L19: Immunology and Pregnancy Flashcards
What does allogeneic mean?
Genetically different
What does syngeneic mean?
Genetically identical
What are the mechanisms of transplant rejection?
- T cells - T helper (Th) cells and Cytotoxic T Lymphocytes (CTLs)
- antibodies
- NK cells
- innate effector cells - macrophages, neutrophils etc
What are the two immune system arms?
Innate and adaptive
What describes innate immune system? What are the example cells?
- cells and molecules that recognise ‘danger’ - pathogens or damage and kill immediately
- examples: NK cells, macrophages, neutrophils, complement
What describes adaptive immune system? what are the example cells?
- cells that recognise ‘non-self’
- require the innate immune system for activation
- slow at first encounter (primary response), but has ‘memory’ - can respond much faster and more effectively on subsequent exposures (secondary response)
- examples: T and B cells, antibody
What describes B cell receptor?
- recognise soluble antigen
- produce antibodies and have antigen-specific receptors
- antigen-binding region made in an entirely random way
- each B cell has a unique specificity
What is negative selection of B cells?
During development those random antigen specific receptors that bind to self-antigens are deleted/killed - negative selection
What happens when antigen-specific B cells are activated?
They produce antibody - soluble version of the BcR, binds to pathogens/foreign tissue - targets them for killing
How does T cell antigen recognition work?
- T cell receptor (TcR) analogous to antigen-binding region of an antibody/BcR - BUT CANNOT bind soluble antigen directly
- antigen peptides must be presented on MHC molecules
- TcR binds both self-MHC and foreign peptide
What is negative selection of T cells?
During development those random antigen specific receptors that bind to self-antigens are deleted/killed - negative selection
What is positive selection of T cells?
- T cells must also recognise ‘self’ MHC
- T cells with random receptors which do not bind to self MHC also deleted/killed – positive selection
What’s the function of MHC molecules?
The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells.
What are the two classes of MHC? What are their differences?
- Class I MHC present intracellular antigens to Cytotoxic T Lymphocytes (CTLs)
- Class II MHC present extracellular antigens to helper T cells
Where can MHCI be found?
on all nucleated cells (not red blood cells) except for neurons
Where can MHCII be found?
only on specialised ‘antigen presenting cells’ eg dendritic cells, macrophages
What are naive T cells? what do naive T cells differentiate to?
- T helper cells which have not yet seen their specific antigen (on MHCII) are termed ‘naive’
- naive T helper cells, when activated, will differentiate into TH1, TH2 or Treg
- which subset they differentiate into depends on signals from the innate immune system
What are Th1 cells?
Inflammatory, good for killing bacteria, but can cause tissue damage/autoimmunity/transplant rejection
What are Th2 cells?
- kill parasites, and can cause allergy - much less damaging and inflammatory
What are Treg cells?
- Regulatory T cells
- supress other immune responses and control autoimmunity
What are CTLs? What is their function?
- Cytotoxic T lymphocytes
- if viral or mutated peptides (non-self) presented on MHC I - killed by CTL
- induces apoptosis through perforin/granzyme release
- protects against viruses/cancer
What are the T cell responses to allografts?
- T cells either recognize foreign cells directly (due to non-self MHC) or non-self antigens are presented to T cells on their own MHC
i) Either way, get immune response and killing of non-self cells - If T cells can only recognise antigens on MHC, why not have the foetus switch off MHC to escape T cell responses
i) Because of killing by NK cells
What are NKs?
- natural killer cells - innate immune cells - no variable antigen-specific receptors
- primed to kill any cell unless they’re told not to
- have killer-cell inhibitory receptors (KIR)
- KIR bind MHC on surface of cells and prevent killing
- so if cell downregulates MHC to escape T cells, NKs kill it instead (viruses and tumours do this)
Why doesn’t the immune system attack the foetus?
- immune-privileged site
- placental membrane is a syncytium
- no cell junctions for maternal immune cells to migrate between (extravasation)
- decidua also lack lymphatics - required for entry and exit of immune cells
- antibodies can get through though
Does foetal tissue express MHC?
- Foetal tissue express no MHC II, and little MHC I
i) Classical MHC I molecules – HLA-A, HLA-B, HLA-C
ii) These are on all nucleated cells - Foetus expresses no HLA-A or HLA-B but some HLA-C
i) Escapes most CTL responses
What immune cells does decidua contain?
- Decidua packed full of NK cells (rare cells elsewhere)
- Decidua -> 70% NK, 20% macrophages, 10% T cells
- With MHC downregulation, these should be primed to kill foetal cells
- However NK doesn’t kill them, because foetus expresses HLA-E and HLA-G (non-classical MHC)
- Bind to NK cell inhibitory receptors
If MHC are downregulated, why do NK cells not kill foetal cells?
- However NK doesn’t kill them, because foetus expresses HLA-E and HLA-G (non-classical MHC)
- Bind to NK cell inhibitory receptors
What are dendritic cells? Are they common in decidua?
- dendritic cells: antigen-presenting cells essential for T cell responses
- very rare in decidua
- may not be able to exit to lymph node where antigen-presentation occurs - lack of lymphatics (entrapment)
- produce IDO - immunosuppressive
- tolerised phenotype - do not produce as high levels of inflammatory cytokines (IL-12) as normal DCs when stimulated
- will tend to induce a TH2 response (non-inflammatory) rather than a TH1 response (damaging)
Which response do decidua dendritic cells induce?
will tend to induce a TH2 response (non-inflammatory) rather than a TH1 response (damaging)
What is the function of decidua macrophages?
- Macrophages – type of phagocyte, very broadly speaking:
i) Can be inflammatory, kill invaders and cause tissue damage – clasically activated/M1
ii) Or anti-inflammatory, involved in tissue repair – alternatively activated/M2 - Peri-implantation decidua macrophages are M1 dominant – promote embryo attachment to decidua
Later: - Decidua macrophages are CD209+ and of M2 phenotype dominant-support foetal development and anti-inflammatory
- Also express IDO and IL-10 – both immunosupressive
- Similarly to decidua NKs, have roles in reorganisation of vasculature in early pregnancy
How does apoptosis of foetal specific T cells happen?
- Further line of defence vs T cell responses: kill antigen-specific T cells
i) In an OVA-expressing foetus, maternal OVA-specific CTLs proliferate only a little, activate poorly and die - Foetal trophoblast and endothelium expresses FasL
i) FasL binds Fas on activated T cells, killing them
ii) FasL-mutant mice get inflammation and necrosis in the foetus - Apoptosis of inflammatory cells due to galectin-1 (Gal-1)
i) Gal-1 expressed by decidua NKs, macrophages and endometrium
ii) Induces apoptosis of activated (inflammatory) T helper cells
iii) Induces suppressive DCs, which in turn produce Tregs
iv) Gal-1-KO mice lose allogeneic pregnancies, but not syngeneic pregnancies
v) Recombinant Gal-1 precents foetal loss
What is FasL?
- Foetal trophoblast and endothelium expresses FasL
i) FasL binds Fas on activated T cells, killing them
ii) FasL-mutant mice get inflammation and necrosis in the foetus
What is galectin-1 (Gal-1)?
- Apoptosis of inflammatory cells due to galectin-1 (Gal-1)
i) Gal-1 expressed by decidua NKs, macrophages and endometrium
ii) Induces apoptosis of activated (inflammatory) T helper cells
iii) Induces suppressive DCs, which in turn produce Tregs
iv) Gal-1-KO mice lose allogeneic pregnancies, but not syngeneic pregnancies
v) Recombinant Gal-1 precents foetal loss
What is IDO? what is its function?
- IDO (indoleamine 2,3-dioxygenase) expressed by decidua and trophoblast
- catabolises tryptophan to metabolites such as kynurenine and picolinic acid, both of which inhibit T cell and NK activation
- Kyurinine also induces apoptosis of TH1 but not TH2 cells
- chemical inhibition of IDO leads to rejection of allogeneic but not syngeneic fetuses
What is the role of T-regs? What is the evidence proving it?
- In normal pregnancy, high proportion of blood and decidua T helper cells are Tregs
i) When on has spontaneous abortion: reduced decidua Tregs, increased inflammatory T helper cells
ii) Pre-eclampsia: reduced Treg expansion, increased blood inflammatory:regulatory T cell ratio - Depleting Tregs early in allogeneic pregnancy – reduced viable offspring
i) No effect of depletion in syngeneic pregnancy - CNS1-KO mice lack ability to make new Tregs
i) Still have self-specific natural Tregs to precent autoimmunity
ii) Have similar rates of pregnancy resorption to total Tref depletion - Tregs induced by TGF-beta, Gal-1 and IDO (all highly expressed by placenta/decidua)
- Also can prevent foetal immune system from attacking mother
What is the evidence proving role of Tregs?
- CNS1-KO mice lack ability to make new Tregs
i) Still have self-specific natural Tregs to precent autoimmunity
ii) Have similar rates of pregnancy resorption to total Tref depletion
What induces Tregs?
- Tregs induced by TGF-beta, Gal-1 and IDO (all highly expressed by placenta/decidua)
What is the role of Phosphocoline (PC)?
- synthetic compound
- Head group from the membrane phospholipid phosphatidylcholine
- Phosphocholine (PC) can be a post-translational modification on proteins, attached to carbohydrates on proteins
- Is immunosuppressive – suppresses T and B cell proliferation, and suppresses inflammatory responses in Rheumatoid Arthritis
i) Presently being developed for clinical trials in RA - Proteins expressed by the foetus are modified with PC, especially Neurokinin B
- Same technique used by some parasitic worms to evade immune system – highly successful xenotransplants
What is the complement system that helps foetus against being attacked?
- Complement – system of soluble proteins in the serum
i) Activation (antibody-mediated or spontaneous) results in a cascade of cleavage, activation and inflammation
ii) Finally results in the formation of the membrane attack complex – forms a lysing pore in cells - Crry – complement control protein – prevents deposition of C3 and C4
i) Expressed by placental trophoblasts
ii) Crry-KO mice do not have successful births
What is the complement control protein? What is the evidence proving it?
- Crry – complement control protein – prevents deposition of C3 and C4
i) Expressed by placental trophoblasts
ii) Crry-KO mice do not have successful births
What happens during Haemolytic Disease of the Newborn (HDN)?
- Caused by a maternal antibody response to paternal antigens on foetal red blood cells
- Destroys RBCs, results in anaemia, jaundice, brain damage and death of newborns
i) Lysed red blood cells release haemoglobin, which is broken down to bilirubin
ii) Bilirubin turns skin yellow and enters brain, building to toxic levels and causing brain damage - Why does this maternal antibody response develop and get through all the defences?
What causes HDN?
- Caused by a maternal antibody response to paternal antigens on foetal red blood cells
How does passive immunity of fetus form? Why is it important?
- During pregnancy, maternal antibodies (IgG) are transferred to foetal bloodstream
- On Neonatal antibody receptor (FcRn)
i) Transfers antibodies from maternal bloodstream across placenta to foetus - On birth, maternal IgA is delivered to babies gut via breast milk
i) IgA adapted to protect from intestinal infections - Allows baby to be born already possessing ‘passive immunity’ against common pathogens
i) Prior to development of baby’s own immune system
On which receptor are antibodies transferred from mother to foetus?
- On Neonatal antibody receptor (FcRn)
i) Transfers antibodies from maternal bloodstream across placenta to foetus
How are maternal IgA transferred after birth?
- On birth, maternal IgA is delivered to babies gut via breast milk
i) IgA adapted to protect from intestinal infections
What is Rhesus disease? How are subsequent pregnancies affected?
- When mother is Rh- and father is Rh+ (1 in 10 pregnancies) problems can occur
i) First pregnancy is fine – mother’s immune system has never seen Rh, so doesn’t have any anti-Rh antibodies
ii) At first delivery, foetal blood is released from the placenta into the mother
iii) An anti-Rh antibody response is raised
iv) On subsequent pregnancies, anti-Rh antibodies enter foetus and destroy red blood cells
v) Each pregnancy boosts maternal response, so each birth has worse symptoms - Can also affect O mother with AB fathers
i) Disease generally less severe due to nature of AB antigens
How is blood group determined?
- A, B and O groups, and Rhesus factor (Rh)
i) Shortened to eg A+ (A blood group, Rh-positive) - A and B are different sugars, while Rh is a protein on the surface of red blood cells
What is the treatment available for HDN?
preventative:
- parents are blood screened prior to birth, if mother Rh- and father Rh+, may test fetus by amniocentesis; mothers also tested for anti-Rh antibodies
- if foetus Rh+ then anti-Rh antibodies given during pregnancy and 24-48 hours after birth - binds Rh antigen and prevents mothers immune system from being sensitised to it
therapeutic:
- if baby affected mildly: may give UV treatment - breaks down bilirubin
- affected moderately: blood transfusion after birth to combat anaemia, and UV treatment
- affected severely: Rh-negative blood transfusion given to foetus every 10-21 days of gestation, followed by treatment on birth
