Microimmune Lecture 21 Study Notes.docx

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Western University
Microbiology and Immunology
Microbiology and Immunology 3300B

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 lymphoid system -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) – apoptosis 7. What is antigen segregation? -most self antigens are retained outside of the lymphoid system by physical barriers (cell membranes/endotheliums) -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 privaledged membranes) -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 immune system? -innermost is the connective tissue, then the cytotrophoblast and the outermost is the syncytiotrophoblast 14.Which layer is in direct contact with the maternal blood? -syncytiotrophoblast 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 recirculates 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 mother 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 Rh+ -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+ child 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 immunologically ignorant -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? -anergy -series of processes which prevent immune responses in the peripheral tissues  antigen concentration  induced anergy  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 bodies 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 TCR/BCR -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
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