Immunology of Pregnancy L10 Flashcards
Describe the immunological paradox of pregnancy.
- The fetus inherits codominantly MHC genes
- Paternally inherited MHC should be recognised as nonself by pregnant woman
- Pregnancy should initiate an immune response leading to immune rejection
- Pregnancy proceeds to term without rejection
- The fetus is nature’s only successful semi-allogeneic graft
Is the placenta an immune barrier?
Yes. The immune status of the placenta is considered crucial to fetal survival without rejection as the fetus is physically separated from the mother’s circulation by a continuous layer of trophoblast cells in the placenta and fetal membranes.
The ______ (syncytiotrophoblast) is bathed by maternal blood.
Placenta
Describe how the placenta serves as an immune barrier.
- The primary mechanism responsible for pregnancy success operates at the level of the placental syncytiotrophoblast cells which form a continuous interface between the mother and fetus
- The syncytiotrophoblast layer of the villous chorion lacks HLA class 1 and class II expression and therefore cannot stimulate an immune response (via class 2) nor serve as targets for CD8+ T cytotoxic cells (via class 1)
- Conclude that the fetus is surrounded by a cocoon of HLA negative trophoblast
Extravillous cytotrophoblast cells invade into uterine spiral arteries and the uterine lining (decidua). Unusually they only express which HLA’s?
HLA-C, HLA-E and HLA-G.
Which leukocytes are present in the decidua (uterine lining)?
- NK cells
- Macrophages
- T cells
Describe the unusual NK cells found in the decidua.
Decidual NK cells (uNKs) are CD56+ CD16-ve large granulated lymphocytes (unlike CD56+ CD16+NK cells in blood).
What prevents uNK cells in the decidua from killing trophoblast cells.
Why?
uNK cell attack is prevented by HLA-G expression on the trophoblast as this is sufficiently “self” to stop uNK cells from attacking.
___4___ Receptors (NKRs) can be ___1___ or ___2___: Killer cell Ig-like receptors (KIRs), C type lectins (CD94/NKGs), Ig-like transcripts (ILTs).
A leader peptide of ___3___ forms a complex with HLA-E on extravillous trophoblast surface and binds to CD94/NKG2 receptor on uNK cells and this inhibits ___4___ cell activity.
Women that lacked ___1___ KIRs and expressed only the ___2___ ___4___ cell receptor in combination with particular HLA-C alleles were at increased risk of pre-eclampsia and recurrent miscarriage when carrying babies.
- Activating
- Inhibitory
- HLA-G
- NK
For successful human pregnancy, extravillous ___1___ invades uterine lining and ___2___ arteries forming dilated high flow vascular channels but the initial changes in ___2___ artery remodelling precede ___1___ invasion uNK cells aggregate around ___2___ arteries uNKs may control ___1___ invasion and vascular remodelling via cytokines and angiogenic growth factor production : IFNg, TGFb, TNFa, IL-6, IL-8, IL-10 and angiopoietin-1, angiopoietin -2, VEGF-C.
- Trophoblast
2. Spiral
Soluble ___1___ stimulates NK cells to secrete ___2___ and proangiogenic factors
The NK KIR receptor CD158d (KIR2DL4) is unusal as it resides in early ___3___ and not on cell surface. CD158d receptor with its soluble ___1___ ligand initiates a kinase signalling pathway involved in DNA repair
Sustained signalling via CD158d receptor with its ___1___ ligand initiates senescence (DNA damage response) and reprograms NK cells.
uNK cell numbers decline in second half of pregnancy when placenta development is ___4___.
- HLA-G
- Proinflammatory
- Endosomes
- Completed
The ___1___ removes potentially damaging anti-paternal HLA cytotoxic ___2___ by acting as a “sink” for ___2___ and restricting their traffic to the fetus.
Mothers make anti-HLA ___2___ with increase in parity but only IgG ___2___ can cross the ___1___ by binding to FcR on trophoblast.
The anti-paternal HLA (IgG) ___2___ bind to HLA+ve cells inside the chorionic villi and do not attack the fetus.
- Placenta
2. Antibodies
Read:
Is the maternal immune system regulated during pregnancy?
- The maternal immune response to infection is adequate and immune responses are normal eg maternal antiviral immunity is not affected by pregnancy so HIV+ pregnant women do not suffer AIDs like disease
BUT - Increased clinical severity of some viral infections (eg influenza), bacterial infections (eg cholera, typhoid) and fungal diseases (eg coccidioidomycosis) in pregnant women
- Reactivation of latent infections eg EBV
- Certain autoimmune diseases ameliorate in pregnancy (eg rheumatoid arthritis) while others flare up (eg SLE)
___1___ T cells recognise paternal alloantigens during mouse pregnancy and pregnancy induces a transient state of tolerance specific for paternal alloantigens.
___1___ immunity is downregulated by nonspecific mechanisms eg. progesterone.
___3___/___2___ concept in pregnancy : Successful pregnancy is associated with ___2___-like response bias (IL-4, IL-6, IL-10) while ___3___ type immunity is incompatible with successful pregnancy (IL-2, IFN gamma, TNF).
During pregnancy there is a need to direct the immune system from cell mediated immunity toward ___2___ antibody reactivity.
- Maternal
- Th2
- Th1
Give evidence for Th1/Th2 involvement in human pregnancy.
- Certain infectious diseases are exacerbated in pregnancy: malaria and CMV, suggesting partial suppression of Th1 type responses
- Peripheral blood leucocytes from women with recurrent miscarriage show increased IFN gamma and TNF beta (Th1) and low levels of IL-4 and IL-10 (TH2) unlike control normal pregnant women
- Evidence suggests bias towards Th2 in normal pregnancy while Th1-type responses are associated with pregnancy loss
- This Th1/Th2 response explains why SLE flares up in pregnancy as this is mediated by excessive autoantibody production (Th2)
