Lec 3- innate immunity part 2 Flashcards
Inflammation
-Complex, multifactorial response to infection, damage, trauma
-Beneficial
-It is not synonymous with infection
-Can be sterile
Cardinal signs: heat, pain, redness, swelling and loss of function
Acute inflammation
- Local reaction
- Movement of proteins and cells from blood to tissue
- Predominantly neutrophils
- Clearance of immune challenge
- Resolution: poorly studied
- Maybe pus- (contains neutrophils carrying myeloperoxidase)
- When acute inflammation containing pus doesn’t come to a point, the core of the abscess isn’t cleared so has to be drained via surgery, this is known as granulomas
Kinetics of acute inflammation
- There are lots of different cytokines and chemokines
- Within 1 hour of infection neutrophils start to increase
- After 6 hrs apoptosis increases this is because the neutrophils fight and DIE
- Around 24hrs later there is an increase in mononuclear cells these are the macrophages which engulf the dead neutrophils
Chronic inflammation
- Prolonged
- Non-resolving
- Leads to loss of function
- Persistent inflammatory cells and mediators
- e.g. RA
Cells of innate immunity recognises pathogens- pattern recognition
- Pattern-recognition receptors (PRR) bind to pathogen-associated molecular patterns (PAMP’s)
- Mannose R, scavenger R, Glucan R are all lectin (links to the lectin pathway of C3 activation) and recognise carbohydrates on microbial surfaces
- CR3 bind iC3b (from complement activation) and LPS
- CD14 binds LPS (lipopolysaccarides)
- All binding leads to phagocytosis
Toll-like receptors (TLR) sense infection
TLR
- Family of signalling receptors
- Expressed by different cells types
- Recognise different pathogens
- Tailor innate immune response to WHAT and WHERE
- TLR signalling switches on cytokine production: informs adaptive immunity
- Has a pathogen recognition domain
TLR’s sense infection
- The receptor location will give a good indication to what type of microbe it will act on
- e.g. microbes that will act on the outside of cells such as bacteria, fungi and parasites will be on the plasma membranes
- The receptors on the endosomes (inside the cells) will effect virus’
Pathogens induce cytokine release
SE= systemic effects
LE= local effects
-On sensing microbial production, macrophages secrete a variety of pro-inflammatory cytokines e.g.
IL-6:(SE) Fever; induce acute phase proteins production by hepatocytes
TNF-a: LE- activates vascular endothelium and increases vascular permeability which leads to increased entry of complement and cells to tissue and increased fluid drainage to lymph nodes; SE- fever (pyrogens), mobliz`tion of metabolites, shock
IL-1b: LE- activates vascular endothelium, activates lymphocytes, local tissue destruction increases access of effector cells; SE- Fever, production of IL-4
CXCL8- LE- chemotactic factor recruits neutrophils and basophils to site of infection
IL-2- LE- activate NK cells
Neutrophils are recruited to sites of infection
- Neutrophils- most abundant white cells: 50 billion in healthy children; short lived around- 2 days
- Huge bone marrow reserves of mature neutrophils
- Production of inflammation attracts neutrophils to sites of infection
- Neutrophils are adapted for working without oxygen
- They will die hours after entry to infected tissue- forming pus (myeloperoxidase)
Neutrophils roll, bind and migrate
1) Rolling adhesion
- It binds to the 1st receptor
2) Tight binding
- then binds to LFA-1/ICAM-1 receptor will slow this down further allowing it to bind to cytokines
3) Diapedesis
- This is the movement of the cell through the endothelial membrane
4) Migration
- Moves into the cell and now starts producing more cytokines meaning that it attracts more neutrophils
Complement components promote inflammation
- Anaphylatoxins act on blood vessels to increase vascular permeability (C3a and C5a)
- Increased permeability allows increased fluid leakage from blood vessels and extravastation of complement and other proteins at the site of infection
- Migration of monocytes and neutrophils from blood to tissue is increased
- Microbicidal activity of macrophages and neutrophils is also increased
Mast cells
- C3a and C5a activate mast cells: anaphylatoxins
- Resident in tissue and sub mucosal
- Release of vasoactive amines e.g. histamine
- Release of cytokines e.g. TNF-a
- Recruits: Ab, complement, fluid (Helps APC drain), cells
Process in local inflammation
- A cut in the skin and microbes enter through the cut
- Complement activation occurs
- Macrophages move into the space partly by chance and partly by complement and start the process of phagocytosis
- Macrophages release cytokines and chemkines
- Complement then activates mast cell to degranulate causing release of inflammatory mediators
- Inflammatory mediators, cytokines and chemokine all act on nearby blood vessels to present receptors to causing migration of neutrophils
- Neutrophils then pass to kill bacteria
Inflammatory mediators
-Cytokines
-Chemokines
-Complement
-Amines
-Lipid mediators e.g.
Eicosanoids (20C chain) e.g. PG’s LT’s and lipoxines
Produced from arachidonic acid by COX-1 and 2 but also lipo-oxygenase
Neutrophils are good eaters
Similar mechanism to macrophages
-PPR and CR
-Unopsonised and opsonised pathogen recognised
-Greater diversity of diet than macrophages
-More antimicrobial weapons than macrophages
Phagosomes fuse with azurophillic (primary) granules and specific (secondary) granules- these contain various enzymes, anti-microbial, toxin
Death comes swiftly
