reproductive immunology

Question 1

what does the success of pregnancy depend on?

Answer 1

depends on ability of maternal immune system to change and adapt in each developmental stage

Question 2

Immune system activation during the journey of pregnancy

what are the three developmental stages?

Answer 2

1. Periovulation stage
2. after coitus (intercourse)
3. during pregnancy (first, second and third trimesters)

Question 3

Immune system activation during the journey of pregnancy - Periovulation

what uterus layer contains the greatest abundance of immune cells and what parts of the menstrual cycle does this increase and why?

for why, think cytokine and chemokines

Answer 3

• endometrial layer
• increases in proliferative and periovulatory phases
• due to influx of leukocytes in response to ovarian hormone regulated chemokine + cytokine expression

Question 4

Immune system activation during the journey of pregnancy - after coitus

after coitus, what induces a proinflammartory response in the ectocervix?

think seminal fluid and antigens

Answer 4

seminal fluid containing:
* paternal alloantigens
* soluble and sperm-associated immune regulatory factors

Question 5

Immune system activation during the journey of pregnancy - after coitus

what does local release of cytokines and chemokines do?

think WBCs

Answer 5

causes:

• recruitment of immune cells into local environment
• primes treg cells and other Leukocytes into the uterine endometrium from the ectocervix

Question 6

Immune system activation during the journey of pregnancy - during Preg.

what type of stages are the 1st-3rd trimester in terms of inflammation

1st = implantatoin and placentation
2nd = fetal growth
3rd = labour

Answer 6

1st: pro-inflammatory stage
2nd: anti-inflammatory stage
3rd: pro-inflammatory stage

Question 7

Immune system activation during the journey of pregnancy - during preg.

what 3 ways can implantation be divided into

Answer 7

apposition
adhesion/attachment
invasion/penetration

Question 8

First trimester immunology

what happens in apposition phase in implantation

think blastocyst

Answer 8

• blastocyst expresses L-selectins

Question 9

First trimester immunology

what happens in adhesion phase in implantation

think blastocyst and ensuring successful attachment

Answer 9

blastocyst promotes cleavage of MUC-1 at the implantation site to ensure successful attachment

Question 10

First trimester immunology

what supports the embryo-endometrial interactions?

think cytokines

Answer 10

Leukemia inhibitory factor (LIF)

Question 11

First trimester immunology

what happens in invasion/penetration phase of implantation

think trophoblast cells and epitheliums

Answer 11

trophoblast cells from blastocyst penetrate endometrial epithelium into stroma

Question 12

First trimester immunology

what happens once embryo breaches the luminal epithelium?

think stromal cells

Answer 12

stromal cells surrounding the embryo transform into decidualized cells

Question 13

First trimester immunology

why are immune cells recruited to the decidua in implantation

Answer 13

specifically recruited to facilitate proper implantation and promote successful pregnancy (NOT due to foreign bodies)

Question 14

THE MATERNAL-FETAL INTERFACE

what is the materal fetal interface composed of

Answer 14

• maternal decidua
• placental trophoblasts

Question 15

THE MATERNAL-FETAL INTERFACE

what is the unique, time-limited function

think development and protection from injury

Answer 15

to nourish and suppport developlment of semi allogeneic fetus and protect from inflammatory or immune-mediated injury

Question 16

Decidua formation

what happens during decidualization and why?

for what happens, think arteries
for why, think gaseous exchange

Answer 16

• fetal and maternal mediated remodeling of spiral arteries
• this is so placenta becomes bathed in maternal blood to facilitate exchange of nutrients, gases and waste

Question 17

Decidua formation

what do maternal leukocytes do in the remodelling process in tandem with fetal trophoblasts?

think arteries and placenta

Answer 17

dilation of spiral arteries to decrease force and maximum volume of maternal blood bathing placenta

Question 18

Uterine Natural killer cells (UNK)

what do the unique phenotypes CD56bright and CD16-neg of uNKs mean for the uNK?

Answer 18

means they have low cytotoxicity and induce Treg generation

Question 19

Uterine Natural killer cells (UNK)

what are uNK cells a potent source of?

Answer 19

immunoregulatory cytokines which help in angiogenesis

Question 20

Uterine Natural killer cells (UNK)

why don’t uNK cells not reject the fetus?

think cytolytic acton and MHC I interaction with trophoblast cells

Answer 20

• uNK cytolytic action is at baseline
• non-classical MHC I molecule interaction on trophoblast cell

Question 21

decidual macrophages

what do decidual macrophages help with

think spiral artery and producing factors

Answer 21

• early spiral artery remodelling by producing factors associated with:
  -tissue remodelling
  -matrix metalloproteinases and
  angiogenesis

Question 22

decidual macrophages

what do decidual macrophages phagocytose?

think cells in vascular wall

Answer 22

• phagocytose apopototic cells in remodeled vascular wall and apoptotic trophoblasts

Question 23

decidual macrophages

what is responsible for inhibition of human uNK cell-mediated lysis of invasive cytotrophoblast?

think growth factor secretion

Answer 23

secretion of transforming growth factor-beta-1 (TGF-B1) by decidual macrophages

Question 24

Dendritic cells (DCs)

what is the 2 roles of dendritic cells in blastocyt implantation?

think: secretion of factors and faciliating attachment of embryo

for 2, think tolerance

Answer 24

1. DCs secrete factors that remove mucin layer of surface epithelium of uterus, exposing adhesion molecules that can facilitate attachment of embryo
2. promotes tolerance to paternal antigens

Question 25

# Regulatory T cells (Treg cells) what is the function of Treg cells ## Footnote then paternal antigens and maternal immune system

Answer 25

to protect fetal cells that express paternal antigens from rejection by maternal immune system

Question 26

# Regulatory T cells (Treg cells) why do Treg cells indicate memory-type regulatory response?

Answer 26

this is because Treg cells persist after delivery adn rapidly accumulate during subsequent pregnancies

Question 27

# 2nd trim : anti-inflammatory stage : TH2-type tissue environment how do Th2 cells play role in anti-inflammatory process?

Answer 27

they secret IL-4, IL-5 and IL-10

Question 28

# 2nd trim : anti-inflammatory stage : TH2-type tissue environment what do Th17 cells do?

Answer 28

help to protect maternal-fetal interface from microbial infection ## Footnote (TH17 cell function regulated by Treg)

Question 29

# 3rd trimester : A pro-inflammatory switch necessary for labour what signalling pathway is initates labour/delivery

Answer 29

the NF-kB pathway

Question 30

# 3rd trimester : A pro-inflammatory switch necessary for labour what receptor activates the NF-kB pathway?

Answer 30

Toll-like receptor 4 (TLR4)

Question 31

# Hypotheses/concepts to explain maternal tolerance of the fetus what are 4 concepts that could explain why there is maternal tolerance of the fetus ## Footnote think HLA, Th1, T regulatory cells and other factors

Answer 31

1. HLA/HLA-G expression by trophoblast 2. The Th1/Th2 balance 3. Regulatory CD4+/CD25+ T cells 4. other factors like LIF, suppressor macrophages and hormones

Question 32

# HLA expression by the trophoblast what actually expresses HLA/HLA-G

Answer 32

extravillous trophoblasts ## Footnote NOTE, does NOT express HLA-A, HLA-B or MHC class II molecules

Question 33

# HLA expression by the trophoblast what does HLA-E on trophoblast do? ## Footnote think CD94 on uNK

Answer 33

* binds to receptor CD94/NKG2A on uNK cells to prevent lysis of tissue cells

Question 34

# HLA expression by the trophoblast what does HLA-G do on trophoblasts ## Footnote think secretion and different factors

Answer 34

binds to ILT2 expressed by uNK and increases secretion of inflammatory and proangiogenic factors

Question 35

# HLA expression by the trophoblast what does KIR do? ## Footnote think HLA-G

Answer 35

binds to HLA-G to reduce cytotoxic function of uNK cell

Question 36

# Other tolerance factors how do APCs play a role in vascular remodelling | APCs = antigen presenting cells ## Footnote think inhibitory receptors and induction of molecules

Answer 36

express inhibitory receptors like ILT2 and ILT4 for HLA-G on trophoblasts, and once they bind together it leads to the induction of anti-inflammatory cytokines & tolerance to trophoblast

Question 37

# Other tolerance factors how do APCs play role in interaction of NK and T cells in decidua ## Footnote think differentiation of cells and IL-15

Answer 37

APCs induce differentiation of endometrial NK cells into activated dNK cells via production of IL-15 | dNK = decidua natural killer cells

Question 38

# Other tolerance factors how do APCs interact with dNK cells? ## Footnote think DC-sign, IFNy and IDO production

Answer 38

via DC-sign/ICAM-3, leading to dNK to release IFNy which upregulates IDO production in APCs, leading to immune supression

Question 39

# Toll Like Receptors (TLRs) what percentage of preterm birth cases is caused by bacterial infection

Answer 39

40%

Question 40

# Viral infection abolishes beneficial effects of commensal microbiota what can viral infection do leading to preterm labour? ## Footnote think IFNB

Answer 40

can abolish IFNB signalling pathway and it immunomodulatory effects