Immunology of Pregnaancy Flashcards
Case study 1: A young woman had her 9th consecutive miscarriage. Her
marriage broke down shortly afterwards.
But within months of finding a new partner, she conceived again
and the pregnancy went without a hitch. - why? (2)
Woman’s immune system took offence to the 1st choice of partner
- over-reacting to the tissue carrying his genes and expelling the fetus.
Infertility, recurrent miscarriage, premature delivery and a dangerous complication of pregnancy, pre-eclampsia, may be strongly linked to immunological abnormalities.
Immunological problems to solve during pregnancy (4)
Half of the fetal genome derives from the father but, unlike a mismatched organ transplant, it isn’t normally rejected!!!!
- Fetal tissue is half foreign – has to be protected from rejection
- Mother’s immune defence must be sufficient during pregnancy to ensure survival
- Fetus often immunologically immature at birth – must have maternal antibodies to ensure survival
How does the baby manage to avoid the mothers immune system?
The maternal/fetal interface is central to overcoming these problems. This interface occurs at the placenta
Dev. of placenta - Where are the mother and babies cells in direct contact? (4)
images
The maternal-fetal interface:
1.Syncytiotrophoblast layer covering the placenta is bathed in maternal blood
2.Invading trophoblast come into contact with decidual immune cells
3.Invading trophoblast come into contact with decidual blood vessels
Why is it diff. to study immunology of human pregnancy? (2)
most immune cells in peripheral blood- easy accessible by taking a blood sample
but blood situated in pregnancy = diff. to get access to
- Syncytiotrophoblast layer covering the placenta is bathed in maternal
blood (2)
The syncytiotrophoblast is 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 - in direct contact w/ immune cells in maternal blood.
- Invasive extravillous trophoblast are in contact with decidual immune
cells (2)
The extravillous trophoblast are differentiated fetal cells which invade into the maternal decidua to transform maternal spiral arteries.
Here they encounter a large infiltration of maternal immune cells in the decidua before they head to arteries
- Invasive extravillous trophoblast are in contact with decidual vascular
cells (3)
The extravillous trophoblast are differentiated fetal cells which invade
into the maternal decidua to transform maternal spiral arteries
here they are at the spiral arteries: the trophoblast dependent model takes place ( immune cells needed for remodelling = temp. loss of endothelial layer + big lumen): trophoblasts express endothelial markers = direct contact of fetal and maternal immune cells
How does the mother could mount an immune response? - immune cells are present at the maternal-fetal interface? (5)
Decidua:
> 40% decidua = leukocytes in early pregn.
- of these approx. 70% are NK cells (killing or cytokine prod.)
-approx 20% = macrophages
- t+b cells make up remaining 10%
Intervillous space + sprial arteries:
same immune cells as maternal blood immune cells
Decidual natural killer cells diff to peripheral NK’s -70% (4)
- dNK cells are different to peripheral blood (pb)NK cells
- Their pattern of receptor expression is unique and they are
identified by CD56hiCD16lo (low in PNK) - 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
= don;t kill but encourage to sec. cytokines = trophoblast invasion
Macrophages in pregnancy - diff to peripheral monocytes 20% (4)
*dMac have a different phenotype to peripheral blood monocytes
*Broadly, macrophages may be:
– M1: pro-inflammatory, secrete (cytokines + GF’s) TNF-α, IL-6
– M2: anti-inflammatory, secrete (reg. factors) IL-10, VEGF
- Decidual macrophages are more M2-like than M1-like (anti-inflammatory)
How do trophoblast evade the immune response? - Medawar’s theories (3)
*Physical separation of maternal and fetal tissues
*Antigenic immaturity of fetal tissues
*Mother is immunologically inert
- Is there a physical separation of maternal and fetal tissues? (6)
- Fetus separated from the mother by the fetal trophoblast cells
- Fetal and maternal circulation is separated
- Maternal cells cannot reach the fetus
But:
- In humans, IgG can cross into the fetal blood via a placental transport mechanism.
- Therefore IgG directed against fetal antigens could also be transferred
fetus is separated but the fetal trophoblast cells are not!
Why doesn’t fetal antigens harm the baby? (2)
Most fetal blood group and histocompatibility antigens are widely distributed on the fetal cells and tissues - IgG would be diluted out.
Many fetal antigens are also present as soluble forms in the fetal blood and amniotic fluid - IgG would be mopped up by free soluble antigen.
- Is there antigenic immaturity of fetal tissues? (4)
- Histocompatibility antigens are targets for rejection
- MHC haplotypes inherited from both parents and are co-dominantly expressed
MHC1a (classical): (HLA-A, HLA-B, HLA) -presenting antigens to CD8+ T cells
interacting with NK cells highly polymorphic
MHC1b (non-classical): (HLA-E, HLA-F, HLA-G) - minimally polymorphic
MHCII: (HLA-DP, HLA-DQ, HLA-DR) - presenting antigen to CD4+ T cells
MHC expression by trophoblasts (3)
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, HLA-E and HLA-G (non-classical)
= expressing things that can be recognised by maternal cell s= not antigenically inert
- Is the mother immunologically inert? (4)
- Maternal blood in pregnancy is able to respond immunologically to the fetus and fetal cells are detectable in the maternal blood
BUT
* 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
Theories of immune evasion in the placenta (5)
- Role for natural killer cells in the decidua
- Selective local induction of programmed cell death in maternal immune cells
- Alteration in the cytokine balance
- Local indoleamine 2,3-dioxygenase synthesis
- Complement regulatory proteins
How does expression of HLA-C, -E and -G by EVT help immune
evasion? - why NK cells don’t attack foetus (4)
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
Trophoblasts interacting with NK cells (5)
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
Inhibitory NK receptor:
CD94/NKG2A
KIR2DL / S1
LILRB-1
Trophoblast:
HLA-E
HLA-C
HLA-G
Experimental evidence for NK not attacking (6)
- Inhibitory receptors are expressed at higher levels in uterine NK cells than
peripheral blood NK cells - HLA-E has higher affinity for the inhibitory receptor than the activating
receptor - More uNK cells found in women with a history of recurrent pregnancy loss
But:
Trophoblast HLA molecules can also bind to activating NK cell receptors
may alter the NK cytokine repertoire
may contribute to how the trophoblast behaves
A role for soluble HLA-G? (4)
- Soluble HLA-G can be released from trophoblasts
- In vitro studies- sHLA-G can induce apoptosis in maternal T cells
- May be an additional way of protecting trophoblasts from attack
IVF: an association between the presence of soluble human leukocyte antigen G(sHLA-G) in human embryo culture supernatants (ES) and implantation success
Selective local induction of programmed cell death in maternal
immune cells
Experimental evidence that trophoblasts can induce programmed cell death (apoptosis) in maternal immune cells.
Apoptosis + mechanisms (5)
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
Fas/FasL MoA : (4)
1) Fetal tropho. releases or has FasL
2) FasL binds to Fas recptor on Maternal immuen cell
3) = triggers FADD signalling + cascade
4) caspases releases = apoptosis
TRAIL MoA (4)
1) Fetal tropho. releases TRAIL
2) TRAIL binds to 2 TRAIL-R1 receptor on Maternal immuen cell
3) = triggers TRADD = triggers FADD signalling + cascade
4) caspases releases = apoptosis
Maternal immune cells: The Th1 / Th2 Balance in pregnancy (4)
T cells differentiate into Th1 or Th2 cells in response to signals given during antigen presentation
Th1 type reaction in placenta mainly generates inflammatory responses, activates T cells and NK cells and is correlated with miscarriages.
eg IFNg, IL-2
Th2 type reaction generates non-inflammatory reactions that are consistent with the survival of the fetus.
eg IL-4, IL-6, IL-10, IL-13
Trophoblasts may be producing cytokines and hormones that promote a Th2 balance
Why might miscarriages due to inflammation occur? (3)
orig. need inflamm response (TH1) to allow for implantation of oocyte
then need a switch into TH2 response
the delay of the switch may result in miscarriages
Maternal T cells- 10% (5)
Skewing the nature of the T cell response to active tolerance rather than active rejection is important
T helpers – Th1, Th2, Th17, Treg
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 are maternal T reg. cells reg. ? (4)
- 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.
Indoleamine 2,3-dioxygenase (5)
- Enzyme that catabolises tryptophan
- 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 T cell
Expression of complement regulatory proteins (4)
a large no. of plasma proteins - interact w/ each other = induces inflamm. response = more susceptib. to opsonisation or recognition to phagocytic cells
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
low levels linked w/ preg. failure or pre-term birth + because creates inflamm in state in uterus
Summary: Theories of immune evasion at the maternal – fetal interface (6)
- Non-classical expression of HLA antigens may help trophoblast evade the
immune response
*Forget what you know about immune cells: DECIDUAL immune cells are
different!
*Trophoblast may promote death of some immune cells
*A Th2 balance is promoted
*Production of IDO by syncytiotrophoblasts may inhibit T cell responses
*Complement regulatory proteins
Is there an immunological basis for disorders of pregnancy? (2)
- This is a controversial and heavily-researched area
*Some incidences of pre-eclampsia and miscarriage may have a basis in
maternal-fetal immunological mismatch
Pre-eclampsia risks lowered/heightened when: (3)
- PE lower risk with different partner for 2nd pregnancy
- Prolonged exposure to paternal semen may lower PE risk
- Donor egg pregnancies at higher risk (non-self)
NK cells and Pre-eclampsia: (3)
- 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
How can we study normal remodelling and determine what is going wrong in PE/FGR?
mostly animal but human studies are tricky
Are immune cells different in the high RI and normal RI pregnancies? (5)
dNK cells: Promote trophoblast invasion (n), Fail to promote
trophoblast invasion (h)
dNK cells: Promote spiral artery remodelling (n), Fail to promote spiral artery remodelling (h)
dNK cells: Differ in cell surface receptors
dNK cells: Differ in cytokine secretion
dMacrophage: Do not induce trophoblast apoptosis (n), Induce trophoblast apoptosis (h)
