Role of the placenta in controlling the fetal environment

Conference

685

Report

Role of the Placenta

in Controlling

the Fetal

Environment

C. P. Sibley Department of Child Ml3 OJH, UK

Health

and School

of Biological

Sciences,

Fetal neurodevelopment is likely to be highly sensitive to the milieu in which it takes place and the placenta has an essential role in controlling fetal homeostasis. This presentation therefore considers the mechanisms by which the placenta regulates the fetal environment. In overview, the placenta controls the fetal environment by (i) acting as a barrier, (ii) facilitating transfer of solutes and water from mother to fetus and from placenta itself to fetus, (iii) facilitating transfer of solutes from fetus to placenta and from fetus to mother. The placenta may provide a good immunological barrier between mother and fetus but predominantly facilitates exchange. There are four main mechanisms of solute transfer across the placenta: flow limited diffusion, paracellular diffusion, transporter protein mediated transfer, and endocytosis/ exocytosis. The placenta is highly permeable to small lipid-soluble molecules, such as the respiratory gases, so they rapidly diffuse between maternal and fetal plasma; their rate of transfer is in fact limited only by the rate of delivery. Transfer of lipidsoluble toxins will therefore also be very rapid and these are likely to be particularly damaging to neural development, as demonstrated in a recent report (Jacobson and Jacobson, 1996). Physiological and morphological data show that there are extracellular water-filled channels across the human placenta which will allow paracellular diffusion of hydrophilic solutes up to the size of proteins such as albumin and alphafetoprotein. Therefore, although the rate of diffusion of small hydrophilic compounds will be orders of magnitude less than that for lipophilic compounds, they will still rapidly equilibrate across the placenta. The syncytiotrophoblast is the major transporting epithelium of the placenta and has a large array of highly specific transport proteins in both its microvillous (maternal facing) and basal (fetal facing) plasma membranes. These will be the major loci of regulation of the composition of the fetal extracellular fluid and will be important for neurodevelopment in a number of ways. (i) They are essential for the provision of nutrients to the fetus and the removal of waste products of fetal metabolism. (ii) There are several transporters for known neurotransmitters and the role of these is unclear (the placenta has no nerves); perhaps they regulate the concentrations of neurotransmitters in the fetal circulation? (iii) Although transporter proteins are quite specific in their affinity for particular molecules they may well also bind similar exogenous, potentially damaging, compounds. Such binding may lead to

University

of Manchester,

St Mary’s

Hospital,

Manchester

transport of the exogenous compound to the fetus at higher than expected rates, or to inhibition of the transporter; cocaine for example, directly reduces the activity of an amino-acid transporter. Endocytosis/exocytosis will not be considered in detail; this vesicular route of transfer will, however, provide accessto the fetal circulation for high molecular weight compounds such as immunoglobulin G. In summary, the human placenta is a highly porous barrier as regards most solutes, but nevertheless, through the activity, particularly, of transport proteins, can regulate the fetal milieu. Any imbalance in these regulatory mechanisms may well lead to alterations in the fetal environment and, consequently, neurodevelopmental disability.

REFERENCES Jacobson JL i? Jacobson exposed to polychlorinated

SW (1996) Intellectual impairment in children biphenyls in utero. N &g/J Med, 335,783-789.

DISCUSSION Nick Morris started the discussion by describing his elegant studies of the effect of glyceryl trinitrate (GTN) on his model of placental perfusion. Les Myatt pointed out that studies by Lee Adamson had shown that GTN led to a diminution in oxygen transfer. Steve Robson pointed out that GTN might not be the appropriate effect to study, i.e. that molecular nitric oxide might be more appropriate. Nick Morris asked whether there were any studies that had demonstrated increased circulating glutamate in intrauterine growth restriction. Colin Sibley replied that there was no definite effect that had been demonstrated. Colin Sibley then referred to studies of increased levels of alpha-fetoprotein being associated with a poor fetal outcome. He suggested that they had been described as reflecting increased placental permeability. Perhaps this change reflected the amount of syncytiotrophoblast denudation, and that increased apoptosis might be involved. Charlie Loke questioned whether this denudation actually occurred in vivo. Colin Sibley replied that it could be seen in all conditions. Dev Sooranna pointed out that the vertical transmission of infection of HIV was probably less than 10 per cent and if such decidual denudation occurred why was this figure so low.

Placenta

686

Cohn Sibley replied that whilst the placenta was porous it was not ‘holey’, and that there were many other mechanisms that could act as a barrier to infection. Steve Robson asked what the mechanism was of basement membrane changes that affected transfer across the membrane. Colin Sibley replied that possible mechanisms included thickening or a shrinking of pores within the membrane. John Kingdom asked whether the recruitment of additional matrix proteins to the basement membrane was involved. Colin Sibley

Immunological

Control

of Human

(1998),

Vol. 19

then described studies in the kidney where if all tissue was removed apart from the basal membrane there was little change in perfusion. Steve Smith discussed the areas of syncytiotrophoblast denudation that had previously been discussed and suggested that these reflected a dynamic process of turnover and apoptosis. Colin Sibley asked what happened to the fragmented trophoblast nuclei after apoptosis, i.e. where did the fragmented nuclei go? There was an audible murmur of “Oxford”!

Implantation:

Innate

or Adaptive

Immunity

Y. W. Loke Department

of Pathology,

University

of Cambridge,

UK

Recent epidemiological observations have indicated that inadequate development of certain organ systems during intrauterine life can have long-term consequences, leading to a higher incidence of disease in adult life. Neurological disability may originate in a similar way. Normal growth of the embryo is dependent on an adequate blood supply being delivered to the feto-placental unit. This, in turn, is due to invading placental trophoblast cells destroying the walls of the decidual spiral arteries converting them from muscular vessels into flaccid sac-like structures no longer responsive to vasoactive stimuli. Thus, it would be important to elucidate how trophoblast invasion into decidua is controlled. At present this is not known. Because these trophoblast cells are fetally derived and therefore foreign to the mother, it might be expected that there could be some immunological recognition by the mother which influences this invasion. Intriguingly, evidence to date suggests that this maternal local uterine immune response is not the same as that seen in transplantation immunology. Whereas most cells in the body express the classical Class 1 HLA-A,B,C antigens, the population of invading trophoblast expresses one classical HLA-C and one non-classical HLA-G. Both these antigens have unusual characteristics which indicate that they probably do not interact with maternal T cells. In this context, it is interesting to find that the predominant lymphoid cells in the uterus are not T cells but NK cells and invading trophoblast. Because of this, we propose that these uterine NK cells play an important role in the control of trophoblast invasion. At present we have not yet established how they do so. The functions of NK cells in general are still unclear, but an

increasing amount of information has become available in the past year which has increased our understanding of these cells. It seems that NK cells, therefore, have the potential to interact with trophoblast. The outcome of this interaction could generate either positive or negative signals mediated via cytolysis of cytokine secretion which could influence trophoblast behaviour. We believe that the immunological relationship between the invading trophoblast and the maternal uterus is not governed by the laws of classical transplantation immunology. Instead, it seems to involve a more ‘primitive’ defence system more akin to that observed between unrelated invertebrates than between vertebrate allograft and host. This has completely altered our conceptual view of the immunology of reproduction.

DISCUSSION Q Can extravillous trophoblast from an index pregnancy be retained at the end of the pregnancy and therefore exert an effect on subsequent pregnancies? A. No, extravillous trophoblast is lost at the end of pregnancy. However, NK cells have memory and remain. They could exert an effect on subsequent pregnancies. Q Are there are studies looking at the mechanisms of excessive placental invasion, e.g. placenta accreta? A. There is no work on placenta accreta, but a group in Hong Kong has looked at hydatidiform mole. Hydatidiform mole expresses HLA-C and -G as does normal pregnancy.