Block C - immunology pregnancy 3

Question 1

what immune cells play an importnat role in labour ?

Answer 1

Many studies suggest that immune cells including neutrophils, macrophages & T cells play an important role in labour.

Question 2

what did transcriptional analysis reveal for labouring women ?

Answer 2

Transcriptional analysis of myometrial and cervical biopsies from labouring women showed an upregulation in a number of chemokines and pathways regulating immune cell trafficking.

Question 3

CXCL8 (IL-8) cells ?

Answer 3

stretch of uterine myometrial cells results in increase in CXCL8 expression.

Question 4

CCL2 ( monocyte chemoattractant protein-1) ?

Answer 4

CCL2 is released by myometrial cells throughout gestation, expression is significantly upregulated immediately before and during labour. Expression was shown to be stimulated by mechanical stretch. Increased accumulation of CCL2 in term myometrium is regulated by progesterone

Question 5

uterine mass decreases rapidly , how come ?

Answer 5

Uterine mass must decrease rapidly through apoptosis, neutrophil entry, enzyme release and phagocytosis of cellular debris.

Question 6

what is miscarridge defined as ?

Answer 6

Royal College of Obstetricians and Gynaecologists (RCOG) define miscarriage as the early loss of a pregnancy (www.rcog.org.uk). This affects approximately 1 woman in every 100, and there are a number of reasons.

Question 7

your age and past pregnancy ?

Answer 7

Your age and past pregnancies
The older you are, the greater your risk of having a miscarriage. The more miscarriages you have had already, the more likely you will be to have another one.

Question 8

genetic factors ?

Answer 8

Genetic factors
For around three to five in every 100 women who have recurrent miscarriages, they or their partner have an abnormality on one of their chromosomes (the genetic structures within our cells that contain our DNA and the features we inherit from our parents). Although such abnormalities may cause no problem for you or your partner, they may sometimes cause problems if passed on to your baby.

Question 9

abnormalities in the embryo ?

Answer 9

Abnormalities in the embryo
An embryo is a fertilised egg . An abnormality in the embryo is the most common reason for single miscarriages. However, the more miscarriages you have, the less likely this is to be the cause of them.

Question 10

autoimmune factors ?

Answer 10

Autoimmune factors
Antibodies are substances produced in our blood in order to fight off infections. Around 15 in every 100 women who have had recurrent miscarriages have particular antibodies, called antiphospholipid antibodies (aPL), in their blood; fewer than two in every 100 women with normal pregnancies have aPL antibodies. Some people produce antibodies that react against the body’s own tissues; this is known as an autoimmune response and it is what happens to women who have aPL antibodies. If you have aPL antibodies and a history of recurrent miscarriage, your chances of a successful pregnancy may be only one in ten.

Question 11

womb structire ?

Answer 11

It is not clear how far major irregularities in the structure of your womb can affect the risk of recurrent miscarriages. Estimates of the number of women with recurrent miscarriage who also have these irregularities range from two out of 100 to as many as 37 out of 100. Women who have serious anatomical abnormalities and do not have treatment for them seem to be more likely to miscarry or give birth early. Minor variations in the structure of your womb do not cause miscarriages.

Question 12

weak cervix ?

Answer 12

Weak cervix
In some women the entrance of the womb (the cervix) opens too early in the pregnancy and causes a miscarriage in the third to sixth month. This is known as having a weak (or ‘incompetent’) cervix. It is overestimated as a cause of miscarriage because there is no really reliable test for it outside of pregnancy.

Question 13

infections ?

Answer 13

If a serious infection gets into your bloodstream it may lead to a miscarriage. If you get a vaginal infection called bacterial vaginosis early in your pregnancy, it may increase the risk of having a miscarriage around the fourth to sixth month or of giving birth early. It is not clear, though, whether infections cause recurrent miscarriage; for this to happen, the bacteria or virus would need to be able to survive in your system without causing enough symptoms to be noticed. This rules out illnesses like measles, herpes, listeria, toxoplasmosis and cytomegalovirus (so you do not need to be tested for them if you have recurrent miscarriages).

Question 14

alloimmune reaction ?

Answer 14

Some people have suggested that some women miscarry because their immune system does not respond to the baby in the usual way. This is known as an alloimmune reaction. There is no clear evidence to support this theory.

Question 15

preeclampsia ?

Answer 15

This is a disorder of late pregnancy , diagnosed by blood pressure >140/90mmHg & proteinuria (>300mg in 24 hrs). If not treated, may progress to Eclampsia which is a life threatening condition characterised by convulsions. It affects 5-10% of pregnancies in developed world. An invasion of trophoblasts into the maternal tissue is abnormal in preeclampsia. The spiral arteries do not undergo full physiological change and hence blood flow to the placenta is reduced. It is associated with excessive maternal inflammatory response, perhaps directed against foreign foetal Ag.Women with preeclampsia have higher cytotoxic T cell responses against paternal antigens than healthy pregnant control women.

Question 16

direct effect of infection on pregnancy ?

Answer 16

Infection can have direct effects on pregnancy:

interfere with the physiology of pregnancy

damage the placenta

interfere with the immunology of pregnancy

result in congenital transmission

Question 17

how does pregnancy change immunity to infection ?

Answer 17

Pregnancy can alter immunity to infection

Result in increased susceptibility to new infections

Cause reactivation of latent infections

Question 18

due to changes in peripheral immunity , pregnancy can result in increased severity to some infections ?

Answer 18

toxoplasma (Luft et al., 1982 Infect. Immun. 38:1164)

Listeria (Luft et al., 1982 Infect. Immun. 38:1164)

Leishamania (Krishnan 1996 J. Immunol. 156:644.)

Plasmodium (Menendez 1995 Parasitol. Today 5:178)

Reduced severity to other conditions

Question 19

reduced severity to other conditions ?

Answer 19

Psoriasis (Raychaudhuri et al., Int J Dermatol. 2003 42:518).

Rheumatoid arthritis (Ostensen et al., Transpl Immunol. 2002 9:155)

Question 20

toxo plasma gondii ?

Answer 20

This is a parasite, which is a tissue cyst found in the brain, muscle of chronically infected animals.

Question 21

life cycle cat and mouse ?

Answer 21

The life cycle is shown above, the mouse has the tissue cysts, when eaten by a predator such a cat, the cyst under easement in the gut and they infect the intestine of the cat. The sexual life cycle occurs only in the cat and there is a production of oocysts which are infective to other animals and humans.

Question 22

humans and live stock ?

Answer 22

Humans can become infected by eating animal products that are infected by the tissue cysts.

Question 23

T gondii transmitted in utero ?

Answer 23

T. gondii can be transmitted in utero and disrupt pregnancy (vertical / congenital transmission)

Question 24

seropositivity ?

Answer 24

Incidence of Seropositivity (antibodies present against pathogen)

Question 25

consequence of toxo plasma to foetus ?

Answer 25

hydrocephalus

Question 26

pregnant mice more succeptible to in response to T gondii

Answer 26

Pregnant mice are more susceptible and produce less IFNg in response to T. gondii than non-pregnant mice. Less of a Th1 response so more susceptible to infection. Administration of IL-2 can reverse above effect with the lack of Th1 response.

Question 27

infection during pregnancy can have adverse effects on the child later in life , how does altered immunity to that infection occur ?

Answer 27

Congenital T. gondii infection alters the immune lifetime response of the exposed foetus into adulthood allowing persistent infection with multiple episodes of reactivation. This is associated with reduced lymphocyte responsiveness although the reasons are not fully understood.

Question 28

T gondii infection can induce immunological conditions that disrupt pregnancy ?

Answer 28

It can promote fetal loss (abortion- humans/resorption- rodents) and there is an increased severity of disease in mothers, creates conditions that facilitate congenital transmission.

Question 29

first trimester incidence of infection

Answer 29

low but severity is high

Question 30

third trimester ?

Answer 30

The third trimester the chance of infection is high but the severity of disease is low.

Question 31

why does abortion occur in first trimester ?

Answer 31

infection during 1st trimester disrupts Th2 bias and results in abortion

Question 32

T gondii have a number of PAMPS such as HSP70 and profilin , once bound to TLR’s on host what occurs ?

Answer 32

T. gondii have a number of pathogen-associated molecular patterns (PAMPs; including HSP70, GIPLS and profilin) which can ligate TLRs on host cells and a chemokine mimic, cyclophilin18, that binds CCR5 to induce activation of neutrophils, dendritic cells and macrophages.
(B) IL-12 produced by these cells act on NK cells to stimulate them to produce IFN-g.

Question 33

IFN gamma and IL-12 promote ?

Answer 33

Together, IFN-g and IL-12 preferentially induce differentiation of Th1 cells.
(D) Th1 cells secrete IFN-g and, preferentially favour M1 macrophage activation.
(E) Th2 cells and Treg cells play a role in reducing inflammation during T. gondii infection.

Question 34

leishmania ?

Answer 34

C57BL6 mice self-cure following Leishmania major infection due to mounting a strong Th1 response. Infection of mice increases resorption of fetuses ( rodent abortion) due to decreased placental , IL-4 and IL-10 ( Th2) and increased placental TNFa and IFNg (Th1).

Increased failure of pregnancy before implantation. Krishnan L, Guilbert LJ, Wegmann TG, Belosevic M, Mosmann TR. (1996) T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions. Correlation with increased IFN-gamma and TNF and reduced IL-10 production by placental cells.

Question 35

why does toxo plasma gondii occue ?

Answer 35

Toxoplasma gondii is a Th1 / Th2 imbalance which leads to congenital transmission

Question 36

influenza associated with ?

Answer 36

Influenza is associated with enhanced maternal infection and there is no placental infection.

Question 37

salmonella ?

Answer 37

Salmonella is associated with maternal infection and severe placental infection.

Question 38

MIA ?

Answer 38

mother immunological activation

Question 39

how does MIA lead to pyschiatric disorders ?

Answer 39

Infection leads to release of pro-inflammatory cytokines and activation of TH17 cells in the mother’s bloodstream (6, 19). A combination of genetic background, autoimmune status, and second hits during childhood and adolescence (including stress and drug abuse) combines with the consequences of maternal infection to increase the likelihood of offspring developing psychiatric disorders as adults.

Question 40

MIA and peripheral immunity ?

Answer 40

Mechanisms underlying the effects of MIA on brain function. Aberrations in the microbiome after MIA can lead to altered development of peripheral immunity, both of which can alter brain development. Deficits in long-range connections between brain regions implicated in SZ and ASD, including the HC, PFC, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and amygdala (AM), have been reported in MIA (3, 4, 14). Specific alterations in activity of glutamatergic neurons in the cortex caused by decreased function of dopaminergic (DA) neurons in the ventral tegmental area (VTA) and decreased GABAergic input also occur in SZ and ASD, as well as in the MIA models (3, 4, 14). Changes in expression of immune molecules in the brain and even at synapses, including cytokines and MHCI molecules, alter synaptic plasticity and function and contribute to the changes in circuitry and connectivity between brain regions that characterize these disorders (6). Finally, alterations in immune and neuronal signaling due to MIA may converge upon the mTOR pathway, which regulates synapse formation, growth, translation, survival, and autophagy (68). mTORC1, mTOR complex 1.