L2-4 Flashcards
LO: Define the main pattern recognition receptor (PRR) families
PAMPS -(Microbial non-self) Recognition of patterns of molecules (PAMPS) found on pathogens and not usually on host cells. These are ‘essential’ to the pathogen, highly conserved.
DAMPS (Consequence of injury of infection) Endogenous molecules to alert the host to tissue injury and initiate repair.
- Intracellularly PRRs identify DNA/RNA outside the nucleus.
- ECM fragments released in response to injury eg. proteins like Tenascin-C (seen in asthma).
Missing Self - Cells express MHC in ordinary health to express host proteins to the immune system (inhibitory signal). If cells lack host MHC, they are killed by NK cells.
LO: Understand the basic concepts concerning the innate immune response during respiratory disease.
Innate immunity
Rapid host defence
We are born with it and it remains unchanged
Evolutionarily conserved
Involves recognition of invading pathogens and activation of response
Emerging as a critical mediator of inflammatory diseases and implicated in the development of some diseases
LO: Briefly summarise the vascular and cellular response to PRR activation using TLR4 as the
example.
TLR4 is a RTK located on the cell surface of sentinel cells such as macrophages, dendritic cells, mast cells and exposed epithelial cells.
In response to viral infections, TLR4 translocates to endosomes where it is bound/activated by pathogen DNA/RNA which appear in phagosomes. It binds the adaptor protein TRIF, which via a signalling cascade triggers the release of pro-inflammatory cytokines and chemokines.
In response to bacterial infections, bacteria cell walls/ endotoxins bind/activate TLR4, which binds Myd88 via the bridging adapter TIRAP. This causes an intracellular cascade which results in MAPK and NF-KB signalling responses.
NF-KB- MAPK signalling has systemic effects via the acute phase response. 5 cytokines act as the ‘main players’
- IL-1B ~ Activated vascular endothelium, activates lymphocytes.
- TNF-a ~ Activated vascular endothelium which increases vascular permeability hence increased entry of IgG. (Also, initiation of adaptive immunity by causing dendritic cells to migrate to lymph nodes).
- IL-6 ~ Activates lymphocytes, incr. antibody production.
- IL-8 ~ Chemotactic factor recruits neutrophils, basophils and T cells to site of infection.
IL-12 ~ Activates NK cells, induces differentiation of CD4 cells into TH1 cells.
Systemic effects - Fever, initiation of adaptive immunity via TNF-a activation of dendritic cell migration to lymph nodes.
LO: Understand the benefits and risks of therapeutically targetting PRRs to limit inflammatory
airway diseases.
Antagonists - Useful in the suppression of unnecessary propagation of immune response, which can be deleterious to the host if allowed to continue. These block ligand receptor or other binding events of common signalling pathways. Side-effects - Potentially repress necessary protective mechanisms.
Agonists - To promote protective responses eg. by activating inflammasomes. Interferons with antivirals, vaccines, so the patient becomes immune to the disease. Side effects - potentially enhance inflammation, which can have long term deleterious effects on health.
What type of cells are actively motile and mediate the innate immune system?
- Describe key features of each cell type
Leukocytes are the actively motile cells that mediate innate immune response.
Polymorphonuclear leukocytes have small granules which are released during infection.
Neutrophils - First WBCs to enter infected/ damaged tissue, facilitated by the inflamed endothelium to move out of ‘leaky’ vessels into infected/ damaged tissue. Attracted to chemotoxins released by pathogen or eg. macrophages. Associated with bacteria.
Eosinophils - Similar to neutrophils but loaded with granules of substances (eg. peroxidase) which kill multicellular parasites. Associated with the late stages of asthma where granule proteins damage bronchiolar epithelium.
Basophils - Similar to mast cells, usually in low numbers except in response to viral infection and myeloproliferative disorders (blood cancer).
