Fitzpatrick notes (Monday)

Take home some general properties of chemokines and cytokines and leucocyte migration. Do not memorize all of them.
3:Chemokines- small proteins tell leucocytess where to go. These molecules are often referred to as cytokines. Term from old literature. About 30 homologous polypeptides that tell naive T or B cells where to go. N terminal C residue defines their classification- divide into 4 families.
4:
1. CC1,2,3- chemokine. CCL-ligand. CCR-receptor.
2. CXC- ELR+ means ELR before the C.
6: Chart from immunobiology book. Ex of CXC class. Numbered based on when they were identified.
A lot of these have been renamed over time. Chemokines produced by a lot of cell types and can bind to more than one kind of receptor.
7: Chart continued. Do not memorize.
8: General Features
Endothelial- line blood vessels.
2 times produced:
inflammatory response-chemokines to tell where infection is. Upregulated during infection, then disappear.
normal homeostasis- tell leucocytes to go to lymphoid organs. Constitutively produced.
9: receptors named for ligands. T cells have a number of different chemokine receptors to tell them to do things at different times.
10: General scheme of receptor- 7 transmembrane helices. Bind to G proteins. Activate a number of pathways in cell.
11:
Chemokines are important for migration as well as other roles.
12:
Immune response- want innate system to respond to site of infection. Chemokines needed to tell cells where to go, and adhesion molecules need to be regulated. Immune cells need to adhere to extracellular matrix of collagen fibers and move through tissue. Binding of adhesion molecules allows cells to move.
13:3 families
selectins induce rolling along the endothelium (blood vessel lining). Slows neutrophil down- bind and release.
integrins- tight adhesion- stops and binds. Then can move into tissue
Ig superfamily- T cell binding to APC. Maintains contact.
14: What happens during inflammation? Endothelial cells normally do not express P selectin. as a result of infection, TNF and IL-1 cause P selectin to be expressed in an area of endothelium near the infection. Cells roll along.
15: In tissue- IL-8 produced and binds to receptor on endothelial cell to produce high-affinity integrin to bind to ligand. Contacts, binds to endothelial cell, and causes shape change in cell so it can squeeze between endothelial cells and into tissue. Inside- more chemokines cause crawling along structural framework to where infection is. Downregulate epxression- cell stops to do its job. Different chemokines attract different cells for the most efficient response.
16: Normal immune cell trafficking:
HOw do cells know to go to lymph node? Stromal cells produce CCL21. Dendritic cells have receptor CCR7. They migrate , bind, migrate into lymph node. T cells have same receptor. Lymph node has a lot of consttitutive production of CCL21,19, etc.
17:Cytokines:
regulate inflammatory response. Autocrine or paracrine.
18: General properties
1. Gene transcribed- there are bursts of cytokine production, and mRNA is degraded fast. All regulated by different means: mRNA degradation, cleavage for activation, post-translational modification, etc. Only neutrophils may store them in granules. All other cells secrete them.
19:
pleiotropic- act on different cell types.
20:
Cytokine cascades exist.
21:
Most produced locally and act locally. Sometimes large infections cause huge amount TNF and IL1.
22:
Bind specific receptors- high affinity. SMall amount produced, but physiologically important.
23: Stimulate T or B cell- upregulates cytokine expression.
24:
Cells respond by differentiating (T cells), activating function (macrophages and radical production), and cell proliferation (Tcells and IL-2- allows to enter S phase)
25: Receptors have similar features.
26: rest of talk. Same cytokines can have a lot of diff functions.
28: What happens when you have infection:
What immune cells normally live in tissues? macrophages and dendritic cells can bind microbes through pattern recognition receptors. Bind to cell wall and generate features. Pull in bug, chew it up, stimulate production cytokines. IL-1, 6,TNf act on vascular endothelium to tell them to upregulate adhesion molecules and produce more chemokines. Also increase vasccular permeability. Loosen tight junction. Gets inmmune cells and products to site.
Neutrophils are great killers .Live up to 24 hours and tend to move in first. IL-8 attracts them to chew up bacteria.
29: TNF
Block TNF, inhibit inflammatory response.
30: TNF- tumor necrosis factor- can cause apoptosis in some tumors.
31: Septic shock- systemic production of TNF, IL-1, IL-6. When in circulation, can affect organs. Fever, liver, appetite suppression, smooth muscle and heart problems.
32: whole body effects from cytokines.
36: local effects are favorable to clear infection. Systemic- blood volume decreases because of leaky vessels. Cells move into un- needed tissues. neutropenia signals influx from bone marrow. multiple organ failure results in death. Principle mediator- TNF. In human patients- blocking TNF does not work to prevent shock.
39:To stop inflammatory response, anti-inflammatory cytokines reduce response.
Ex: IL-10 shuts off recruitment of cells. Downregulate MHC class II and costimulatory molecules.
p13:
viral infections:
IFN alpha and beta secreted to act on other cell types. Bind to alphabeta receptor. Other cells stimulated to produce proteins to inhibit oligodenylate synthetase, to inhibit transcription of RNA and upregulate Class I MHC for presentation to cytotoxic T cells. ALso promotes development of Th1 cells and inhibits proliferation of cells.
14:
Macrophages and innate response activated. Cytokines like IL12 tell adaptive response what to do.
Th2- important for extracellular bacteria. Il-4 present directs this difference.
IL-12-Th1 response- cell-med response. Activate macrophages, etc.
IL-12- mediates innate and links innate and adaptive. Tells adaptive that infection is intracellular
Il-2: growth factor for T cells. Produced by activated T cells- autocrine growth factor.
Interferon gamma- no antiviral properties- principal activator macrophages.
19: during inflammation, cytokines can tell bone marrow to produce more cells.
Colony stimulating factors- stimulate differentiation progenitor cells.
back of handout- cartoon of cytokines and cell lineages.