Microimmune Lecture 21 Study Notes
1. What is tolerance?
-non-responsiveness to an antigen
2. What is self-tolerance?
-non-responsiveness to self-antigens
3. What is acquired or induced tolerance?
-the suppression of a specific, systemic immune response to foreign antigens
induced by the specific actions of lymphocytes
4. What is fetal tolerance?
-the suppression of a specific, systemic immune response to foreign antigens found
within a developing fetus
5. What is oral tolerance?
-the suppression of a specific, systemic immune response against antigens
encountered via the enteric (oral) route
6. What are the layers of self tolerance?
-central tolerance (occurs in the bone marrow and thymus); deletion and editing
-antigen segregation (peripheral organs); physical barrier to self antigens; access to
-peripheral anergy (secondary lymphoid tissue) – cellular inactivation by weak
signaling without co-stimulus
-regulatory T cells (secondary lymphoid tissues and sites of inflammation) –
suppression by cytokines, intercellular signals
-functional deviation (secondary lymphoid tissues and sites of inflammation) –
differentiation of reg T cells that limit inflammatory cytokine secretion
-activation-induced cell death (secondary lymphoid tissues at sites of inflammation)
7. What is antigen segregation?
-most self antigens are retained outside of the lymphoid system by physical barriers
-in the absence of tissue damage these antigens are not encountered by immune
cells (because immune cells don’t see whats inside our cells – intracellular proteins) 8. What are the immune privileged sites?
-brain, testes, placenta and fetus and eyes
-our immune system is actively excluded from these tissues
9. Describe immune privileged sites,
-sites capable of tolerating the introduction of an antigen without eliciting a
damaging immune response
-tissue grafts into these tissues often can survive without immunosuppressive drugs
10.What are the mechanisms of immune privaledged sites?
-restricted entry of immune cells blood brain barrier
-expression of class 1b MHC in preference to classical MHC1 tend to present
formyl peptides not self antigens
-high expression of complement inhibitors
-local production of TGF beta
-minimal or no draining to the lymphatics
-constitutive expression of apoptosis-inducing ligands (FASL and TRAIL)
-tissue-specific immunomodulation (placenta: expression of indolamine 2,3
dioxygenase (IDO) remove tryptophan, preventing T cells from proliferating T
cells cant make their own tryptophan; need it from the outside environment (breaks
down tryp and inhibits T cells within the placenta)
11.What is the FAS/FASL system?
-free floating Fas protein with its death domain
-trimeric Fas ligand binds to and trimerizes Fas
-clustering of the death domains (DD) in the Fas cytoplasmic domains allows Fas to
recruit FADD via its death domain (DED)
-DED and FADD recruit procaspase 8 via similar DEDs in the procaspase
-this allows immune tissue to kill incoming immune cells (on our immune
-on immune privaledged sites: causes death of incoming immune cells
12.Why is a fetus foreign?
-50% of a fetus’s proteome is foreign (from the father)
-some antigens won’t even have “close matches” in the maternal genome
-a male child has over z dozen genes with no homologs/paralogs in the mother
(very unlikely that male and female spouses will have the same MHC molecules)
-because the genes are different; MHC haplotope will be different rejection
similar to a transplanted tissue 13.What are the 3 layers of cells that stand between the mothers and fetus
-innermost is the connective tissue, then the cytotrophoblast and the outermost is
14.Which layer is in direct contact with the maternal blood?
15.Does the maternal blood come into contact with the fetal blood?
-no, structure of fetal tissues go into the placenta, arteries/veins/capillaries, blood
perculates through (fetal)
-this tissue is submerged in the placenta which is full of maternal blood
-maternal blood flows into the placenta, contacts the syncytiotrophoblast then
16.Discuss the placenta as a physical barrier
-immune cell entry is limited by the syncitium (fused cells) that separate the
mothers blood and the fetus blood
-huge sheet of cells fused together that provide few junctions for immune cells to
enter (would have to drill through them)
17.Discuss the placenta as an immune barrier.
-no HLA-A/B/C expression (no MHC 1)
-HLA-E and G are expressed instead: minimally polymorphic (not much variation);
interact primarily with NK cells (prevent NK cells from attacking the placenta
thorugh missing self mechanism)
-maternal Treg cells present in large number (suppress TH1/2)
-neurokinin B, IDO & phosphocholine suppress immune responses
-high expression of FASL
-all are acting to maintain seperation/non reactiveness between the fetus and
18.Discuss maternal to fetal transfer of antibodies.
-fetus’s don’t have an adaptive immune system (T/B cells)
-getting passive immunization through maternal blood/milk
-fetal placenta and neonatal intestines transport IgG into the fetus/neonate
-there are specialized Fc repcetors(FcRn) that bind IgG and transport it across the
epithelial layers via transcytosis 19.Discuss transfer through the intestines.
-FcRn on the neonatal intestinal lumen side (low pH) grabs IgG; internalizes it in an
endosome and FcRn releases it into the neonatal blood
-Fc receptor binds and transports it across via transytosis
20.Discuss transfer through the placenta.
-maternal blood is taken up into the syncytiotrophoblast; fuses with an early
endosome; its acidified; then released into the fetal circulation at physiological pH
21.What is Rhesus Disease?
-if your Rh+ you have the antigen found on your RBC
-if your Rh- then you don’t
-if a woman is Rh- and has a child with somebody that is Rh+ then the baby could be
-during pregnancy the blood doesn’t make contact however when the placenta
detaches some of the blood can mix
-the maternal blood will start making antibodies against this foreign antigen
-therefore the first born is unaffected but in the second pregnancy: the antibodies
are transferred across the placenta so it will attack the child
-can result in low birth weight or miscarriage
-this occurs with A+ blood type and O- blood type
22.Discuss prevention of Rh disease.
-Rh- mothers are injected with purified anti-Rh IgG soon after birth of every Rh+
IgG will bind fetal blood cells and destroys them through compliment mediated
lysis before the maternal B cells have a chance to see it; so the mother will remain
-any Rh+ cells which transfer to mother during birth are destroyed before an
immune response can be induced
-developed by Jack Bowman (1925-2005) at Winnipeg Childrens Hospital
23.What is peripheral tolerance?
-series of processes which prevent immune responses in the peripheral tissues
removal of germinal centre B-cells -if they are too autoreactive they are cleared
-little activity is selected for
-if they ever got reactive though they could induce an autoimmune disease
-peripheral tolerance keeps mildly auto reactive cells from causing harm in our
24.What is antigen concentration?
-this is key to maintaining peripheral tolerance
-at a low concentration of antigens there is insufficient antigen to activate the
-essentially immunological ignorance
-these cells can be later activated with co-stimulation
-not really a mechanism of control
-at a high concentration of antigens; BCR: antigens usually are non-crosslinking so it
doesn’t activate the cell (self antigens)
-strong stimulation of the BCR or TCR may induce apoptosis (AICD = activation
induced cell death = prevents excessive immune response and removes auto
reactive T cells
25.What is AIC