immunology of pregnancy

Question 1

which systems adapt during pregnancy?

Answer 1

endocrine
respiratory 
cardiovascular 
gastrointestinal 
renal function and fluid homeostasis 
reproductive 
immune system 
metabolic

Question 2

why is pregnancy an immune paradox?

Answer 2

the fetus is 50% foreign BUT its worth maternal investment to ensure genetic material passed on, there is maternal tolerance of fetal semi-allograft

Question 3

what gene expression occurs at implantation?

Answer 3

increase in growth factors, proteolytic enzymes and inflammatory mediators = facilitates implantation
change in expression of proteins needed for immune response preventing blastocyst rejection and inappropriate blastocyst invasion

Question 4

how does a blastocyst implant?

Answer 4

endometrium develops transient receptivity for an embryo = WOI
may span cycle day 20-24
implantation will not happen if outside this time frame
human blastocyst undergoes interstitial implantation = decider permits invasion, primary decimal reaction = uterine stromal cell enlargement, uterine NK cells prominent
hypoxic conditions (2-5%) facilitates cut-trophoblast differentiation, maternal decidua = permissive function

Question 5

what do cytotrophoblast cells differentiate into?

Answer 5

extra-villus trophoblast (EVT)

syncytiotrophoblast (ScTB)

Question 6

why is the blastocyst not rejected?

Answer 6

Syncytiotrophoblast cells have no self:non-self markers so unlikely to stimulate the maternal immune system
extra-villus trophoblast cells have modified self:non-self markers = modified maternal immune response

Question 7

what immune markers are present on maternal immune cells?

Answer 7

HLA-A
HLA-B
HLA-C
MHC-II

Question 8

what immune markers are present on EVT?

Answer 8

HLA-G
HLA-C
HLA-E

Question 9

what is the role of uterine natural killer cells?

Answer 9

70% of decimal immune cells, CD56 + and CD 16-
express killer cell Ig-like receptors high bind to MHC-I
they are less cytotoxic
they synthesis cytokines and chemokine - close interaction with EVTB o facilitate invasion,
uNK cell has HLA-G receptor which causes inflammation and immunomodulates IL8,10 VEGF, PGF
uNK cells have HLA-C receptor which can determine implantation outcome
HLA_-E receptor inhibits NK cell cytotoxicity, and prevents EVTB death

Question 10

how does placentation occur?

Answer 10

first interaction = loose adherence, apposition
interstitial invasion = EVT migrate from cell columns, anchoring villi invade decimal glands. invasion is limited by decide basalis
spiral arteries are = small bore, high resistance, facilitates hypoxia. EVTs plug spiral arteries which may exacerbate hypoxia
serial artery re-modelled = wide bore and low resistance
endovascular invasion = driven by EVT and uNK cells, taps into maternal blood supply, is completed by 10-12 weeks

Question 11

how far do EVT cells invade into the myometrium?

Answer 11

inner third

Question 12

what happens if EVT endovascular invasion fails?

Answer 12

invasion localised to decidua, reduced acquisition of maternal blood supply causes various pathologies

Question 13

what diseases are caused by failed endovascular invasion?

Answer 13

premature birth 
fetal growth restriction 
recurrent miscarriage 
placental abruption 
pre-eclampsia

Question 14

what happens in invasion in placenta creta?

Answer 14

absence of decidua causes chorionic villi invasion, usually at site of Caesarean section,

Question 15

how far is the invasion in acreta, increta and percreta?

Answer 15

acreta = superficial myometrium just past the decidua basalis 
increta = deeper myometrium 
percreta = penetrates uterine serosa, invades into surrounding organs - bladder, bowel etc

Question 16

what are the risks of placenta acreta?

Answer 16

poor placental separation

significant post-partum bleeding

Question 17

how does a T-helper cell become Th1 and Th2?

Answer 17

Th-1 = IL-12 and INF gamma 
Th2 = IL-4

Question 18

what kind of immunity does Th1 cells produce?

Answer 18

NK cells
T-cells
macrophages
= cell-mediated immunity

Question 19

what kind of immunity does Th2 cells produce?

Answer 19

B-cells
antibodies
= humeral immunity

Question 20

what happens to T-helper cells during pregnancy?

Answer 20

progesterone causes inhibition of Th1 cells so cell mediated immunity is suppressed, cytokine balance favours Th2, meaning maternal humeral immunity active so can still fight infection and the fetus is protected therefore immune response is modified

Question 21

what happens if Th2 cell bias does not occur?

Answer 21

INF gamma increases, exaggerated inflammatory response => maybe pre-eclampsia, re-current miscarriage, IUGR

Question 22

what antibodies are present in pregnancy?

Answer 22

IgA - secreted in breast milk
IgD - B-cell membranes, no known effector function as serum protein
IgE - mast cells = anaphylaxis
IgG - only Ig to cross the placenta
IgM - pentameric structure early antibody

Question 23

how does the mother prevent a harmful immune response to paternal HLA antigens?

Answer 23

IgG cross resting with paternal HLAs are removed to stop response. (the paternal HLAs are present on placental macrophages, chorionic villus) immune complexes then removed by macrophages

Question 24

how does haemolytic disease of the new born occur?

Answer 24

maternal Ig raised against paternal antigens on fetal red blood cells, IgG against paternal HLA antigen are not removed and then cause lysis of fetal RBCs

Question 25

how do you treat rhesus disease?

Answer 25

anti D prophylaxis - this destroys anti Rh +ve IgG therefore fetal RBCs not attacked

Question 26

how does rhesus disease occur?

Answer 26

1st preg = sensitisation
- fetal blood mixes at term/post natally
- maternal immune response to Rh +ve antigens on fetal RBC, usually IgM subtype and IgM cannot cross the placenta, creates a memory B-cell to fetal Rh+ve antigen
subsequent preg = rapid immune response to fetal Rh+ve antigens on RBCs, IgG subtype made due to memory Bcell, only IgG crosses placenta. causes fetal demise due to lysis of fetal RBCs if no intervention