Innate immunity / Antigen presentation Flashcards
What physical barriers do we have that protect entrances to the body?
What happens if physical barriers are breached?
- DAMPs :Danger associated molecular pattern molecules e.g. DNA, RNA ECT.. bind to receptors Initiates inflammatory response through inflammatory cytokine release
What are the 3 pro-inflammatory cytokines?
Why do pro-inflammatory cytokines result in Swelling,heat and pain?
Pro-inflammatory cytokines are released into the surrounding tissue :
- Act on endothelial cells of blood vessels to weaken the tight junctions between cells. This causes the vessel to become more permeable and fluid to leak into the tissue > Swelling - Tumour
- They also cause the blood vessels to increase in diameter, increasing and slowing blood flow to the area > Redness and Heat - Rubor+ Calor
- Swelling + Bradykinin released by activated vascular endothelial cells makes nerve endings more sensitive causing pain. Dolor
What happens when pathogens enter the body?
-Pathogen associated molecular patterns recognised by tissue and immune cells through their Pattern Recognition Receptors (PRRs)
>Same response for all pathogens
What types of receptors do we have?
What is toll like receptor?
- Recognition of a pathogen transmits a signal to the nucleus
- A protein called NFκB assembles and binds the DNA this instructs the cells to produce new proteins
- These include pro-inflammatory cytokines and cell surface molecules
What is a phagocytic receptor?
-These receptors are expressed on phagocytic cells and allow them to recognise a pathogen and engulf if.
How does a macrophage kill a pathogen?
- The pathogen is recognised by receptors and phagocytosis is induced
- The pathogen is internalised in a phagosome which fuses with a lysosome which contains antimicrobial peptides, lysozyme and nitric oxide.
- The pathogen is broken down and destroyed
What are complement proteins? What is the important one?
-Produced in liver > Circulate blood > Activate when enter tissue due to inflammation
- Binding of complement to the surface of the pathogens makes it visible to the complement phagocytic receptors
C3 > C3b + C3a
-C3b attaches on to pathogen as tag, opsonisation
What are chemokines?
- Chemokines- small attractant protein which help cells move to site of inflammation
What happens during neutrophil recruitment?
- During normal conditions the neutrophils circulate in the blood and bind weakly to E-selectin via their proteoglycans
- When an infection occurs or the tissue is damaged pro-inflammatory cytokines and chemokines are released
> Macrophages respond and also release pro-inflammatory cytokines, and a chemokine - The cytokines IL-1β and TNF-α up regulates adhesion molecules on the blood vessels at the sight of inflammation. (ICAM-1)
Macrophages secrete chemokine CXCL8 which adheres to the inner lumen of the vessel alongside adhesion molecules that have been upregulated - The neutrophil attaches to E-Selectin and rolls along the vessel before being firmly attached to ICAM-1 via LFA-1. The cell also recognises CXCL8 via its receptor (CXCL8RP). Starts to extravasate where the inflammation is occurring. The neutrophils follow the chemokines to the site of infection
-Then recognises and phagocytoses pathogen
What does it mean that neutrophils have granules? What are the 3 types? Their function?
-Neutrophils have granules containing antimicrobial proteins and peptides which disrupt and digest microbes
>1. Neutrophils phagocytose pathogen into a phagosome, binds to the lysosome to form a phagolysosome, which then fuses with the granules
- Primary granules contain hydrogen peroxide
- Secondary granules contain nitric oxide
2. NAPDH oxidaseis formed by secondary granule binding
3. This produceslots ofsuperoxide radicals, lowering the pH and activating peptides within 3mins of phagocytosis to help break down the pathogen
What does Neutrophil respiratory burst release?
- toxic oxygen species which diffuse out of the neutrophils, making the environment harsh for pathogens in surrounding tissue
Neutrophil netosis?
Once done the neutrophil cannot replenish and dies either through apoptosis or netosis.
1. During NETosis the nucleus swells and bursts
2. This expels the chromatin, which is covered with histones and granule contents, out of itself and over the tissue it is in
3. This traps bacteria in that tissue sites, forming Neutrophil Extracellular Traps.
→These can trap pathogensextracellularly
What happens when virus infects inside a cell? Toll like receptor response?
- Intracellular TLR > within endosome transmits signal to nucleus
- IRF binds to DNA and instructs to produce new proteins
- Cytokines: Interferons α and β - Type 1
What are the other 2 intracellular receptors?
What do Interferons α and β result in?
(induce co-stimulatory molecule expression )
What is the difference between MHC molecules?
How are MCH1 processed?
- Proteins in cytosol passed through proteasome > broken into small peptides
- Passed through endoplasmic reticulum to be placed on MHC1
- MCH1 delivered to surface for presentation
How do natural killer cells identify when a cell is infected with a pathogen?
> Inhibition overides activation receptor
- Receptors
-Granules (perforin + granzyme) which can kill cells
+ produce interferon γ
Summarise the process of viral innate viral infection.
- The virus attaches to the cells and infects them.
- The viral proteins in the cytoplasm can become processed through the MHCI pathway.
- Additionally recognition of the virus by TLRs induces the release of IFNβ which signals both paracrine to neighbouring cells and autocrine > block viral protein synthesis, promote viral RNA degradation and increase MHCI expression
- IFNβ induces the release of IFNα activates NK cells and chemokines
- NK cells release perforins and granzymes which kill the virus infected cells
Summarise the process of recognition of intracellular bacteria.
- When in the cytoplasm the bacteria can be recognised by receptors such as NOD which activates NFκB
- Pro-inflammatory cytokines are released and depending on the pathogen IL-12 is also secreted
How is autophagy enhanced?
> NOD2 receptors activates autophagy pathway
1. Stalled phagosomes and free bacteria detected cand engulfed again through autophagy
2. The autophagosome merges with a lysosome and the pathogen is destroyed
Also allows us to present antigens on MHCII
How is MHC2 processed ?
- The pathogen is internalised by phagocytosis
- A lysosome merges with the phagosome to produce a phagolysosome and digest the pathogen
- A second vesicle containing (MHCII) fuses with the phagolysosome to pick up peptide fragments
- MHCII with peptide bound is delivered to the surface for presentation
What is cross presentation?
> way for dendritic cells to present phagocytosed antigens on MHCI
1. Partially degraded antigen can be pushed from the phagolysosome into the cytosol to be processed through ER to MHCI
2. The dendritic cells also have vesicles with MHCI in as well as MHCII. These can fuse to the phagolysosome to load peptide on MHCI for the surface
