4 - Inflammation - Angyal Flashcards
Overall, what is the key result of inflammation?
Allows immune cells, defence molecules, coagulation factors to reach site of infection or tissue damage.
More specifically, what are the 4 things that occur during inflammation that allows the body to clear an infection?
- dilation of arterioles, venues, capillaries
- increased blood flow and permeability
- immune cell migration into inflammatory sites
- release of inflammatory mediators once pathogen detected
What are the 5 classic signs of inflammation?
redness, pain, swelling, loss of functional, heat
what are the 7 inflammatory mediators that are released once a pathogen has been detected?
- lipid mediators, prostaglandins
- chemoattractants, fMLP
- chemokine and cytokines, CXCL8, TNFa
- complement, C3a/C5a
- clotting factors
- small molecules eg ROS, RNS
- vasoactive amines
Describe the FULL process of extravasation
1) cytokines released by cells @ site of infection cause endothelial cells to express adhesion molecules (eg selectins, ICAM-1). Leukocytes also express counter receptors to ICAM1 known as Integrins which form weak interactions.
2) neutrophils are captured by the P/E selectins when glycoproteins (Sialyl Lewis) binds to them. Integrins on neutrophils also bind to ICAM-1/VCAM-1 - adhesion
3) neutrophils can squeeze between endothelial cells through an increasing number of interactions (therefore making them stronger) -> DIAPEDESIS
How can chronic inflammation occur, why is this bad and what are the causes?
- when acute inflammation goes on for too long. inefficient release of anti-inflammatory cytokines and molecules released
- TB and autoimmune conditions can cause this
- depletes the body’s resources
What are the 3 systemic actions of cytokines?
autocrine - act on themselves eg T cells produce IL2 but also have receptors for IL2
paracrine - act on nearby cells
endocrine - travel in bloodstream to reach a far away target eg IL1 acts on hypothalamus
Is it only immune cells that produce cytokines?
no, non immune cells can too
What are cytokines commonly referred to as?
hormones of the immune system
Cytokines have pleiotropic effects - what does this mean
cells w/ same receptor can be stimulated by same cytokine but may result in different effects
How are cytokines grouped into families?
grouped based on structure but may have different functions
Describe the 5 main classes of cytokines
- TNF. Exist as TM proteins, need to be cleaved & act as trimers
- haemopoietin superfamily eg IL2/4/6. responsible for cell growth and differentiation in bone marrow
- IFNs - response to viral infection following recognition of viral ssRNA uncapped
- chemokines - responsible for movement of cells eg IL-8 induces chemotaxis of neutrophils
- IL-1 family. made as inactive precursor. require activation by inflammasomes (caspase action)
Give 2 examples of cytokines; name the cells that produce them and what their role is
- IL2. Made by T cells. Induce T cell growth and differentiation
- IL8. Made by macrophages, dendritic cells. Chemotaxis of neutrophils
Give the 2 main ways in cytokine receptors signal
- enzyme coupled receptor dimers (JAK/STAT pathway)
- GPCRs
Give some examples of cytokines secreted in the early induced immune response by macrophages/dendritic cells
- CXCL8. chemotactic factor which recruits neutrophils and T cells to site of infection
- IL6 - activation of lymphocytes, increased Ab production
- TNFa - increases permeability of vascular endothelium allowing increased entry of IgG and complement to infection site. also, increased fluid drainage to lymph nodes.
- both IL6/TNFa give rise to systemic effects eg fever
What is the typical structure of TNFa originally and how does it develop into the active structure?
exists as a TM protein that requires proteolysis/cleavage by macrophages. LPS is a potent stimulus. TNF forms trimers
Give the name of the TNF receptor family and state briefly that happens upon binding TNFa.
TNFR1 family. Binds TNFa as trimer therefore receptor trimerises -> signal. cross linking of 3 receptors
What are the local effects of TNFa?
- increased platelet adhesion to endothelial walls and influx of platelets. stops spread of infection through clotting of capillaries
- microthrombus formation. link between inflammation and coronary thrombosis
- efflux of fluid from capillaries to lymph nodes. APCs and dendrites can then stimulate the adaptive immune system
- increase in vascular permeability -> increased migration of lymphocytes / phagocytes to the surround infected tissue
What are the systemic effects of TNFa?
At less than 1ug/ml, TNFa can stimulate receptors all over the body. Leads to pyrexia (fever) which acts on hypothalamus, increases body temp to 39.5C (compliments the adaptive response), inhibits bacterial/viral replication.
Also causes cachexia (wasting/weight loss). thought to be protective effect against cancer, infection
What happens in a systemic infection with a G-ve bacteria?
SEPSIS - TNFa conc are > 1ug/ml in blood = dangerous. Exhaustion of clotting factors causes internal bleeding and infection spreading. increase in vascular permeability -> hypotension and reduced blood vol. Disseminated/widespread thrombus formation can lead to cardiac infarction and organ damage.
ALL leads to multiple organ failure and septic shock (80% fatal)
When are interferons produced and what do they do?
produced upon viral infection and interfere w/ viral replication
How can IFN genes be induced?
Induced following activation of TLRs (endosomal or cytoplasmic bound), RIG-I (intracellular) which detects viral ssRNA
Name the 2 types of IFNs and give examples of each
Type I/II
TI - IFNa/B
TII - IFNy
How do IFNa/B induce resistance to viral replication in cells?
IFNa/B binding - STAT pathway.
- inducing 2’-5’ linked adenosine oligomers which activate endoribonucleases which degrade viral RNA
- inducing production of PKR (protein kinase R) which inhibits eIF2 which stops translation initiation
- production of IFITs. suppress viral RNA translation
- induce NK cells to kill virally infected cells
- increase MHC class I expression to express the viral peptides. signal for these cells to be killed
How do naive CD4+ T helper cells differentiate into further subsets?
presence of specific cytokines in environment influence transcription and therefore differentiation into particular subset
Name a cytokine that stimulates differentiation of a naive T cell into a particular T cell subset. Name this T cell and what are its effector function (ie the new cytokines it produces)
IL-4 stimulates differentiation of naive T cell -> TH2 cells. produced IL4/5/13 and useful in response to helminth infections
