What is the late phase acute inflammation composed of
- Neutrophils
- Complement
- Dendritic cells
What are the local effects of pro-inflammatory mediators
Describe endothelial migration
- Endothelial cells express - Selectins for carbohydrates on neutrophils
- Week binding - causes rolling of neutrophils
2. Endothelial cells express iCams for intigrins on neutrophils
- Stronger binding causes stable adhesion and agregation of neutrophils
- Transendothelial migration
Describe acute inflammaiton
- Macrophages, mast cell -> Histamine, pro-inflammatory cytokines and chemokines
- Increased vascular permeability
- Vasodilation and increased blood flow
-
Endothelial cell activation, adhesion molecules - Icams and Selectins
-
Transendothelial migration - nuetrophils squeez through endothelial cells
How do neutrophils migrate to the site of injury
Through chemokines produced by macrophages and mast cells
Describe neutrophils
- polymorphonuclear cells
- phagocytes that circulate in the blood
- Charateristic features: Intra-cellular granules and multilobed nucleus
- Recuireted by cytokines and proinflammatory mediators
what are the functions of neutrophils
- Kill pathogen
- Release more pro-inflammatory cytokines - TNFa
What are the 3 types of neutrophil killing mechanisms
- Phagocytosis
- Degranulation
- NETs
Describe neutrophil phagocytosis
After encapsulating the bacteria, neutrophils can kill via 2 mechanisms
- Anti-microbial proteins and enzymes
- Reactive oxygen species
Describe the 1st phagocytic mechanism of neutrophils
-
Encapsulating bacterai into cytoplasm - phagosome formation
- Phasome fuses with Azurophillic and specific granules
-
PH of phagosome rises
- Antimicrobial responce is activated and bacterium is killed
-
PH Descreases - fusion with lysosomes
- Acid hydrolases degrades the phagosome compeletly
Describe the 2nd mechanism of Neutrophil phagocytosis
-
Neutrophil activation via pro-inflamamtory mediators
- Assembly of NADPH oxidase complex
- Production and release of ROS into phagosome
- NADPH oxydase dependent mechanism
How does neutrophil granulation clear infection
- Release of anti-microbial proteins directly into extracellular millieu
- Direct killing of extracellular pathogens
- can lead to tissue damage and systemic inflammation
How do neutrophils trap extra-cellular pathogens via NETs
- Activated neutrophils release intracullar structures (DNA HIstones etc) into extracelluar spaceto trap potential pathogens
- Imobilize pathogens
- prevent them from spreading
- Facilitates their phagocytosis
Main difference between macrophages and neurophils
Neutrophils are short-lived - Pus
Decribe the complement system
- Family of 30 proteins
- produced by the liver- circulate in blood as inactive precursors - enter infected or inflammad tissue
- Activated directly or indirectly by pathogens
- When activated they cleave each other dowstream in an enzamatic cascade reaction
What are the 3 pathways of complement
- Classical pathway
- Mannose binding lectin pathway
- Alternative pathway
whats the function of complement
- Pathogen Opsonisation
- Pathogen killing
- Recruitment of Leukocytes and inflammation
- Removal of immune complexes
Describe the mannose binding lectin pathway of complement
- Mannose (bacterium) binds to MBL (mannose-binding lectin)
- This triggers activation and cleavage of C3
- C3 is cleaved into C3a and C3b
- Leads to downstream events and amplification loop
Describe the alternative pathway
- Spontanous cleavage of C3 into C3a and C3b
-
C3b is then either rapidly degraded
- Or binds to Bactieral carbohydrates/protein ligands to stabalise them
- Binding to C3b to these ligands then triggers an amplificaiton loop
- This results in more cleavage of C3 protein
- this is also selective because human cells express inhibitory proteins that results in degradation of any bound C3b
What happens when theres activation of downstream complment proteins in the 2 pathways
- Pathogen opsonisation
- Pathogen killing
- Recruitment of leukocytes and inflammation
- Removal of immune complexes
Describe pathogen killing by complement
- Formation of membrane attack complex - defense againts encapsulated bacteria
-
C5b binds to surface pathogens
- C6, 7, 8, 9 assemble with C5b to form the membrane attack complex
- Inserts into pathogen - forms a whole
- Osmotic cell lysis
Describe opsonisation by complement
Coating of bacterial by humeral factors to enhance phagocytosis
- Examples : C3b , CRP, IgG/IgM
- Phagocytes express opsonine receptors on their surfaces to bind the opsonised pathogen
- Esp Encapsulated bacteria
Describe leukocyte recruitment by conplement
-
C3a and C5a are known as anaphylatoxins
- Activation of mast cells - released of pro-inflammatory mediators and chemokines - Which leads to increased permeanbility - leakage of fluid containing opsosnines and antibodies and recruitment of inflammatory cells
- Also can act directly on blood vessels to produce these effects
How is the complement system regulated
1. Only cleaved Complement proteins are active
2. Active Complement proteins have very short half-life
3. Some Complement proteins are only produced during an Acute Phase Response
4. Some Complement proteins do not bind to human cells
5. Complement inhibitors and regulatory proteins limit activation of the system
Describe dendritic cell activity
