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35 Cards in this Set
- Front
- Back
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What is immunological tolerance?
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Immune cells can attack your tissues. By restricting circulation of immune cells to lymph nodes, lymphatic system and blood stream, it prevents any autoreactive cell from gaining access to the tissues of your body it is capable of responding to.
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How are the APC, naive T cells and effector T cells efficiently directed to a central point in an immune response?
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Trafficking depends on 3 things:
1. inflammation 2. chemokines 3. adhesion molecules |
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How does inflammation work?
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Heat and redness occurs. The vascular diameter of blood vessels increases, increasing blood flow and allowing for T cells to get to lymph node quicker. In the capillaries, blood flow decreases to allow leakage of cells through endothelial cells into tissue.
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What two types of cytokines are induced by inflammation?
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1. pro-inflammatory cytokines e.g. tumour necrosis factor alpha (TNFa)- induce chnages in endothelial cells to promote inflammation and migration of T cells
2. chemotactic cytokines called chemokines |
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How do seven-transmembrane chemokine receptors work?
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Mediated by intracellular heterotrimeric G protein; subunits a, B and y. Inactive state: G protein binds GDP. Chemokine binding allows G protein to bind to receptor and replace GDP with GTP. It then dissociates into a and By subunits which can activate other proteins. a subunit then cleaves GTP to GDP, allowing for reassociation of subunits.
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What kind f activity do a and By subunits promote?
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Secretion of other molecules, change in surface molecule structures, change in motility of cell.
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What is the chemokine gradient?
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The stronger the concentration of appropriate chemokine, the stronger the signal for the cells to move there
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What are constitutive/basal trafficking or homing chemokines?
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Produced all the time. Expressed constitutively at homeing sites e.g. LN, skin, mucosa.
Receptors are mainly on lymphosites Regulate adaptive immunity (mainly) |
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What are inducible/inflammatory chemokines?
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Only produced when you're infected to signal that there is danger in the body. Produced by stromal cells and infiltrating cells at sites of inflammation Recruitor cells: monocytes, granulocytes, effector T cells.
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How did people think chemokines could be used to prevent autoimmunity?
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In diabetes, the T cells home in on the B cells in the pancreas, destroying them. People looked at most dominant chemokine in tissue and created antibody to block that chemokine, preventing it from moving in. It didn't work because chemokines have high redundancy.
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What is high redundancy?
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When one chemokine replaces another to do its job. This makes it hard for us to stop autoimmunity. But very good for the immune system (back up plans)
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What are the steps in chemokine action in an immune response?
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1. Pathogens induce inflammatory cytokines/chemokines from macrophages
2. Immature APC express CCR1, 5 and 6 - respond to inflammatory chemokines -move to site of inflammation to pick up Ag 3. After Ag uptake, APC down-regulate CCR1, 5 and 6 and up-regulate CCR7 -responsive to CCL19 and CCL21 -migrate via lymphatics to LN |
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What is CCR7
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Receptor on activated DC, naive T and B and central memory T cell, which binds to CCL19 and CCL21.
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What are CC19 and CCL21?
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Expressed by high endothelial venules, endothelium in lymphatics and stroma in LN. Different concentration of these in lymph node itself so that cells are directed to right compartments.
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What is the role of adhesion molecules?
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Allow for extravasation:
1. When approaching desired tissue, cells attach themselves to endothelial ells and start to roll, looking for a signal (primary adhesion) 2. Chemokines trigger conformational changes in adhesion molecules on leukocyte, leading to leukocyte activation. 3. This results in firm adhesion (secondary adhesion) 4. Cells move through basement membrane in diapedesis. |
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How are the different parts of extravasation controlled?
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Tethering and rolling = selectins
Activation of endothelial cells = chemokines Firm adhesion = integrins Transmigration = metalloproteinases |
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What is E-selectin?
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Constitutively expressed on endothelial cells.
Mediates neutrophil adhesion. Up-regulated by pro-imflammatory mediators (IL-1, TNF, LPS) |
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What is P-selectin?
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On activated platelets and activated endothelial cells
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What is L-selectin?
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Constitutively expressed on leukocytes down-regulated upon activation. Most important because they enable T cells to bind to the HEV lining secondary lymphoid tissues. Do this by binding to vascular addressins
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What are vascular addressins?
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Ligands containing carbohydrates. Different vascular addressins direct entry of leukocytes into particular tissues e.g. MadCAM-1 directs selectin-bearing cells into the mucosa.
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How do integrins stop the cell from rolling?
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LFA-1 is most common which helps tether cell to membrane. Usually heterodimers of a and B. Activated by chemokines results in conformational change that transforms their binding ligand for cells to bind.
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What do integrins bind to?
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Molecules of the Ig gene superfamily.
VLA-4 binds VCAM-1 |
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What is ICAM?
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Inter cellular adhesion molecule. Expressed on ECs and leucocytes at low levels. Up-regulated by IL-1 and TNF
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What is VCAM?
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A vascular cell adhesion molecule. Expressed on ECs only at sites of inflammation. Up-regulated by IL-1 and TNF
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How does an effector T cell get into infected tissue?
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Uses extravasation but it replaces CD62L and CCR7 with VLA-4 and LFA-1, releasing cell from recirculating via lymph nodes and allowing it to adhere to endothelial cells.
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What is a naive T cell?
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Cell which is specific for a particular peptide but it hasn't encountered it. Small.
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What is an activated (primed) cell?
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Proliferating and changing cell surface molecules. Large.
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What is an effector cell?
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Licensed to release all the effector molecules neccessary to deal with the pathogen. Large.
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How do integrins act on the immunological synapse?
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Stabilize it by binding LFA-1 with ICAM-1 (on APC), enabling prolonged contact of T cell with APC. This is signal 3.
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Why is it important that an activated T cell doesn't need signal 2?
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Effector CD8+ T cells must be able to act on any cell infected with a virus, whether or not the infected cell can express co-stimulatory molecules.
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What happens to T cells after the pathogen threat is eradicated?
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They die; interaction between FasL and Fas triggers apoptosis. The FADD (attached to bottom of Fas receptor) binds pro-caspases e.g. pro-caspase8 which trigger caspase cascade leading to apoptosis.
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How can the immune system ensure that you will survive subsequent attack by the same pathogen?
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It induces memory cells which are long-lived, small 'resting' cells. They do not need the presence of a pathogen for survival; there is a balance between proliferation and death. Express survival genes Bcl- and require cytokine IL-7 and IL-15. Have higher levels of integrins LFA-1 and CD2 on surface than naive T cells.
Have faster and more powerful response than initial activation. |
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What are effector memory T cells?
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Specialised for rapidly entering inflamed tissue:
CCR7 negative- don't go to lymph nodes Rapidly mature to effector cells Secrete large quantities of cytokines early after stimulation Express receptors for pro-inflammatory chemokines and integrins |
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What are central memory T cells?
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Specialised for migrating through lymphoid tissue:
CCR7 positive- circulate through lymph nodes Take longer to be reactivated than effector memory cells Do not secrete large amounts of cytokines Differentiate into effector T cells |
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Why are memory cells sometimes called sentinel cells?
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They have tissue-selective homing properties which enhance the efficiency of the immune system by targeting immune surveillance and effector responses to tissues most similar to those where the Ag initially entered the body.
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