PREGANANCY

• Role of the immune system

  • Defense, but also important physiological roles in: Pregnancy, Turn-over of cells, Wound healing, Cytokine production has a variety of effects: Proliferation, angiogenesis, differentiation, Phagocytosis (e.g. M Φ, neutrophils)
• Immunological stages of pregnancy

  Initial misconception was host/graft relationship, Studies in non-pregnant models
• Fertilisation, cleavage, hatching


  1. Product of fertilisation – 1 cell diploid embryo

  2. Subsequent cell divisions

  3. Forms blastocyst

  4. Blastocyst release (hatching) into uterus lumen
• Implantation (1)


  • Blastocyst consists of: Inner cell mass, Outer layer of cells (trophoblast), Trophoblast is important in implantation, Differentiates into extraembryonic membranes surrounding the embryo
• Implantation (2)


  Developing blastocyte must invade the maternal decidua, Gain access to blood supply, Nutrient transport, Waste removal, Implantation resembles metastatic implant
• Implantation (3)


  • 3 main stages of implantation, Both implantation and metastasis result in inflammation
• Implantation (4)


  Apposition, Attachment, Invasion
• Implantation (5)


  • Trophoblast penetrate through the epithelium, Invades uterine stroma, Trophoblast cells differentiate to become syncytiotrophoblast, Inflammation, Supports angiogenesis, tissue remodelling, M Φ recruitment (apoptotic cell removal)
• Cells present in early pregnancy

  • M Φ, NK cells, and CD8+ T cells, T reg
• Inflammatory mediators in implantation

  M Φ, NK cells, others, IL-1, IL-6, GM-CSF and LIF-1 (leukaemia inhibitory factor), Changes in adhesion molecules on epithelial layer, Removal of mucin layer to allow attachment, Production of various proteases including matrix metalloproteases (MMP), ECM breakdown, Invasion of maternal decidua, Important for: Anchoring conceptus, Accessing maternal spiral arteries, Must be controlled to limit invasion
• Spiral artery remodelling (1)

  Maternal spiral arteries supply endometrium, Structurally transformed during early pregnancy, ~100x increase in blood flow, Arteries become capable of high conductance at low pressure, Reduction in velocity of the blood entering the placenta
• Spiral artery remodelling (2)

  Trophoblast cells induce maternal endothelial cell death, Replaced by trophoblast cells, Extravillous trophoblast cells (EVT) invade into the decidua
• Spiral artery remodelling (3)

  • Uterine NK (uNK) cells: Weakly cytotoxic, Potent source of immunoregulatory cytokines, MMP, angiogenic factors (along with M Φ), Factors mediate ECM remodelling, trophoblast invasion, angiogenesis, M Φ (Hofbauer cells): Remove apoptotic cells associated with spiral artery remodelling, e.g. maternal endothelial cells, apoptotic trophoblasts
• Clinical relevance of implantation

  Trophoblasts are highly invasive, Must be actively controlled by the maternal decidua, Excessive invasion: Uterine rupture, Maternal death, Insufficient invasion: Restricted fetal blood supply, Can result in miscarriage, fetal growth restriction (FGR) or pre-eclampsia
• Pre-eclampsia (1)


  • Periodic or continuous elevation in blood pressure, oedema, Proteinuria in severe cases, Affects ~4% of pregnancies, Severe pre-eclampsia can give rise to the convulsive state of eclampsia, Typically see in first pregnancies, develops in 3rd trimester, Associated with growth retardation, premature labour, low birth weight (FGR), placental abruption, future risk of maternal cardiovascular disease
• Pre-eclampsia (2)


  Genetic differences contribute, Failure of trophoblast invasion?, Poor placental perfusion may lead to formation of free radicals (oxidative stress, inflammatory responses), Environmental influences (e.g. obesity, maternal age, multifetal pregnancy)
• Pre-eclampsia (3)


  Diagnosis: The new onset of hypertension (blood pressure >140/90 mmHg) and proteinuria (either a 24 h urinary protein >300 mg/24 h, or a protein-creatinine ratio ≥0.3) after 20 weeks of gestation, Risk factors: Nulliparity, Multiple gestation, Diabetes mellitus, History of renal disease, Chronic hypertension, History of preeclampsia, Extremes of maternal age (>35 years or <15 years), Obesity, Antiphospholipid antibody syndrome
• Pre-eclampsia (4) – severe features

  • Severe elevation of blood pressure (>160/110 mmHg), Evidence of central nervous system (CNS) dysfunction (headaches, blurred vision, seizures, coma), Renal dysfunction (oliguria or creatinine >1.5 mg/dL), Pulmonary oedema, Hepatocellular injury (serum alanine aminotransferase level more than twofold the upper limit of normal), Haematologic dysfunction (platelet count <100,000/L or disseminated intravascular coagulation [DIC])
• Pre-eclampsia (5) - treatment


  Resolves within a few weeks after delivery, Delivery reduces mother's morbidity; exposes fetus to risk of premature birth, Women with preeclampsia without severe features: Managed conservatively with limited physical activity, Close monitoring of blood pressure and renal function, Careful fetal surveillance, Delivery is recommended by 37 weeks gestation, Women with preeclampsia with severe features: Delivery is recommended regardless of gestational age
• Conditions associated with pregnancy

  • Obesity
  • Antiphospholipid antibody syndrome
  • Pre-eclampsia
• Pre-eclampsia with severe features

  • New-onset hypertension, proteinuria, end-organ damage
  • Severe elevation of blood pressure (>160/110 mmHg)
  • Evidence of central nervous system (CNS) dysfunction (headaches, blurred vision, seizures, coma)
  • Renal dysfunction (oliguria or creatinine >1.5 mg/dL)
  • Pulmonary oedema
  • Hepatocellular injury (serum alanine aminotransferase level more than twofold the upper limit of normal)
  • Haematologic dysfunction (platelet count <100,000/L or disseminated intravascular coagulation [DIC])
• Treatment for pre-eclampsia without severe features

  1. Managed conservatively with limited physical activity

  2. Close monitoring of blood pressure and renal function

  3. Careful fetal surveillance

  4. Delivery is recommended by 37 weeks gestation
• Treatment for pre-eclampsia with severe features

  1. Antihypertensive agents and IV magnesium sulfate (prevent seizures)

  2. Delivery is recommended by 34 weeks gestation
• Fetal tolerance


  • Characterised by fetal growth and Th2-type responses
  • Tolerance to allogenic fetus must be generated
  • Maternal blood is in contact with the villous trophoblast (VT)
  • Extravillous trophoblast cells (EVT) invade into the decidua and intermingle with maternal tissue
• Trophoblast cells


  • Do not express the HLA-A or HLA-B, limiting their ability to activate T cells
  • They express HLA-C (and non-classical HLA-E and HLA-G) molecules
  • Interactions of these molecules with uNK cells promotes the production of soluble mediators and trophoblast invasion but not cytotoxicity
• Regulatory T cells (Treg)

  • Subset of CD4+ T cells
  • Express tx factor Foxp3
  • Act to suppress immune responses
• Decidua after implantation


  • Favour an anti-inflammatory environment
  • Characterised by presence of Th2-type immune responses
  • Decidual MΦ have an 'M2‑like' phenotype, associated with tissue renewal, anti-inflammatory cytokines
  • Phagocytosis of dying trophoblast cells prevents release of paternal antigen
  • MΦ IFN-β production allows protection against disease, without disrupting maternal tolerance
• Oestrogen and progesterone


  Promote Th2 and Treg responses
• Passive immunisation of the fetus

  • Involves maternal IgG transfer across the placenta
  • These are gone by ~6 months
• Labour


  • Characterised by increased myometrial contractility, cervical dilatation, and rupture of the chorioamniotic membranes
• Labour


  • Associated with a shift back to pro-inflammatory state
  • Impairments in shift (e.g. infection) may induce pre-term labour
• Pre-term birth


  • Birth before 37 weeks gestation
  • 5-18% of pregnancies
  • Leading cause of neonatal death
  • Neonates are at risk of complications due to immaturity of multiple organ systems
  • 2/3 pre-term births result from spontaneous premature onset of labour
  • 1/3 from maternal or fetal complications (e.g. pre-eclampsia or IUGR)
• Proposed mechanisms of disease implicated in spontaneous preterm labour

  • Genetic factors
  • Environmental factors
• Intrauterine infection


  • Primarily subclinical
  • Lower genital tract organisms, ascending from vagina
  • Maternal/fetal immune response activation
  • Maternal infection used as a model for pre-term birth, developmental defects etc.
• Intrauterine infection leading to preterm labour

  1. Bacteria from lower genital tract gain access to the amniotic cavity

  2. Stimulate production of chemokines and cytokines (IL-1α, TNFα)

  3. Inflammatory mediators (prostaglandins and reactive oxygen radicals)

  4. Proteases

  5. These products can initiate myometrial contractility and induce membrane rupture leading to pre-term labour
• Pregnancy


  • Associated with changes in susceptibility to, or severity of, infectious diseases
  • Associated with worsening or improvement of autoimmune diseases (dependant on underlying mechanism of disease)
  • Pregnancy is a time when additional vaccination will be considered
• 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