fit and used as a justification for the Th1/Th2 paradigm. It postulates that there is always some circumstantial evidence that the one woman from a group of 11 benefiting from IT does so because the Th1/Th2 balance is re-established from an initial Th1 bias. This result is from the only meta-analysis performed and is for a woman for whom there is no positive diagnosis according to the results of the ‘meta-analysis group’[26]. However, if monocyte IL-12 priming is a normal component of a successful pregnancy, why ‘dampen’ inflammation and NK cell activity? This is even more so the case for implantation, where some want to use IT to treat implantation failure using the rationale that it would down-regulate activated NK cells.
  • (b) 
    It suggests that we should in fact reconsider (uterine) NK cell and monocyte ‘activation’. This term is used indiscriminately to describe when NK cells either: (i) secrete growth-promoting cytokines and/or useful angiogenic cytokines or (ii) secrete TNF, promote intravascular coagulation, or are engaged in a cytotoxic/cytostatic pathway. The former appears necessary, the second detrimental, for fetal survival. The difference between these NK pathways may be linked to the type of KIRs/KARs engaged at the uterine NK cell surface and this calls for a further analysis of the local NK repertoire and real activation status during pregnancy.
  • (c) 
    It suggests (but does not prove, albeit the companion data have already been presented at meetings and their full length publication is eagerly awaited) that this systemic activation is due to placental debris generation/deportation. It leaves open, and in fact pre-empts, the exciting possibility that excessive activation of the innate system (itself linked to excessive deportation/release of debris) will result in excessive IL-12 production, activation of NK cells in a detrimental fashion causing an attack against the placental cells and damage to the vascular endothelium, resulting in a vicious loop of continuous ‘hyperactivation’. The loop could be triggered by improper recognition of placental MHCs resulting in initial placental damage. Thus, vascular and immunological events in pre-eclampsia need not be opposed and observations such as excess oxidative stress and involvement of inositol phosphoglycans (IPGs) [27] are not incompatible with an immune aetiology.

The data therefore lead to a better understanding of human (and murine) pregnancy, definitely switching the focus away from materno–fetal tolerance and moving it towards the concept of a continuous materno–fetal immunological dialogue (which is also a stage-specific process but whose details remain outside the scope of this review) with a central role for the innate immune system. Potential treatments, diagnostic tools, as well as further studies to understand these conditions, are obvious goals for pre-eclampsia, but are likely to be so for a subset of recurrent spontaneous abortions, and possibly early implantation failures. Besides showing us (the conceptual revolution) that we must go beyond the Th1/Th2 paradigm, and by showing a new facet of the involvement of the innate immune system during pregnancy, the results of Sacks et al.[25], combined with other data cited in this editorial, should act as a further severe warning for those who advocate without due exploration the ‘dampening of NK cell activity’ by allo-immunization for RSA and implantation failures.

In fact, by demonstrating another facet of the materno–fetal relationship, one that is totally at odds with the long-standing tolerance concept, Sacks et al. [25] cast the light for further exploration of a new cytokine and cellular network. Their data are an important new development in our continuous search for knowledge of the processes which, as mammals, lead us to birth, and pave the way for future studies.


  1. Top of page
  2. References
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