Immunology of pregnancy I

Question 1

Immunological Problems During Pregnancy:

Answer 1

Foetal tissue is half foreign – has to be protected from rejection.

Mother’s immune defence must be sufficient during pregnancy to ensure survival.

Foetus often immunologically immature at birth – must have maternal antibodies to ensure survival.

The maternal/fetal interface is central to overcoming these problems. This interface occurs at the placenta.

Question 2

Development of the Placenta - what is key?

Answer 2

The key to the development of the placenta is the trophoblast cells as they are responsible for invading the endometrial tissue.

Question 3

The Maternal-Foetal Interface:

Answer 3

SYNCYTIOTROPHOBLAST LAYER
INVASIVE TROPHOBLAST – IMMUNE CELLS
INVASIVE TROPHOBLAST – DECIDUAL VASCULAR CELLS

Question 4

SYNCYTIOTROPHOBLAST LAYER

Answer 4

A multi-nucleated layer which arises from fused cytotrophoblasts. It forms a barrier and performs endocrine functions as well as gas and nutrient exchange from maternal blood.

Question 5

INVASIVE TROPHOBLAST – IMMUNE CELLS

Answer 5

The extravillous trophoblast are differentiated foetal cells which invade into the maternal decidua to transform maternal spiral arteries.

Question 6

INVASIVE TROPHOBLAST – DECIDUAL VASCULAR CELLS

Answer 6

The extravillous trophoblast are differentiated foetal cells which invade into the maternal decidua to transform maternal spiral arteries

Question 7

Which immune cells are present at the maternal-foetal interface?

Answer 7

Decidua
>40% decidual cells are leukocytes in early pregnancy.
Of these, approximately 70% are NK cells (subpopulation of cytotoxic lymphocytes)

Function by cell killing or cytokine production.
Approximately 20% are macrophages.

T and B cells make up the remaining 10%.
Intervillous space and spiral arteries, same as maternal blood.

Decidual NK Cells:
dNK cells are different to peripheral blood (pb)NK cells.
Their pattern of receptor expression is unique and they are identified by CD56hiCD16lo.
They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

Macrophages
Another immune cell found in the decidua is the macrophage: makes up about 20% of immune cells in the decidua so is the second most abundant immune cell.

dMac have a different phenotype to peripheral blood monocytes.

Broadly, macrophages may be…
M1: pro-inflammatory, secrete TNF-α, IL-6.
M2: anti-inflammatory, secrete IL-10, VEGF.
Decidual macrophages are more M2-like than M1-like – tend towards anti-inflammatory side.

Question 8

The theory of maternal tolerance - How do trophoblast evade the immune response?

Answer 8

1. Physical separation of maternal and foetal tissues.

Foetus separated from the mother by the foetal trophoblast cells.
Foetal and maternal circulation is separated.
Maternal cells cannot reach the foetus.
But In humans, IgG can cross into the foetal blood via a placental transport mechanism. Therefore, IgG directed against foetal antigens could also be transferred.

This is not fatal to the baby as most foetal blood group and histocompatibility antigens are widely distributed on the foetal cells and tissues - IgG would be diluted out. Many foetal antigens are also present as soluble forms in the foetal blood and amniotic fluid - IgG would be mopped up by free soluble antigen. EXCEPT IN RHESUS ANTIGEN AND HAEMOLYTIC DISEASE OF THE NEW-BORN.

2. Antigenic immaturity of foetal tissues.
   Histocompatibility antigens are targets for rejection.
   MHC haplotypes inherited from both parents and are co-dominantly expressed.
   Class Ia HLA-A, HLA-B, HLA-C
   (classical) Presenting antigens to CD8+ T cells.
   Interacting with NK cells.
   Highly polymorphic

Class Ib HLA-E, HLA-F, HLA-G
(non-classical) Minimally polymorphic

Class II HLA-DP, HLA-DQ, HLA-DR
Presenting antigen to CD4+ T cells.

3. Mother is immunologically inert.
   Maternal blood in pregnancy is able to respond immunologically to the foetus and foetal cells are detectable in the maternal blood.
   Pre-sensitisation to paternal antigen does not prevent pregnancy.
   There is neither a generalised or specific depression of maternal immune responsiveness.
   The quality of the maternal immune response may be what differs.

Question 9

Haemolytic Disease of the New-Born:

Answer 9

Rhesus D antigen = Major blood group antigen.
RhD –ve mother
RhD +ve father
If baby is RhD +ve mother may mount immune response.

Question 10

MHC Expression by Trophoblasts:

Answer 10

Syncytiotrophoblasts lack both MHC Class I and II antigens.

Extravillous trophoblasts lack Class II but express an unusual combination of MHC class I antigens – HLA-C (classical), HLA-E and HLA-G (non-classical).

Question 11

Theories of Immune Evasion in the Placenta:

Answer 11

Role for natural killer cells in the decidua – cytokine producing cells not killing cells.
Selective local induction of programmed cell death in maternal immune cells.
Alteration in the cytokine balance – pro/anti-inflammatory environment.
Local indoleamine 2,3-dioxygenase synthesis.
Complement regulatory proteins.

Question 12

How does expression of HLA-C, -E and -G help immune evasion?

Answer 12

By binding to receptors on NK cells.

NK cell receptors…
Killer-cell immunoglobulin-like receptors (KIRs)
CD94/NKG2 receptors
Leukocyte immunoglobulin-like receptor (LILRs)
There are both inhibitory and activating members of these families of receptors.

Question 13

Trophoblasts Interacting with NK Cells:

Answer 13

Binding of HLA class I molecules to inhibitory NK cell receptors inhibits the cytotoxic action of the NK cell, therefore the trophoblast is not attacked.

Question 14

Soluble HLA-G can be released from…

Answer 14

trophoblasts

In vitro studies have shown that sHLA-G can induce apoptosis in maternal T cells – this may be an additional way of protecting trophoblasts from attack.
Implantation after IVF only occurred if the embryos secreted sHLA-G.

Question 15

Selective Local Induction of Programmed Cell Death in Maternal Immune Cells:

Answer 15

Experimental evidence that trophoblasts can express factors that can induce programmed cell death (apoptosis) in maternal immune cells.

Apoptosis…
Cell shrinks, nucleus reorganises, DNA fragments, membranes bleb and cell fragments into membrane bound apoptotic bodies.
Regulation of apoptosis depends on a balance between pro- and anti-apoptotic factors.

Mechanisms…
Fas-Fas L
TRAIL-TRAIL R

Question 16

Maternal immune cells - The Th1 / Th2 Balance in pregnancy:

Answer 16

Th0 precursor T cells differentiate into Th1 or Th2 cells in response to signals (cytokines) given during antigen presentation.

Th1 type reaction in placenta mainly generates inflammatory responses, activates T cells and NK cells and is correlated with miscarriages e.g. IFNg, IL-2.

Th2 type reaction generates non-inflammatory reactions that are consistent with the survival of the foetus e.g. IL-4, IL-6, IL-10, IL-13.

Trophoblasts may be producing cytokines and hormones that promote a Th2 balance.

Not strictly defined that pro-inflammatory is bad and anti-inflammatory is good as it is thought that a small amount of pro-inflammatory responses is necessary early on when establishing a pregnancy.

Question 17

Maternal T-Cells:

Answer 17

Skewing the nature of the T cell response to active tolerance rather than active rejection is important.

Sufficient Tregs needed in the endometrium for implantation and pregnancy.

Tregs CD4+CD25+ – anti-inflammatory, immune suppressive.

Act on other immune cells, produce suppressive cytokines such as TGFb and IL10.

How is this regulated?
Appropriate cytokine balance.
Correct phenotype of endometrial leukocytes to allow Treg activation.
Stabilisation of Treg phenotype by estrogen and progesterone.
Priming of Tregs by male partner seminal fluid-stimulates expansion of endometrial Treg population.

Question 18

Indoleamine 2,3-dioxygenase:

Answer 18

Enzyme that catabolises tryptophan (an α-amino acid that is used in the biosynthesis of proteins).

Synthesised and secreted by syncytiotrophoblasts.
Shown to be essential for successful pregnancy.

IDO may break down tryptophan in maternal T cells in the decidua.

This can reduce or inhibit immune responses.

Question 19

Expression of Complementary Regulatory Proteins:

Answer 19

In normal pregnancies, excessive complement activation is prevented by complement regulatory proteins that are highly expressed on trophoblast membranes (MCP, DAF, and CD59). This prevents cell lysis.

CD46 – MCP – membrane co-factor protein
CD55 – DAF – decay accelerating factor
CD59 - MAC-IP- MAC inhibitory protein

Question 20

Pre-eclampsia:

Answer 20

PE lower risk with different partner for 2nd pregnancy.
Donor egg pregnancies at higher risk (non-self).
Prolonged exposure to paternal semen may lower PE risk.

Question 21

NK-Cells and Preclampsia…

Answer 21

dNK receptors may be Type A or B, and trophoblast receptors may be type C1 or C2.

If the match is KIR-A and HLA-C2, pre-eclampsia risk is increased. This may be because this interaction leads to less cytokine production which helps the trophoblast invade.

Lots is not known as it is difficult to study…

Question 22

First trimester studies of pregnancies with spiral artery related pathologies:

Answer 22

Uterine artery Doppler Ultrasound scanning 9-14 weeks…

A high resistance index in the uterine arteries reflects a high resistance index in the spiral arteries. High RI group - decreased endovascular trophoblast invasion and artery plugging.