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MVST1B HR > Placentation and immunology > Flashcards

Placentation and immunology Flashcards

1
Q

Extraembryonic sacs include ….

A

Extraembryonic sacs include the amnionic and the yolk sacs.

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2
Q

describe the amnion

A

The amnion is a membrane that creates a fluid-filled sac in which the embryo/fetus is suspended.

It provides a protective environment for the fetus to develop.

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3
Q

describe the yolk sac

A

The yolk sac is a structure outside of the developing embryo and is connected by the yolk stalk. It is vascularized with fetally-derived vessels, and is involved in nutrient uptake, protein synthesis, and is the first site of hematopoiesis.

It transports nutrients, such as amino acids and glucose, from the fluid in the extraembryonic coelom for fetal use.

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4
Q

describe the outer surface of the yolk sac

A

The outer surface of the yolk sac is like an absorptive epithelium with microvilli. The glucose transporter GLUT1 (and other nutrient transporters) are present on this outer surface.

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5
Q

alpha-fetoprotein?

where is it produced, and what does it do

A

The yolk sac also synthesizes proteins including alpha-fetoprotein. An increased level of alpha-fetoprotein in the maternal circulation indicates abnormal placental permeability and pathology or fetal death

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6
Q

While the ________ is maintained throughout pregnancy, the _________ regresses by 20 weeks of pregnancy when the placenta is established.

A

While the amnion is maintained throughout pregnancy, the yolk sac regresses by 20 weeks of pregnancy when the placenta is established.

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7
Q

Around the time of implantation, the inner cell mass is divided into two layers

what are they?

A

Around the time of implantation, the inner cell mass is divided into two layers, the epiblast and the primitive endoderm (also known as hypoblast)

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8
Q

The dorsal surface of the epiblast faces the ________ whereas the primitive endoderm faces _________

A

The dorsal surface of the epiblast faces the amnionic cavity whereas the primitive endoderm faces the blastocoel.

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9
Q

do you understnad the cahnges in:

teh extraembryonic cavity

the yolk sac

the amnion

A
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10
Q

As development continues, the amnion expands around the ventral surface of the embryo and by 12 weeks of pregnancy, the amnion pushes against the inner surface of the _______, obliterating the extraembryonic coelom.

A

As development continues, the amnion expands around the ventral surface of the embryo and by 12 weeks of pregnancy, the amnion pushes against the inner surface of the chorion, obliterating the extraembryonic coelom.

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11
Q

The yolk sac becomes connected to the embryo via the ….

A

The yolk sac becomes connected to the embryo via the yolk sac stalk.

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12
Q

the placenta does lots of roles.

give some exampes

A

For example,

gas transfer (lung);

excretory functions,

water balance,

pH regulation (kidney);

catabolic and resorptive function (gut);

synthetic and secretory functions (most exocrine glands);

metabolic functions (liver);

haematopoiesis (bone marrow);

and immunological interations and protection (immune system).

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13
Q

dimentions of the placenta?

A

The mature placenta is a discoid organ that is 20-25 cm in diameter and weighing 400-600 g.

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14
Q

The side of the placenta that faces the fetus is called the…

A

The side of the placenta that faces the fetus is called the chorionic plate

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15
Q

The basal plate of the placenta is apposed to the ____ _______ (maternal tissue that is formerly the endometrial stroma).

The basal plate is through which the maternal blood enters the placenta

A

The basal plate of the placenta is apposed to the decidua basalis (maternal tissue that is formerly the endometrial stroma). The basal plate is through which the maternal blood enters the placenta

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16
Q

The functional unit of the placenta is called the …

A

The functional unit of the placenta is called the fetal villus tree

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17
Q

The functional unit of the placenta is called the fetal villus tree, which arises from the _____ _______ and consists of …..?

A

The functional unit of the placenta is called the fetal villus tree, which arises from the chorionic plate and consists of two layers of trophoblast cells (syncytiotrophoblast and cytotrophoblast) surrounding fetal capillaries.

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18
Q

The first cells of the placenta appear at the blastocyst stage of the embryo as ________

A

The first cells of the placenta appear at the blastocyst stage of the embryo as trophectoderm

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19
Q

describe how trophoectoderm cells being the formation of the placenta

A

At implantation, the trophectoderm attaches to the endometrial epithelium and invades between the cells. Two trophoblast cell populations form: an inner layer of mononuclear cells called cytotrophoblast cells and an outer multinucleated layer called syncytiotrophoblast

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20
Q

Two trophoblast cell populations form: an inner layer of ______________ cells called cytotrophoblast cells and an outer ___________ layer called syncytiotrophoblast

A

Two trophoblast cell populations form: an inner layer of mononuclear cells called cytotrophoblast cells and an outer multinucleated layer called syncytiotrophoblast

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21
Q

Syncytiotrophoblast are ___________ cells that are generated by ….?

A

Syncytiotrophoblast are non-proliferative cells that are generated by continual fusion of cytotrophoblast cells.

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22
Q

spcaes called what form within the syncytiotrophoblast?

A

lacunae

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23
Q

after the formation of lacunae, what hapens nect regarding placental formation

A

the syncytiotrophoblast cells form trabeculae between the lacunae into which the cytotrophoblast cells and extraembryonic mesoderm penetrate.

This results in the earliest placental villi.

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24
Q

Side braches from the trabeculae form into the lacunae. These gradually branch again to become more complex. Repeated branching forms the placental villus tree.

The lacunae are now referred to as the….

A

Side braches from the trabeculae form into the lacunae. These gradually branch again to become more complex. Repeated branching forms the placental villus tree.

The lacunae are now referred to the intervillus space

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25
Q

The placental villus structure consists of…..

A

stem villi, which extend from the chorionic plate.

Branches from the stem villi are referred to as intermediate villi

from which terminal villi arise.

Anchoring villi attach the villus trees to the basal plate of the placenta.

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26
Q

when are most terminal villi formed?

A

during the second half of pregnancy

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27
Q

describe how the pattern of placental villi formation changes during pregnancy

A

Initially during pregnancy, the placenta villi form over the entire chorionic sac.

At about 20 weeks, the villi have regressed to one pole to form the discoid placenta.

The placenta membranes remain in regions where the villi have regressed and when ruptured, provide an exit route at birth.

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28
Q

histotropic vs haemotropic nutrition sources?

A
  • first 10-12 weeks of pregnancy
  • fetus relies on nutrients and gases from oviductal and uterine secretions taken up by yolk sac (histotropic nutrition)

but:

  • placenta villi = haemotrophic nutrition
  • This allows nutrient, gas and waste exchange to occur between the maternal and fetal circulations.
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29
Q

describe what sort of things the feetus used during histotrophic nutrition

A

the principal source of nutrients is carbohydrate- and lipid-rich secretions from the endometrial glands.

Glandular secretion is stimulated by progesterone and signals from the trophoblast cells.

This provides a low oxygen environment for the embryo since it is during this time that it is particularly sensitive to reactive oxygen species and teratogenesis.

Furthermore, low oxygen favours fetal and placental stem cell development.

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30
Q

low oxygen favours what developemnt?

A

low oxygen favours fetal and placental stem cell development

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31
Q

good picture of placenta

A
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32
Q

Fetal capillaries are surrounded by a _____ of trophoblast cells

A

Fetal capillaries are surrounded by a bilayer of trophoblast cells

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33
Q

describe Embryonic versus fetal period of development

A

The embryonic period of development is when the major organ systems are differentiating (0-8 weeks post-fertilization; approx. the first trimester).

The fetal period of development is between 9-38 weeks post-fertilization.

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34
Q

During this period, the _____ has the highest risk of congenital malformations and is particularly sensitive to external factors (e.g., oxygen, mutagens, alcohol).

is this embryo or fetal?

A

During this period, the embryo has the highest risk of congenital malformations and is particularly sensitive to external factors (e.g., oxygen, mutagens, alcohol).

0-8 weeks

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35
Q

Most embryonic deaths will occur in which period?

A

embryonic period

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36
Q

The _____ is less sensitive to external factors.

A

The fetus is less sensitive to external factors. (compared to the embryo)

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37
Q

The human pregnancy is divided into ______, each consisting of 12-13 weeks.

A

The human pregnancy is divided into trimesters, each consisting of 12-13 weeks.

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38
Q

describe Maternal blood flow into the placenta

A

Establishing the maternal circulation poses unique haemodynamic challenges of combining high volume flow with low velocity and pressure.

High volume is required for optimal nutrient and gas exchange but the placental villus tree is fragile and so blood flow rate and pressure must be reduced. The mature placenta contains 150mL of maternal blood, and this volume is replaced 3-4 times every minute.

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39
Q

4 things Effective placental exchange requires:

A
  1. Stable low-pressure, high volume maternal blood supply
  2. Large surface area in placental villi
  3. A high transplacental gradient (diffusion)
  4. Transporter mechanisms for polarised or hydrophilic molecules (transporter abundance)
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40
Q

describe the spiral arteries

A

The spiral arteries are highly coiled, allowing for expansion as the uterus expands, and are highly muscular.

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41
Q

describe the process of how spiral arteries are invaded

whcih cells invade the spiral arteries?

A

To enable increased maternal blood flow to the placenta, extravillous trophoblast cells (EVTs) migrate away from the anchoring villi and invade into the spiral arteries.

The invasion of EVTs into spiral arteries leads to a loss of vascular smooth muscle and the endothelial cells lining the spiral arteries.

A fibinoid material is left in its place.

This results in vessel dilation and loss of vasoreactivity, thereby slowing the rate of blood flow into the intervillous space and reducing blood pressure.

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42
Q

Failure of conversion spiral arteries is associated with complications of pregnancy including ….

A

Failure of conversion spiral arteries is associated with complications of pregnancy including pre-eclampsia with or without intrauterine growth resetriction (IUGR).

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43
Q

upon conversion of the spiral arteries, uterine artery Doppler waveform shows what characteristic?

A

Upon conversion of the spiral arteries, uterine artery Doppler waveform shows an increased diastolic flow, which indicates a reduction in vascular resistance.

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44
Q

conversion of the spiral arteries is associated with what in the spiral artery vessel wall?

A

Conversion is associated with presence of EVTs in the vessel wall.

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45
Q

Poor placental development and/or function are directly correlated to i…..

A

Poor placental development and/or function are directly correlated to intrauterine growth restriction (IUGR).

46
Q

describe placenta villi in the early placenta

A

In the early placenta, placental villi have a low surface area to volume ratio because the villi have yet to undergo substantial branching morphogenesis.

47
Q

picture for spiral artery remoddeling

A
48
Q

each villi is surrounded by what?

A

Each villi is surrounded by a bilayer of an outer syncytiotrophoblast cells (form a syncytium) and an inner cytotrophoblast layer.

49
Q

early placenta:

The early villi are surrounded by an intervillous space that …..

A

The early villi are surrounded by an intervillous space that if filled with uterine gland secretions and a low level of maternal blood.

50
Q

early vs late placenta

A
51
Q

describe how the syncytiotrophoblast cells make a thin diffusion distance between materal and feta lblood

A

First, the nuclei in the syncytiotrophoblast cells become clustered or compartmentalized together causing the remaining portion of the cell to produce a very thin diffusional barrier.

52
Q

T or F

The underlying layer of cytotrophoblast cells is no longer consistent

A

T

Although the absolute number of cytotrophoblast cells increases during pregnancy, they are often more difficult to find on histological sections due to morphological changes in the villous structure.

53
Q

Effective placental exchange requires the following:

(4 points)

A
  1. Stable low-pressure, high volume maternal blood supply, which is achieved by spiral artery remodeling by extravillous trophoblast cells.
  2. A large surface area, which is generated by branching of terminal villi
  3. The presence of transport mechanisms
  4. A high transplacental gradient between maternal and fetal circulations.
54
Q

describe diffusion in the placenta

A

passive

No carrier proteins are involved and molecules (e.g., oxygen, carbon dioxide, free fatty acids, urea) passively diffuse between cells, through the cell membrane, or through transcellular pores.

55
Q

how does the outer syncytiotrophoblast cell membrane incerase the surface area>

A

presence of microvilli

56
Q

The placenta consumes at least ___% of the total oxygen that diffuses into the trophoblast cells.

A

For example, the placenta consumes at least 30% of the total oxygen that diffuses into the trophoblast cells.

57
Q

oxygen saturation of fetal blood leaving the placenta and content is not much different than in maternal blood.

how?

A

fetal hemoglobin, which have a higher affinity for oxygen than adult hemoglobin.

58
Q

describ the double bohr shift that happens in the placenta

A

a double Bohr shift occurs in the placenta to facilitate transfer of about 10% of the oxygen in a fetal direction.

The fall in pH of maternal blood due to uptake of fetal carbon dioxide drives the release of maternal oxygen and the rise in fetal pH due to the removal of its carbon dioxide facilitates uptake of oxygen.

59
Q

Molecules crossing the placental barrier depend upon the presence of membrane carrier proteins that act…. by using ATP or not?

A

Molecules crossing the placental barrier depend upon the presence of membrane carrier proteins that act independent of ATP

60
Q

which GLUT protein are in the placenta

A

There are several isoforms of GLUT proteins and glucose transport is important in the placenta since the fetus is unable to undergo gluconeogenesis.

For example, GLUT1 is expressed on the microvilli of the surface of the syncytiotrophoblast cells that face the maternal circulation.

61
Q

describe how the plcaenta steals amino acids

A
  • ATP dependant
  • high fetal protein levels
  • transporters are expressed on the trophoblast membranes facing both the maternal and fetal circulations.
  • Remarkably, the fetus can sense when maternal (and therefore, fetal) amino acid levels are low. The fetus will send a signal to the placenta to upregulate the correct amino acid transporter to increase uptake into the placenta.
62
Q

There are three main carrier systems in the placenta:

(3)

not sure you need to know this

A
  1. System A and ACS: Na+ dependent and open to neutral amino acids
  2. System XAG: Na+ dependent and selective for acidic amino acids
  3. System L: Na+ independent and open to neutral amino acids
63
Q

how is IgG antibody taken up by the fetus?

A

Receptor-mediated endocytosis enables the uptake and transport of IgG antibodies from the maternal blood to the fetal circulation to help convey passive immunity to the fetus.

the IgG molecules bind to receptors on the microvillus membrane and become concentrated in the coated pits at the base of the microvilli. These are endocytosed and transported in vesicles through the cell

64
Q

can HIV cross the placenta?

A

HIV (human immunodeficiency virus) cannot cross the placenta to infect the fetus but maternal IgG antibodies against HIV can through receptor-mediated endocytosis

65
Q

why is maternal HIV antibodies crossing the placenta bad for birth?

A

The presence of maternal antibodies in the newborn prevents normal diagnosis of HIV transmission from mother to neonate at birth. This is because HIV diagnosis involves the detection of antibodies. Therefore, an alternative method of diagnosis is required (e.g., PCR to detect viral DNA in fetal blood).

makes detection of HIV difficult

66
Q

can the placenta control maternal metabolism

A

yes

67
Q

with regards to the placenta regulating maternal metabolism…

early pregnancy vs late pregnancy?

A

In early pregnancy, these hormones will stimulate maternal appetite and deposition of nutrient resources. In later pregnancy, these hormones will mobilize these resources for transfer to the fetus during its growth period and also for use during lactation.

68
Q

give some hormones the placenta uses to control maternal metabolism

A

Peptide hormones:

  • hCG
  • hPL
  • PGH
  • Leptin
  • PAPP-A

Steriod hormones:

  • progesterone
  • oestrogens
69
Q

describe HCG

A

Maternal recognition of pregnancy

Acts on LH receptors in corpus luteum (increase progesterone)

Glycoprotein with two non-covalently linked subunits

It is secreted by syncytiotrophoblast as a luteotropic factor and acts on LH receptors in the corpus luteum. In turn, the corpus luteum is maintained and continues to secrete progesterone

  • Alpha subunit identical to FSH, LH and TSH, unique beta subunit

Pregnancy test. Molar pregnancies.

Morning sickness?

70
Q

describe hPL

A

A hormone that stimulates maternal appetite, lipolysis, and free fatty acid levels.

It induces growth and differentiation of mammary gland tissue.

The amino acid sequence is similar to growth hormone (GH) but its effects are less growth promoting in comparison.

Secreted by the syncytiotrophoblast, levels of hPL are highest in the later stages of pregnancy.

71
Q

describe PGH

A
72
Q

describe leptin

A

Pregnancy is a state of peripheral leptin resistance, which allows the mother to lay down adipose reserves.

Leptin resistance results in a lack of appetite suppression, which results in increased maternal appetite.

Leptin, secreted by syncytiotrophoblast cells, has paracrine and autocrine effects since it simulates increased expression of placental transport proteins on syncytiotrophoblast cells.

Its peak levels are at the end of the second trimester and the beginning of the third trimester.

It is thought to be regulated by hCG and oestrogen.

73
Q

describe Pregnancy associated protein A (PAPP-A)

A

A hormone that promotes growth and cell proliferation by acting as a protease that cleaves IGFBPs to enhance their bioavailability.

Syncytiotrophoblast cells secrete PAPP-A, the levels of which continuously increase in maternal serum through pregnancy.

Low levels of PAPP-A in maternal blood during the first trimester are used as an indicator of IUGR or fetal aneuploidies (e.g., Down syndrome).

74
Q

describe progesterone

A
75
Q

describe oestrogens

A
76
Q

A consistent decline of oestriol over a period of days is an indicator that ___what____ should be induced.

A

A consistent decline of oestriol over a period of days is an indicator that premature delivery should be induced. (

77
Q

does the placenta protec tthe fetus against the mothers hormones?

A

yes

78
Q

One case is the action of placental 11beta-hydroysteriod dehydrogenase, which does what?

A

One case is the action of placental 11beta-hydroysteriod dehydrogenase, which metabolizes maternal cortisol to inactive cortisone and allows the fetal pituitary adrenocortical axis to mature in isolation.

79
Q

what does P-glycoprotein do? in the placenta

A

P-glycoprotein aids in the transport of foreign organic compounds out of the placenta to protect the fetus against xenobiotics (e.g., toxins, drugs, or substances that are present in much higher concentrations than usual).

80
Q

does the placenta also act as a barrier against viral infections?

A

yes

81
Q

which virus can infect a fetus?

A

An exception to this is the Zika virus, which was shown to infect the first trimester trophoblast cells to gain access to the fetus

82
Q

________ cells slough off from the placenta during development and end up in the maternal circulation

A

Trophoblast cells slough off from the placenta during development and end up in the maternal circulation

83
Q

Fetal DNA is present in _________ fragments than circulating maternal DNA.

A

Fetal DNA is present in shorter fragments than circulating maternal DNA

84
Q

Two sites of interaction of fetal trophoblast with maternal immune cells:

what are they?

A

Invasion is unusually deep in humans and so brings fetal EVT into contact with maternal immune cells in the decidua. Second site of interaction is in the intervillous space where villi are bathed in maternal blood as nutrient and gas exchange takes place. Villi are in contact with systemic immune cells circulating in mothers blood.

85
Q

What mechanisms allow this contact without detrimental activation of maternal immune cells?

A
  • In placental villi - syncytiotrophoblast (SYN) is in direct contact with maternal blood. Neither syncytiotrophoblast nor villous cytotrophoblast express ANY MHC class I or class II ligands. So no recognition by maternal T cells in blood.
  • Maternal NK cells might be expected to ‘kill’ MHC negative SYN, due to missing self response. But don’t do so- reasons unclear, but SYN may lack key ligands for activating receptors on NK cells, while also lacking MHC ligands for inhibitory receptors. So NK killing expected due to missing self is not triggered?
  • Recently, a subset of maternal macrophages have been identified adhering to SYN, named ‘placenta-associated maternal macrophages’ (PAMM). They express factors, such as fibronectin and may aid in repair and maintenance of SYN integrity.
86
Q

Reduced extent of trophoblast invasion and/or vascular conversion by EVT during the first trimester are believed to contribute to common diseases of pregnancy including…..

A

pre-eclampsia (PE),

fetal growth restriction (FGR) and

recurrent miscarriage (RM)

87
Q

Alsogive some epidemiological evidence that Pre-eclampsia has an immunological component

A
  • Disease of first pregnancies (4-10% varies ethnically)
  • Risk falls in subsequent pregnancies - unless change of partner
  • Highest PE risk in oocyte donation (~30%), entirely non-self (fetal HLA differ from mother)
  • Epidemiology suggests genetic contribution from both mother and father
  • Normally only seen in humans - unique mechanism, so animal studies of limited use.

These observations suggest that PE, FGR and RM share a common aetiology- reduced spiral artery remodelling.

88
Q

Pathogenesis of pre-eclampsia and FGR

A
  1. Extravillous trophoblast fails to invade decidua and modify spiral arteries adequately
  2. Altered maternal blood supply to placenta - Less villous branching
  3. Placental Stress - release of soluble factors including soluble flt and placental debris.
  4. Resulting maternal systemic endothelial disease gives rise to pre-eclampsia and/or FGR
  5. Reasons why some pregnancies manifest PE, others FGR and some both of these together are not understood
89
Q

are Trophoblasts inherently invasive?

A

yes

Trophoblast inherently invasive and old experiments in primates show if trophoblast transplanted to other sites, trophoblast invades them aggressively.

90
Q

Ectopic pregnancy - describe trophoblast invasion?

A

Ectopic pregnancy- implantation in fallopian tube (no decidua) can be life-threatening emergency as trophoblast invades right through the fallopian tube.

91
Q

what is pre-eclampsia?

A
92
Q

pre-clampsia has a higher risk in oocyte donation?

A

yees

93
Q

do fetal cells in the villi of the placenta express HLA molecuels?

A

yes - but theyre not normally exposed to maternal blood

94
Q

what MHc molecules od EVT express?

A

EVT express no MHC class II, but a very unusual repertoire of MHC class I:

95
Q

which HLa do EVT cells express?

A

No HLA-A or HLA-B, but do express HLA-E, HLA-G and HLA-C, of which only HLA-C is significantly polymorphic.

96
Q

describe how uNK cell numbers change in the decidua?

A

uNK increase rapidly in endometrium during secretory phase of menstrual cycle.

Their proliferation is stimulated by the action of progesterone which induces stromal cells in endometrium and decidua to secrete the cytokine IL-15.

uNK proliferate in response to IL-15 and this continues in decidua during the first trimester of pregnancy.

Numbers of uNK in decidua decline in second trimester and are low at term.

97
Q

T or F

uNK are much less cytotoxic (less able to kill) than NK cells from blood against K562 and uNK are unable to kill trophoblast (EVT) unless artificially activated.

A

T

98
Q

T or F

EVT has a unique array of MHC class I molecules, and these are major ligands for both NK cells and other immune cells. Of course EVT express other ligands recognised by various maternal immune cells including NK cells, but for the most part these ligands and the corresponding receptors that bind them don’t vary much across the population.

A

T

99
Q

HLA-G is normally only expressed where

A

trophoblast

100
Q

T or F

only HLA-C will vary from pregnancy to pregnancy

A

T

101
Q

Picture

A
102
Q

Learn this

the KIR binding (3)

A

KIR2DL1 strong inhibitory receptor binds HLA-C2 KIR2DS1 strong activating receptor binds HLA-C2 KIR2DL3/L2 weak inhibitory receptors bind HLA-C1

103
Q

T or F

Each pregnancy will result in different KIR/HLA-C combinations -

A

T

104
Q

2DL1/HLA-C2 combination associated with increased risk of

PE, FGR or RM.

A

true

105
Q

T or F

This suggests it is the recognition by KIR2DL1 of fetal HLA-C2 on EVT that is detrimental.

A

T

106
Q

how do uNK cells affect trophoblast migration?

A

Instead, binding

of KIR2DS1 on uNK to HLA-C2 stimulates the uNK cells to secrete the cytokine GM-CSF. This cytokine has been shown to enhance trophoblast migration in vitro.

107
Q

Instead, binding

of KIR2DS1 on uNK to HLA-C2 stimulates the uNK cells to secrete the cytokine GM-CSF. This cytokine has been shown to enhance trophoblast migration in vitro.

This beneficial response seems to overcome the inhibitory response generated by KIR2DL1 binding to trophoblast C2.

A

True

im so tired

108
Q

Discuss the idea that interactions between KIR and HLA-C may act to stabilize human birthweight between clinically undesirable extremes.

A
109
Q

pregnancy is a state of ______ rather than immunosuppression.

A

pregnancy is a state of immunomodulation rather than immunosuppression.

110
Q

read and understand immunology of pregnancy please

A

its so confusing

111
Q

fat

A

mamba

MVST1B HR (13 decks)

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