Immunology of Pregnancy and the Fetus

Question 1

The Pregnancy Paradox

Answer 1

A developing fetus expresses paternal antigens, so it’s a naturally occurring graft, that is not rejected by the mother, even though, the mother can make immune responses against fetal antigens (the paternal portion of the fetal antigens).

Question 2

Examples of the Pregnancy Paradox

Answer 2

Rhesus negative mothers make antibodies against fetal Rhesus positive blood

Mothers who have had several children have antibodies against paternal MHC antigens

Question 3

____________ is critical for the absence of fetal rejection

Answer 3

Growth within the uterus is critical for the absence of fetal rejection. This is why gestational surrogacy is possible!

Question 4

Wholly ______ fetuses can develop successfully in the uterus of an unrelated female.

Answer 4

Wholly allogeneic fetuses can develop successfully in the uterus of an unrelated female.

Question 5

Developmental process of Pregnancy (Order)

Answer 5

1. Implantation and Placentation
2. Fetal Growth
3. Parturition

Question 6

Impantation and Placentation

Answer 6

Implantation = attachment of the blastocyst to the uterine lining, which occurs approximately 6 or 7 days after conception (fertilization).

Placentation = Development of the placenta, after the blastocyst burrows deeper into the endometrium (decidua).

Question 7

Specifics on Placentation

Answer 7

During invasion the trophoblast (which is formed from the outer layer of the blastocyst) invades the endometrium and differentiates into an inner cytotrophoblast and outer syncytiotrophoblast.

The syncytiotrophblast invades the maternal uterine wall and blood vessels. This invasion incites an inflammatory response that supports the active breakdown and restructuring of the uterine tissue and angiogenesis. These processes are important for proper placental development.

Question 8

Parturtition

Answer 8

Childbirth. The physiologic process of expelling a fetus from the uterus.

Question 9

What type of immune cells support all stages of pregnancy?

Answer 9

Decidual immune cells.

Question 10

What cells shape and regulate the immune milieu of the maternal decidua?

Answer 10

Trophoblastic cells.

Question 11

The trophoblastic regulation can be disrupted by __________.

Answer 11

The trophoblastic regulation can be disrupted by uterine and placental infection.

Question 12

What happens after trophoblastic invasion?

Answer 12

A range of innate and adaptive immune cells are attracted to the site of trophoblastic invasion.

Trophoblastic cells secrete cytokines that modulate these inflammatory cells. For most of the first trimester this is a pro-inflammatory process, but when placentation is fully established, there is development of anti-inflammatory immune responses.

For example, there is reduced NK cell cytotoxicity and differentiation of macrophages into M2-phenotype cells, in preparation for the second immunological stage of pregnancy– rapid fetal growth.

Question 13

The trophoblast/syncytiotrophoblast cells secrete what? What does this substance do?

Answer 13

The trophoblast/syncytiotrophoblast cells secrete TGF-beta.

TGF-beta induces regulatory T cell development and promotes tolerance at the maternal-fetal interface.

Question 14

The syncytiotrophlast cells also express what?

Answer 14

The syncytiotrophlast cells also express a non-polymorphic HLA molecule, HLA-G.

HLA-G is recognized by the inhibitory ligand on maternal NK cells and so prevents them from killing fetal cells.

Question 15

What is another mechanism that keeps maternal cells from killing fetal cells?

Answer 15

Reduced expression of HLA Class I and II molecules on the placental tissues

Reduced complement activity at the maternal-fetal interface.

Question 16

Inflammatory Response During Each Trimester

Answer 16

1st Trimester = Implantation and Inflammation

2nd Trimester = Fetal growth and TH2 response

3rd Trimester = Inflammation, TH1 response, labor

Question 17

Inflammatory Response 1st Trimester

Answer 17

The pro-inflammatory processes that facilitate implantation and placentation increase the expression of adhesion molecules on the surface of endometrial epithelium which encourages tight adhesion of the blastocyst to the uterine epithelium and subsequent implantation.

Question 18

Inflammatory Response 2nd Trimester

Answer 18

The anti-inflammatory milieu, the expansion of regulatory T cells, especially those that are specific for paternally-derived antigens, are important for protecting the growing fetus from rejection.

Question 19

What triggers parturition (onset of labor)?

Answer 19

It is triggered by a switch to another phase of pro-inflammatory signaling pathways, which cause an influx of immune cells into the myometrium. This influx of cells promotes uterine muscle contraction and expulsion of the fetus.

Question 20

Infection at the maternal-fetal interface can lead to _____________.

Answer 20

Infection at the maternal-fetal interface can lead to preterm delivery.

Question 21

How do uterine immune cells and trophoblastic cells facilitate the onset of labor?

Answer 21

Both the uterine (decidual) immune cells and the trophoblastic cells express PRR and are able to sense PAMPs (and DAMPs).

This leads to heightened inflammatory responses, which disturb the trophoblastic modulation of the maternal immune system and induce uncontrolled pro-inflammatory responses that facilitate the onset of labor.

Question 22

Most common route of infection in early pregnancy?

Answer 22

Most common route is transplacentally. The main organisms are viruses.

Transplacental infection may or may not result in placental damage, but it does tend to reach the fetal blood, which is filtered by the fetal liver and spleen. Such hematogenous spread may manifest as septicemia with involvement of heart, liver, spleen, meninges and adrenal glands.

Question 23

Most common route of infection in late pregnancy?

Answer 23

Maternal genital tract infections predominate. Most commonly due to cervico-vaginal bacteria.

These might penetrate the fetal membranes or occur after the rupture of membranes.

This leads to infection of the amniotic fluid, which is then inhaled or ingested by the fetus with infection of lungs and/or GIT. In addition, fetal skin, eyes and ears are in contact with the infected amniotic fluid, causing skin, ocular, omphalitis (infection of the umbilical stump) and meningitis.

Question 24

What is one uncommon but possible route infection can reach the pregnant uterus?

Answer 24

From the peritoneal cavity.

Question 25

Pregnant women have diminished ______ making them more predisposed to some pathogens such as toxoplasma, malaria, Listeria, etc.

Answer 25

Pregnant women have diminished cell mediated responses, making them more predisposed to some pathogens such as toxoplasma, malaria, Listeria, etc.

Question 26

When does the mother pass IgG antibodies to the fetus?

Answer 26

Mother begins passing IgG to the infant from about 13 weeks of gestation. The vast majority of IgG antibodies are passed to the fetus in the last 4 weeks of pregnancy.

Preterm infants won’t have the full benefit of protection provided by adequate levels of maternal IgG.

Question 27

The pregnant uterus is protected by?

Answer 27

a thick mucus plug

the secretion of anti-microbial peptides

secretory IgA

Question 28

The human placenta expresses what? What do they do?

Answer 28

The human placenta also expresses a unique set of microRNAs.

MicroRNAs are non-coding RNA and which regulate specific gene expression. A fraction of the microRNAs, released to the extracellular environment, induce a state of anti-viral immunity.

Question 29

What is the does the protective membranes around the fetus secrete?

Answer 29

The cells of the protective membranes secrete microbial peptides into the amniotic fluid.

Question 30

When does the fetus began to produce IgM?

Answer 30

At about 20 weeks gestation.

The fetus in utero can respond to infection by making IgM

Where there is suspicion that a newborn might have been infected in utero (e.g. with rubella), serological tests are done to establish if there are rubella-specific IgM antibodies in the baby. If yes, then it is inferred that the baby was infected with rubella in utero.

Question 31

Pregnancy is “a unique immune condition that is _____ but not _______”

Answer 31

Pregnancy is “a unique immune condition that is modulated but not suppressed”.

Pregnancy is now viewed as a unique immune state for the mother, in which her response to any infection is the sum of her immune system, the modulation of this by the fetal-placental unit, and the pathogenicity of the infectious organism.

Question 32

Infections associated with increased maternal mortality?

Answer 32

Influenza

Malaria, toxoplasma, (mycobacateria (TB & leprosy)

Listeria

Question 33

When are T and B cells produced?

What can induce early production of fetal IgM?

Answer 33

The production of T and B cells begins very early in intrauterine life and intra-uterine infection such as rubella will induce the production of fetal IgM from as early as week 11, though fetal IgM is usually detected in the baby’s blood at around 20 weeks of gestation.

Question 34

When and from where does the fetus receive most of its antibody protection?

Answer 34

Most the antibody protection is from the transplacentally transferred maternal IgG (begins at about the beginning of the second trimester but is maximal from about 32 weeks of gestation (the last 4 weeks of gestation)) and by IgA in breast milk after birth.

Question 35

What mediates the transport of maternal IgG across the placenta and across the neonatal intestinal epithelium?

Answer 35

an IgG-specific Fc receptor called the neonatal Fc receptor

Question 36

When do T-cells reach their full capacity in a baby?

Answer 36

Despite early intrauterine production of T-cells their functional development is slow and they really only achieve full functional capacity at approximately 2 months after birth.

Question 37

Fetal immune responses are _________.

Answer 37

Fetal immune responses are tolerogenic. It is less likely to mount aggressive immune responses to new antigens.

Promote tolerance to self, as tissues develop and new antigens are expressed.

Prevent immune responses to protective maternal proteins, such as maternal IgG.

Question 38

At birth ______ numbers are high and ____ production is normal but the production of other important cytokines is low.

Answer 38

At birth CD4 T cell numbers are high and IL-2 production is normal but the production of other important cytokines is low.

CTL and NK cell function are also not optimal.

These findings are thought to account for the severity of neonatal infections caused by viruses and intracellular pathogens, such as HSV, CMV, Listeria and Toxoplasma.

Question 39

When does the baby attain adult levels of IgM, IgA, and IgG?

Answer 39

IgM = attains adult levels in the first few months of life

IgA = attains adult levels later childhood/adolescence

IgG = IgG in the baby’s blood at birth are as high as or higher than that of the mother and this is what provides protection to the infant in the first few months of life.
The infant begins to make its own IgG from term (40th week of pregnancy).

Question 40

Benefits of breastfeeding

Answer 40

Protects infant during a period of immune system immaturity

Prevents damaging inflammatory responses in the immature infant gastrointestinal tract

Modulates the development of the infant’s mucosal immune system

Question 41

How does breastmilk benefit an infant’s GI system?

Answer 41

The infant’s gastrointestinal mucosa is ‘leaky” and its microbiome is being established.

Breast milk provides factors including secretory IgA and antimicrobial peptides that protect the infants leaky GIT from pathogen invasion and also modulates growth of different types of microbes in the infant’s GIT.

Question 42

Anti-inflammatory components of breast milk include

Answer 42

Soluble TNF receptors = prevent inflammatory responses

Epithelial growth factors (ex: lactoferrin & epithelial growth factor) = enhance the development of the neonatal GIT AND decrease the higher permeability of the infant’s GIT.

Question 43

Breast milk influences the development of the infant’s mucosal immune responses by:

Answer 43

Influencing the types of organisms in the gut microbiota

Enhancing systemic and mucosal production of antibodies

Priming for the production of interferon-alpha in response to viral infection

Influencing the development of infant’s immune responses and repertoire

Question 44

Breast milk is a VERY complex mixtures of substances and its composition__________.

Answer 44

Breast milk is a VERY complex mixtures of substances and its composition changes as the baby matures. Thus its composition for a newborn baby is different from that when the baby is 6 months old!!

Question 45

Breast milk protects the infant from what potentially fatal inflammatory condition?

Answer 45

Necrotizing enterocolitis (NEC), which tends to occur in preterm infants. Breast milk decreases the incidence and severity of NEC.