L18 Immunology of Pregnancy Flashcards
Why is pregnancy an immunological paradox?
- Baby is 50% foreign; maternal immune system should see it as a semi-allograft
- However, it is worth maternal investment to ensure genetic material is passed on (evolutionary argument)
- As a result the uterus must be an immunoprivileged organ
What differential gene expression takes place at implantation and why is this important?
- Increased GFs, proteolytic enzymes (MMPs), inflammatory mediators (facilitating invasion)
- Key changes: altered protein expression, differentiation of immune cells
- Failure of this immunomodulation can result in blastocyst rejection or inappropriate blastocyst invasion
Implantation and placentation in humans: what type do we have and when does it occur?
- Window of implantation may span cycle day 20 - 24
- Humans have interstitial implantation
- Subsequent placentation is haemochorial
Key components of the primary decidual reaction:
- Uterine stromal enlargement
- Uterine natural killer cells prominent
- Promoting a ‘permissive’ phenotype as well as interacting with cytotrophoblasts to influence their differentiation
What are the phenotypes differentiated from cytotrophoblasts?
- 2 key lineages arise from CTB progenitor cells following implantation
- 1: Synctiotrophoblasts (result of fusion, multinucleate to form continuous surface for defence and nutrient exchange)
- 2: Extravillous trophoblasts (invasive phenotype, for remodelling of environment
How and why does the maternal immune system react to different cell types (maternal, EVTs, STBs, uNKs)
- Maternal cells express HLA 1a antigens (MHC-I; HLA A, B, C) and APCs (such as lymphocytes and macrophages) express MHC-II antigens which define them as ‘self’
- Extravillous trophoblasts have a different pattern of HLA (C, E and G) resulting in modification of self: no-self categorisation
- Synctiotrophoblasts have no HLA -> no immune response
- uNKs thought to be involved with innate immunity (memory function)
What are the hallmarks of the uterine NK cell phenotype?
- CD56 positive (Bright) rather than dim as in peripheral NKs
- CD16 negative (found on all other NK cells)
- Express Killer cell Ig-like receptors (KIR)
- Less cytotoxic
- Synthesise cytokines and chemokines which interact with EVTBs to facilitate invasion
- Key: memory property
Outline the interactions preventing rejection of the fetus between EVTBs and uNKs:
- EVTB has HLA-G, C and E
- HLA-G is most crucial and interacts with specific KIR on uNK cell -> triggers immunomodulation, proinflammatory and angiogenic cytokines
- HLA-C has 2 types which interact with different KIRs on uNK; combinations of HLA-C:KIR thought to determine implantation outcome (variance by paternal specificity)
- HLA-E interacts with CD94 on uNK, inhibiting uNK cytotoxicity thus preventing EVTB death
How are uNK KIRs associated with recurrent miscarriage?
- KIR2D (2 Ig-like domains) -> KIR-B and KIR-A
- Fetal HLA-C1 and maternal KIR-B activates uNK cell promoting EVT invasion
- Fetal HLA-C2 and maternal KIR-A inhibits uNK cells resulting in poor EVT invasion (and possible link with pre-eclampsia)
- Women who have EVTBs which overexpress HLA-C2 may experience recurrent miscarriage
Clinical evidence that Th cells function in pregnancy:
- Rheumatoid arthritis symptoms improve during pregnancy (Th1 mediated)
- Systemic lupus erythromatosus symptoms worsen during pregnancy (Th2 mediated)
- Mechanisms unclear
In intrauterine growth restriction, how is Th1:Th2 dysfunctional?
- Th2 bias not observed during gestation
- Increased INFy
- Exaggerated Th1 inflammatory response lasts too long following implantation
Basic roles of Th, cytotoxic T and B cells:
- Th: recruited by APC -> activation against antigen -> recruit cytotoxic T OR differentiate into helper t memory cell
- Cytotoxic T: matured by APC presenting antigen -> cytotoxic effect on that signal
- B cell: differentiate into plasma cells and produce specific antibodies
What major histocompatability complexes do T, Th and B-cells have?
- CD8+ T-cells have MHC-I
- CD4+ Th cells have MHC-II
- B-cells have MHC-II
How do Th1 and Th2 cells mutually inhibit each other?
- Th2 secretes IL-4 and IL-10 against Th1
- Th1 secretes INFy against Th2
Under normal conditions (i.e. non-pregnant) what cytokines determine Th1 vs Th2 differentiation upon contact of naive Th0 with antigen?
- IL12, INFy -> Th1-> Cell mediated immunity
- IL-4-> Th2 -> humoral immunity
During pregnancy, how is Th2 dominance induced?
- Secretions from placenta and possibly trophoblasts (IL-4, IL-10) trigger differentiation of naive Th0 into Th2
- They also have an effect of dampening Th1 response (supported by action of progesterone against Th1)
- Overall, cell mediated response is relatively suppressed to prevent graft rejection by humoral immunity is robust -> can still fight infection
Th0 cell fates during progressing phases of implantation and placentation:
- Encouraging implantation: Th1 dominant -> INFy secretions promote invasion of decidua, regulating trophoblast invasion and angiogenesis
- Early implantation: Th17 -> recruits neutrophils and protects TB from pathogens
- Th22 thought to have a protective role against rejection (lowered Th22 results in dysfunction of decidua and NKs)
- Mid gestation: Tregs can form Th2 -> tolerance b oth directly and indirectly via Th9, as well as repression of Th1 and Th17
- Late gestation: Tfh supports Th2 (favours humoral immunity) -> allograft tolerance
What antibodies do maternal b cells produce?
- IgA: Secreted in breast milk
- IgD: B cell membranes
- IgE: mast cells (anaphylaxis)
- IgG (4x subtypes) -> Crosses placenta!
- IgM (irrelevant)
How does maternal IgG cross into the placenta and what is its role in fetal circulation?
- Able to bind fetal Fc receptors on STB -> actively transported into chorionic villi, entering fetal circulation
- Provides immunity to fetus
- Those that cross-react with paternal HLAs are removed, and the paternal HLAs are presented by APCs which are removed by macrophages -> preventing humoral rejection
What is haemolytic disease of the newborn?
- aka Rhesus disease
- Results from maternal Igs raised against paternal HLA on fetal RBCs (which aren’t properly filtered out) -> targeted by humoral immunity
- Only affects fetal RBCs
Why is transplant failure more common in women who’ve been pregnant?
- Immune system has experience with foreign material
- During pregnancy, increased anti-HLA antibodies from 1st trimester onwards
- Documented increase in transplantation sensitisation due to immune memory
List 4 obstetric complications that can arise from immune dysfunction during pregnancy:
- Preeclampsia
- Rhesus disease
- Recurrent miscarriage
- Preterm labour
