esthers

• Physiological roles of the Immune system

  -Pregnancy

  -Turn-over of cells

  -Wound healing
• Effects of cytokine production

  Proliferation

  Angiogenesis

  Differentiation
• What is the product of fertilisation?

  1 cell diploid embryo
• Fertilisation


  Cell divisions

  Form blastocyst

  Hollow sphere of cells

  Blastocyst release (hatching) into uterus lumen
• What does a blastocyst consist of?

  Inner cell mass

  Outer layer of cells (trophoblast)
• Why are trophoblasts important in implantation?

  Differentiates into extraembryonic membranes surrounding the embryo
• Implantation


  Developing blastocyte must invade maternal decidua

  Resembles metastatic implant
• Why is it important for blastocytes to invade the maternal decidua?

  -Gain access to blood supply

  -Nutrient transport

  -Waste removal
• What results in inflammation?


  Implantation and metastasis
• 4 main stages of implantation

  Apposition

  Attachment

  Invasion

  Inflammation
• Apposition


  Loose interaction between blastocyst and epithelium of endometrium
• Attachment


  Stronger interactions via adhesion molecules
• Invasion


  Trophoblast penetrate through the epithelium

  Invades uterine stroma

  Trophoblast cells differentiate to become syncytiotrophoblast
• Inflammation


  Supports angiogenesis

  Tissue remodelling

  Macrophage recruitment (apoptotic cell removal)
• What cells are characterised in early pregnancy?

  Innate and adaptive cells:

  - MΦ, NK cells, and CD8+ T cells, Treg

  Determined by maternal inflammatory factors
• How are pro-inflammatory mediators generated by?

  Endometrial cells and immune cells:

  - MΦ, NK cells, others. - IL-1, IL-6, GM-CSF and LIF-1 (leukaemia inhibitory factor)
• Consequences of pro-inflammatory mediators

  -Changes in adhesion molecules on epithelial layer

  -Removal of mucin layer to allow attachment

  -Production of various proteases including matrix metalloproteases (MMP)
• What is the importance of ECM breakdown?

  Leads to invasion of maternal decidua

  Important for:

  -Anchoring conceptus

  -Accessing maternal spiral arteries

  -Controlled to limit invasion
• Spiral artery


  Maternal spiral arteries supply endometrium

  Structurally transformed during early pregnancy (~100x increase in blood flow)
• Why is it important that arteries become capable of high conductance at low pressure?

  Reduction in velocity of the blood entering the placenta
• Spiral artery remodelling


  Trophoblast cells induce maternal endothelial cell death (replaced by trophoblast cells)

  Extravillous trophoblast cells invade into decidua
• Uterine NK (uNK) cells


  Weakly cytotoxic

  Potent source of immunoregulatory cytokines, MMP, angiogenic factors (along with macrophages)

  Factors meditate ECM remodelling, trophoblast invasion, angiogenesis
• MΦ (Hofbauer cells)


  Remove apoptotic cells associated with spiral artery remodelling

  eg maternal endothelial cells, apoptotic trophoblasts
• Why is a balance of implantation important?

  Excessive invasion=uterine rupture, maternal death

  Insufficient invasion=Restricted fetal blood supply, result in miscarriage, fetal growth restriction or pre-eclampsia
• Pre-eclampsia


  Periodic or continuous elevation in blood pressure, odema

  Proteinuria in severe cases

  Affects ~4% of pregnancies
• Severe pre-eclampsia


  Give rise to convulsive state of eclampsia:

  -Seen typically in 1st pregnancy, develops in 3rd trimester

  -Associated with growth retardation, premature labour, low birth weight, placenta abruption, future risk of maternal cardiovascular disease
• Genetic differences and pre-eclampsia

  Failure of trophoblast invasion

  Poor placenta perfusion may lead to formation of free radicals (oxidative stress, inflammatory responses)
• Diagnosis of pre-eclampsia


  New onset of hypertension (blood pressure >140/90mmHg)

  Proteinuria (either 24h urinary protein >300mg/24h 0r protein-creatinine ratio >0.3) after 20 weeks
• Risk factors for pre-eclampsia

  -Nulliparity

  -Multiple gestation

  -Diabetes mellitus

  -History of renal disease

  -Chronic hypertension

  -History of preeclampsia

  -Extremes of maternal age

  -Obesity

  -Antiphopholipid antibody syndrome
• Pre-eclampsia severe features


  End-organ damage

  -Severe elevation of blood pressure (>160/110mmHg)

  -Evidence of CNS dysfunction

  -Renal dysfunction

  -Pulmonary oedema

  -Heptaocellular injury

  -Haematologic dysfunction
• Pre-eclampsia Treatment


  Resolves within a few weeks after delivery:

  Delivery reduces mother's morbidity

  Exposes fetus to risk of premature birth
• Treatment of preeclampsia without severe features

  Managed conservatively with limited physical activity

  Close monitoring of blood pressure and renal function

  Careful fetal surveillace

  Delivery is recommended by 37 weeks gestation
• Treatment of preeclampsia with severe features

  Antihypertensive agents and IV magnesium sulfate (prevent seizures)

  Delivery recommended by 34 weeks gestation
• What is fetal tolerance characterised by?

  Fetal growth and Th2-type responses:

  Tolerance to allogenic fetus must be generated

  Potential for maternal immune system to recognise as non-self
• What don't trophoblast cells express in fetal tolerance?

  HLA-A or HLA-B

  Limits ability to activate T cells
• What do trophoblasts express in fetal tolerance?

  HLA-C (and non-classical HLA-E and HLA-G) molecules
• What happens when HLA-C molecules interact with uNK cells?


  Promote production of soluble mediators and trophoblast invasion but not cytotoxicity
• Regulatory T cells (Treg) and fetal tolerance

  Subset of CD4+ T cells

  Express tx factor FoxP3

  Act to suppress immune responses
• Where do cells present in fetal tolerance?

  In the decidua after implantation

  Favour an anti-inflammatory environment

  Characterised by Th2-type immune responses
• What do Decidual Macrophages have and what do they associate to?

  M-2 like phenotype

  Associated with tissue renewal and anti-inflammatory cytokines

  Phagocytosis of dying trophoblast cells prevent release of paternal antigen