Immunology of Reproduction Flashcards
What is the clonal selection theory?
One lymphocyte expresses many of the same kind of receptor and another lymphocyte does another. When an infection occurs the antigen binds and causes clonal expansion only in the lymphocyte with its receptor. Diversity is achieved by random gene rearrangement (RAG genes) and somatic mutation.
What is immunological tolerance?
Self reactive B and T cells getting eliminated in the bone marrow so that they do not cause autoimmune diseases etc. This is central tolerance or peripheral tolerance (if lymphocytes found in other tissues apart from lymphopoiesis).
What two cases clonal expansion does not work?
Fetal development as they are made up of half antigenically foreign material to the mother
Transplants as differences in this cause histo-incompatability and rejection.
What are the genes that encode histocompatability?
Polygenic (gene duplication) and polymorphic (multiple alleles) which differ between individuals
Is the placenta a barrier against the immune system and why would one be needed?
Sort of
Physiological adaptations in the uterus and immunological adaptations to avoid maternal rejection
What is a haemochorial placenta?
Maternal tissue layers all removed and the fetal chorian sits in mothers blood
Found in humans
What is the endotheliochorial placenta?
Maternal uterine epithelium and connective tissue removed, endothelial basement membranes in contact with fetal chorion
What is the synepitheliochorial placenta?
Maternal uterine epithelium removed in places, connective tissue in contact with fetal chorion
What is the epitherliochorial placenta?
Maternal uterine epithelium intact and in contact with the fetal chorion
Does maternal and fetal blood mix in the haemochorial placentation as thisis a mixture of fetal and maternal cells?
No
What diseases can be caused by this maternal/fetus barrier not being good?
HDN (see slides about this)
How does passive protection occur then through this barrier?
Syncytiotrophoblasts express the neonatal Fc receptor (FcRn) which binds IgG and facilitates antibody transfer through the placenta delivering passive protection
Does the fetu express paternal molecules?
Yes
How does the placena get maternal blood to the chorion?
EVT invasion into the decidua opens up the arteries (blood supplies never mix though).
What molecules are responsible for tissue rejection during transplants?
MHC
WHat are the allelic variations of MHC class 1 and 2?
MHC class 1 = (MHC-A, MHC-B, MHC-C = these are classicla), (MHC-E, MHC-F, MHC-G these are non-classical)
MHC class 2 = MHC-D
What MHC’s do EVTs express and why might this help them not be destroyed by the mothers immune response?
HLA-C, HLA- E, HLA-F and HLA-G and these are all lowly polymorphic so could be the exact same as the mothers and therefore not destroyed
The pregnant uterus and NK cells?
uNK cells differ from NK cells found in the peripheral blood of the mother and these can spot any missing MHC which is why removing MHC would not pretect the fetus
How are CD8+ T cells and NK cells activated?
NK cells are on all the time and are switched off the the MHC on cells secreting cognate signals.
CD8+ T cells are switched off unless they get signals from foreign antigens which turn them on
What is the activatory and inhibitory signals NK and CD8+ T cells receive and how does this work?
KIR and CD94/NKG2
KIRs are made up of long and short tails. The Long tail has inhibitory motifs (ITIMs) whilst the short has activation motifs (ITAMs). There are two haplotypes A and B.
What does B haplotype contain?
KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, KIR3DS1 (all activatory apart from KIR2DL5)
What does A haplotypes contain?
KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL3 and KIR2DS4 (the only one which is activatory)
What do activated uNK cells produce?
Factors important for remodelling of spiral arteries and trophoblasts invasion
What are do all HLA-C allotypes bind to, give one example of a mother, fetus combo that does not make uNK cells and one that does?
KIR
HLA-C2 binds to KIR2DL1 and KIR2DS1 (A and B haplotypes and is inhibitory)
Which means KIR AA homozygous mum and C2C2 fetus doesnt make uNK cells
Remeber A and B are haplotypes so
KIR AB mum or KIR BB mum gives activatory signals
What does HLA-E bind to?
CD94/NKG2 which is inhibitory
What does HLA-F bind to?
No idea
What does HLA-G bind to?
KIR2DL4 but they dont know what this does
What do KIR-HLA interactions determine?
uNK (which is needed) activation and function which influences pregnancy outcomes
What types of uNK cells are there and what do these do?
uNK1 regulate placentation due to localisation, characteristics and interactions with EVT
uNK2
uNK3 = immune defence by producing high IFN gamma
Is there a spectrum of MHC/KIR signals?
Yes
What regulatory cytokines are found in the placental microenvironment?
IL-10 and TGF-beta
Tryptophan degradation by fetal trophoblasts IDO tolerizes maternal CD8+ve T cells in paternal antigens
Is the mother fully immunosuppressed during pregnancy?
No as this would be bad for baby
What happens to some autoimmunity in pregnancy and what does that lead you to discover?
Rheumatoid arthritic and MS go into remission and SLE (lupus) flares up.
RA and MS are associated with TH1/proinflammatory cytokines (IFn-y) whereas SLE with TH2/Inflammatory cytokines (IL-4, IL-5 and IL-13).
There is less IFN-y in the maternal periphery resulting in a TH1/Th2 shift.
What elevated cytokine ratio predicts pregnancy failure?
Th17 and Treg
What cytokines and hormones could explain how RA and MS go into remission and SLE flares up during pregnancy?
Oestrogens and progesterones inhibit Th1 and Th17 whilst promoting Th2
Instead of being immunosupressed what does pregnancy do to the immune system?
Modulates it
