Lecture 19; Immunity in Reproduction Flashcards
What are the three major branches of the immune system;
Physical barriers
Adaptive Immunity
Innate Immunity
When does the first barrier to infection (Skin) develop?
Outer layer of epithelium (Stratum Corneum) builds up to several layers during the third trimester
What do preterm babies (<30 weeks) have an increased risk for?
Preterm infants <30 weeks are at increased risk of infection due to underdeveloped skin
At what point does skin provide ‘adult’ protection?
2–3 weeks post partum skin provides “adult” protection regardless of gestational age
Describe the genesis of neutrophils in the fetus;
- 6–8 wks Yolk sac
* 8–12 wks Liver & bone marrow
What happens to preterm babies neutrophil count?
• Low number of neutrophils found in mid
gestation fetuses & preterm infants
• Preterm neutrophils functionally deficient (e.g. migration, adherence)
What produces macrophages and monocytes in the fetus?
Monocytes & macrophages
• Yolk sac 1st trimester
• Bone marrow 2nd trimester
Despite producing adult numbers of macrophages and monocytes, what is wrong with these in the fetus?
• Fetus can produce “adult” numbers but function is reduced
– Reduced synthesis of cytokines (e.g. GM-CSF, IL-6) – Reduced response to GM-CSF
– Reduced migratory activity
In terms of leukocytes, what is one of the dominant cells in the fetus from early on?
- One of the dominant fetal cell types in the placenta, especially in the 1st trimester
- Function is unknown (potentially vasculature development)
When does complement synthesis in the fetus occur?
• Synthesised by fetus
– At term 50% of adult levels
– Adult levels reached by 6–18 months
Summerise the development of the innate immune system in the fetus;
• Components are produced in different tissues/locations during gestation
• Most components are present at birth (term)
• Most components have reduced
function/quantity
• Some components have non-immune roles
Where do fetal B cells develop?
- 3 weeks Yolk sac
- 8 weeks Liver
- 12 weeks Bone marrow (30 weeks exclusive)
At 10 weeks the pre b cells that are produced, what are their functions?
– In mice become anergic upon exposure to antigen – Help to induce tolerance to self antigens?
Describe the b cell immunoglobulins produced over time in the fetus? I.e their receptors
- week15–IgM
- week20–IgG
- week30–IgA
(class switching)
What are fetal b cells more susceptible to?
Tolerance
At what point are the adult levels of B cells?
22 weeks
At what point in time can a humans B cells isoswitch easily?
• Fetal/neonatal B cells differentiate to IgM secretory cells readily, but do not readily undergo class-switching to IgG or IgA secretion until 2 and 5 years respectively
At what point does the thymus develop?
• Thymus is formed by 8 weeks (rudimentary )
16 weeks is similar to term structure
Where do preT cells initially come from?
• Pre T cells migrate to thymus from yolk sac, liver & bone marrow from ~8 weeks
At what point do we see adult levels of T cells?
• 16–20 weeks T cells and T cell subpopulations CD4+ & CD8+ at adult levels
Are the genes of fetal APC similar to adult ones?
Gene expression mapping shows fetal and adult APS express similar genes
What are the fetal DC genes?
- DC1
- (Conventional) cDC2
- CD14+monocyte/macrophages
- Fetal APCs in midgestation express tissue specific markers (eg lung cf gut)
what is the inflammatory profile like in the fetus?
The fetus has a stronger anti-inflammatory profile than inflammatory
At what point do DC start to circulate the lymphatics?
Gut and skin DCs migrate in lymphatics to lymph nodes from 16 weeks
What point do T cells enter the lymph nodes?
• The lymph nodes contain T cells from 10 weeks
When can the fetus mount a conventional T cell mediated response?
• Can mount a conventional T cell mediated
response from about 17 weeks gestation
How do Fetal DCs differ in mixed lymphocyte reactions to adult DCs?
– Fetal DCs induce CD4+, CD25+, FOXP3+ CD127- CTLA4+ Tregs preferentially
– Fetal DCs stimulate CD8+ T cells less than adult DCs
What point is the fetus capable of mounting an acquired immune response?
• 20 weeks the fetus has the capability to mount an acquired immune response
– i.e. B cells (IgG/IgM) and T cells (Tc/Th)
At what point is the fetus capable of producing a term antibody production response?
Preterm infants >23 weeks can mount an immune response (antibody production) similar to a term neonate
Is the uterus sterile?
No placental microbiome
How can the fetus gain immunity?
• Fetus gains immunity by ACTIVE transport of IgG from maternal blood across the placenta
What receptor is necessary for the active transport of IgA across the placenta?
• Requires a specific receptor
– FcyRn – consists of b2 microglobulin and an HLA-like a chain- binds IgG in acidic endosomes (pH 6.0)
When does most maternal IgG transport occur?
• Most IgG transport occurs after 22 weeks
– Maternal levels reached at 34 weeks then exceeded
When does the fetus begin to produce its own IgG?
• Following delivery (and exposure to antigen) the neonate begins production of Ig’s
What is another source of aquired immune response?
Breast feeding
What is in breast milk that makes it an aquired immune response;
– lgA major immunological factor in milk
– 5–7.5 mg/L slgA (more in colostrum)
– Breastfed infant up to 0.5 mg lgA/day
– Sterile gut of neonate rapidly colonised by various species e.g. E. coli, Klebsiella
What is responsible for Haemolytic disease of the new born?
Maternal immune reaction to Rh antigens, particularly Rh D is responsible for HDN
• The Rh (rhesus) blood antigen system differs from the classical A, B, O groups
What is haemolytic disease of the new born?
- Mum Rh- & dad Rh+ then babe will be Rh+
- Fetal blood into maternal circulation
- Sensitisation of maternal immune system & anti-Rh antibodies
- In subsequent pregnancies antibodies cross placenta & destroy fetal RBCs (not a problem in first pregnancy)
How can haemolytic disease of the newborn be tested for?
1) Direct Test (AB there)
2) Indirect test (AB added)
What are the treatments for HDN?
Anti D Prophylaxis
Interuterine Transfusion
Intravenous Immunoglobulin
What happens in anti D prophylaxis?
– Antibodies to Rh D antigen produced in volunteers by RBC immunisation
– γ globulin fraction purified & administered to Rh- mothers of Rh+ babies following delivery
– Passive immunisation destroys transfused fetal RBCs before a strong maternal response
What happens in interuterine transfusion?
– Used for Rh-ve women who already produce antibodies to Rh antigens (due to previous Rh +ve pregnancy)
– A fetus effected by HDN is transfused in utero with maternal-compatible blood injected into an umbilical vessel or the abdominal cavity
– Initially done using x-ray guidance now much improved by use of ultrasound
What happens in intravenous immunoglobulin?
– Alternative to intrauterine transfusion
– Mechanism not clear
• Possibly occupying Fc receptor sites, thus competing with the anti-D sensitised neonatal erythrocytes & preventing further haemolysis
How does the placenta protect from autoantibodies?
- IgM/IgA autoantibodies do not enter the fetal circulation e.g. rheumatoid factors, ANA
- Organ “non-specific” antibodies may encounter their antigen and be trapped in the placenta - the placental “sink”
Do all autoantibodies not cross the placenta?
• Many autoantibodies do cross the placenta
– Cause symptoms in fetus
• Myasthenia gravis: acetyl choline receptor antibody
• Thyrotoxicosis: antibody stimulates thyroid
• These autoantibodies induce transient disease which resolves upon catabolism of the maternal antibody
What autoantibodies can cause still birth?
- Fetal death (still birth/miscarriage)
- Exact mechanisms unknown but appear to attach the placental trophoblast
- Rapidly enter the syncytiotrophoblast via receptor (not FcRn) mediated process and disrupt mitochondrial function
