Immunology Of Early Human Placenta Including Function Of Decidual NK Cells

Immunology Of Early Human Placenta Including Function Of Decidual NK Cells

It was generally assumed that implantation of the human trophoblast would be governed by the
laws of classical transplantation immunology and that there would be a maternal T-cell response to
the non-self-histocompatibility antigens of the fetal placenta. Surprisingly the situation is more
complex in that implantation appears to be predominantly influenced by an unusual immune
system. The mechanism of this system probably involves natural killer cells (NK cell) rather than T

Trophoblast expression of MHC antigens.

The genes responsible for recognition of non-self in graft rejection are those encoding the major histocompatibility complex (MHC) antigens. HMC Class I antigens are expressed on the surface of most nucleated cells and in humans are known as human leukocyte antigens (HLA’s). Six HLA class I loci that have expressed protein products are recognised: three classical loci (HLA- A –B –C) and three non-classical loci (HLA-E –F –G). The three classic antigens are those normally expressed by nucleated cells. The population of trophoblast cells invading the uterus (collectively known as extra villous trophoblast) express at least one classical molecule (HLA-C) and one non-classical molecule (HLA-G).

The balance of evidence seem to warrant the conclusion that abundant expression of HLA-G is probably restricted to extra villous trophoblast. HLA-C was detected in extra villous trophoblast by a specific antibody. In the formulation of any hypothesis regarding immune recognition of extra villous trophoblast by the mother it is necessary to consider HLA-G and HLA-C. The overall impression is that HLA-G and HLA-C might be relatively unimportant as ligands for T cells compared to HLA-A and HLA-B. NK cells appear to be increasingly strong candidates for binding HLA-C and HLA-G.

Leukocyte population in the uterus

Analysis of leukocytes in the uterus has shown NK cells are the predominant populations. They are
referred to as large granular lymphocytes (LGL’s) because of the prominent granules in their
cytoplasm. The total number of these cells in the uterine mucosa varies throughout the menstrual
cycle. They are sparse during the proliferative phase, increase significantly throughout the secretory
phase and remain high in the decidua during the early stages of gestation. Their numbers are
particularly high in the decidua basalis at the site where trophoblast cells invade the uterus.
Phenotypically decidual NK cells (CD56bright CD-16) differ from NK cells in the peripheral blood.

T cells are sparse in the decidua. In humans in vitro experiments analogous to the mixed
lymphocyte reaction (MLR) have shown that decidual lymphocytes (including T cells) do not
proliferate in response to trophoblast. Decidual T cells appear to be relatively anergic as are
lymphocytes in intestinal mucosa. It is proposed that interaction between the invading trophoblast
and decidual NK cells could provide the basic mechanism for allogenic recognition of the placenta
by the mother.

NK cells express receptors capable of recognising HLA class I molecules. The first family of NK receptors to be found belong to the immunological super family and is known as the killer inhibitory receptor (KIR) family because interaction of these receptors with class I HLA molecules leads to the transmission of signals that inhibit cytolysis and cytokine production. Subsequently other members of the same receptor family killer activatory receptos (KAR’s) were observed to transmit positive signals that trigger effector functions such as cell killing or production of cytokines. The class I locus that might be most pertinent in influencing NK function is HLA-C. Two KIR’s that are specific for HLA-C alleles who recognise HLA-G lending support to the notion that HLA-G might be as universal inhibitor if cytolysis by NK cells. The repertoire of KIR’s and KAR’s has been shown to vary among indiviuals. Investigation accords to the idea of HLA-G triggering inhibitory signals to decidual NK effectors.

A potential in vivo scenario could be that decidual NK cells recognise HLA-C or HLA-G expressed by invading trophoblast via KIR’s or KAR’s resulting in a combination of positive and negative signals that regulate cytokine production and cytolysis. Decidual NK cells are known to secrete a variety of cytokines and trophoblast cells express receptors for many of these cytokines. This would suggest that this recognition system between maternal uterus and placenta is capable of variable outcomes in different pregnancies.

Every paragraph in this account of immunology in early human pregnancy are taken from the following reference.


Immunology of Human Placental Implantation: Clinical implications of our current understanding.

Molecular Medicine Today. Review April 1997;3(4):153-159

As decidual NK cells are known to secrete cytokines and have receptors for these cytokines and trophoblast cells secrete cytokines and express receptors for many of these cytokines, these interactions at cell wall linings will have the effect that PGE2 is synthesised from these cell wall linings.

Dinarello C A

Biology of Interleukia 1

Faseb J 1988;2:108-115

Progesterone and Glucocorticoid Immunology Functions

Progesterone blocks the response of T cells to allorgenic cells in the mixed lymphocyte reaction (1).
Contrasting progesterone and glucocorticoids immunological reaction. Glucocorticoids besides blocking T cells and macrophage functions, inhibit prostaglandin synthesis by interfering with membrane phospholipases and decreasing arachadonic acid release. They were not able to find a similar effect of progesterone on lymphocytes (1). This may be one reason that glucocorticoids reduce symptoms of nausea and vomiting of pregnancy.



 Immunological and Endocrine Inter relationships in Pregnancy.

Biology of Reproduction 1982;26:1-14.



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