Immunology of Pregnancy Flashcards
T or F. Synctiotrophoblast is a single cell layer
T,
no cell borders so lymphocytes can’t get through = physical barrier?
Is the ST barrier effective against pathogens?
Supposedly, but TORCH
= associated with congenital anomalies
- toxoplasmosis
other = syphilis, varicella-zoster, parvovirus, B19, Zika
- Rubella
- CMV
- Herpes
first time infection of CMV transmission rate
40%
microchimerism
- bi-directional trafficking of fetal and maternal cells
- low levels (1 fetal cell per 1 mill maternal cells)
- cells are detected decades after delivery and likely persist for a lifetime
- highly conserved across species
maternal positive effects of microchimerism
- existing Tregs may enhance fetal protection in the next pregnancy
- pluripotent fetal microchimeric cells may differentiate into and replace diseased cells in maternal tissues (eg. islet cells)
where is IDO expressed?
normally in circulating monocytes, macrophages, and dendritic cells
IDO
intracellular heme containing enzyme
indoleamine dioxygenase
what does IDO do?
- catalyzes first step in tryptophan catablism
- suppresses T cell proliferation
- increased by infection and inflammatory cytokines
- constitutively expressed at maternal-fetal interface in pregnancy
function of the placenta
- oxygen and nutrient exchange
- removal of waste
- barrier against maternal immune response and infections
routes of congenital infections
villous placental (through free villus)
extravillous placental
across the membranes
routes of transplacental infections
A: passive diffusion of HCMV through ST and TBM
B: IgG-bound HCMV transported through ST
C: infection via basal release from HCMV infected ST
D:infection via infected maternal monocytes migrating through damaged ST
offspring positive effects of microchimerism
- protection against fetal wastage in next generation pregnancies under conditions that interrupt fetal tolerance mechanisms
- may contribute to immune response maturity in fetus/nb
- increased Tregs may dampen inflammation from microbial colonization = training neonatal immune response
-reduced rejection of transplants
negative effects of microchimerism
autoimmunity
- the more # of male cells in women, the more likely for MS
protective physiology of placenta towards fetus
- no killing by maternal T cells (no MHCI/II expression)
- expression of non-classical MHC I (-G, -E, -C) and polymorphic HLA-C = no killing by maternal uterine or peripheral NK cells
- ST expresses Fas ligand = kills maternal immune response that tries to attack placenta
> IDO depletes tryptophan
> inhibits T cell proliferation
> decidual IL-10 and TGFB inhibit T cell responses
normal function of Tryptophan in T cell activation
released by APCs to proliferate T cells
normal feedback mechanism to reduce T cell activation by IDO
IFNy (from T cell) shuts down tryptophan by producing IDO in APC = pulls tryptophan from the environment into cell
IDO degrades tryptophan to reduce amount in the environment to shut down T cell response
constitutive action of IDO in trophoblasts
Constitutive activity of IDO in trophoblasts = but no interaction
IDO pulls tryptophan in all the time = creates an environment where cells are prevented from proliferating = protection against activation
Mellor/Munn experiment
found that using an IDO inhibitor (1-methyl-tryptophan) to block IDO-unduced tryptophan degradation matters if pregnancy is allogeneic (mom and dad different MHC)
if IDO blocked = no protection for fetus = unviable pregnancy
SO pregnancy turns off rejection in MHC-specific manner
during pregnancy, these cells predominate in the decidua
Th2 cells
( lower number since ratio expressed as Th1/Th2)
T or F. Pregnant mice fail to resist Leishmania major infections in a study
T, mor effective in clearing gut worms more efficiently
NOTE: reduced = NOT GONE; still have ability for CMI (cell-mediated immune response
T or F. Type 1 response (CMI) is better in pregnant women for autoimmune disease states
T
T or F. Pregnant women can deal better with intracellular pathogens (CMI/type 1 response)
F! poor response
T or F. The higher the MHC matches among couples, the higher the chance of pregnancy loss
T
There needs to be some mismatching at the beginning of pregnancy to have higher chances of survival
T or F. There is evidence of harmful adaptive immune responses against paternal MHC antigens
F! opposite is true
25% of the T cells in th pregnant uterus are these
T reg cells (CD4+25+Foxp3+)
= maintains tolerance to the fetus
beneficial effects of sperm/seminal plasma in pregnancy
less contact with partner’s seminal plasma (less sexual cohabitation, less use of oral contraceptives, younger women, more barrier methods, knew partners for less time = more likely to develop preeclampsia
T or F. Women with greater and longer exposure to seminal plasma from same partner are at reduced risk for preeclampsia
T
role of NF-kb
drives inflammation cytokine production
drives immune suppressors down
T regs are lower in the following three conditions:
spontaneous abortion compared to induced
infertility
preeclampsia
peripheral vs decidual/uterine NK cells
- pNK kill cells that do NOT express HLA antigens
- dNK inhibited from killing because invading placental cells express non-poly HLA antigens (ex. -G)
- dNK promote vascular growth of decidua by producing pro-angiogenic factors
- dNK cells produce chemoattractant that encourage placental cell invasion = remodels maternal spinal arteries
pro-angiogenic factors
VEGF
TGF-B1
IL-6
IL-8
inhibitory ligand for KIR2DL4 receptor found on all NK cells
HLA-G
- shuts off cytotoxic effects
- produces proangiogenic factors for uterine remodelling
- preg disorders = reduced HLA-G expression
CD16-dim/CD56+bright
decidual/uterine NK cells (dNK)
CD16+, 56+
peripheral NK cells (pNK)
what is the spiral artery?
allow blood flow into where placenta is; embedded in uterine wall
NK cells attract these to help anchor decidua to the uterine wall
trophoblasts
T or F. dNK have the capacity to be cytotoxic
T!
