Download Biochemical Markers in the inflammatory response

Biochemical Markers in the
inflammatory response
Dr Claire Bethune
Consultant Immunologist
Derriford Hospital
Role of the inflammatory response
• Killing of invading micro-organisms
– Macrophage activation, recruitment of effectors
• Barrier to the spread of infection
– Microvascular coagulation
• Repair of injured tissue
The inflammatory response
• Recognition of “insult” initiation of the inflammatory
response
• Amplification of the local response
– Induce vascular permeability
– Change adhesive properties of endothelium to attract more
phagocytes
– Activate incoming phagocytes
– Activate NK cells enhancing cytotoxicity and inducing
further cytokine production
• Systemic involvement
• Attenuation and resolution
Local inflammatory response – the
main players
• Macrophages, mast cells and dendritic
cells
– Recognition of infection
– Cytokines, Lipid mediators of inflammation
•
•
•
•
Complement
Interferons
Kinin system
Coagulation cascade
Pathogen recognition
• Macrophage receptors
• Mannose receptors – stimulate phagocytosis
• Toll-like receptors and NOD1 +2 – stimulate cytokine production,
expression of co stimulatory molecules
• Mannose binding lectin
• Complement activation
• Blood vessel injury triggers enzyme cascades
• Kinin system activation
• Coagulation system activation
Figure
2-5
Pathogen recognition by
macrophages resulting in
initiation of the
inflammatory response
Toll-like receptors
• Macrophages and mast cells.
• Recognition of microbial components by Tolllike receptor
• Leads to synthesis and secretion of
proinflammatory cytokines and lipid mediators
• Recruitment of soluble immune components
and immune cells from the blood.
Figure 2-39
Arachidonic acid-derived lipid
mediators
Local inflammatory response – the
main players
• Macrophages, mast cells and dendritic
cells
– Recognition of infection
– Cytokines, Lipid mediators of inflammation
•
•
•
•
Complement
Interferons
Kinin system
Coagulation cascade
The Complement Cascade
Figure 2-18
Main components of the Complement Cascade
Figure 2-19
Local inflammatory response – the
main players
• Macrophages, mast cells and dendritic
cells
– Recognition of infection
– Cytokines, Lipid mediators of inflammation
•
•
•
•
Complement
Interferons
Kinin system
Coagulation cascade
Interferons
• IFN-α and IFN-β produced by host cells in
response to viral infection
• Binding to interferon receptors signals production
of proteins with antiviral effects
• Promote MHC-1 expression on infected cells
• Activate NK cells to kill virally infected cells and
produce cytokines
Local inflammatory response – the
main players
• Macrophages, mast cells and dendritic
cells
– Recognition of infection
– Cytokines, Lipid mediators of inflammation
•
•
•
•
Complement
Interferons
Kinin system
Coagulation cascade
Kinin
• Enzymatic cascade of plasma proenzymes that is triggered by tissue
damage to produce inflammatory
mediators including Bradykinin
• Bradykinin causes increase in vascular
permeability and pain
Local inflammatory response – the
main players
• Macrophages, mast cells and dendritic
cells
– Recognition of infection
– Cytokines, Lipid mediators of inflammation
•
•
•
•
Complement
Interferons
Kinin system
Coagulation cascade
Coagulation system
• Enzymatic cascade, triggered by blood
vessel damage.
• Activation results in the formation of a
fibrin clot, prevents infectious
microorganisms from entering the blood
stream
Il-6 and shift to monocyte involvement
• Il-6 produced by macrophages
• Neutrophils shed their Il-6 receptors on
entering site of infection
• Endothelial cells can respond (via gp130) to Il6 receptor/Il-6 complexes by decreasing the
production of CXC chemokines and increasing
production of CC chemokines such as MCP-1
and MCP-3 to attract monocytes
Systemic effects
• TNF promotes catabolism of fat and
muscle to release energy
• IL-1 and IL-6 induce the liver to produce
proteins involved in immunity and wound
healing – the acute phase response
• IL-1 and IL-6 act on the hypothalamus to
induce fever and induce glucocorticoid
release by the adrenals
• Induction of leukocytosis
Figure 2-46
Figure 2-47
CRP
• Pentraxin protein family
• Binds phosphocholine of bacterial or
fungal cell wall lipopolysaccharides
• Oposonisation
• Complement activation via C1q
Mannose-binding lectin
• Normal low levels in serum, increased
during acute-phase response
• Opsonisation
• Complement activation
Figure 2-45
Regulation
• TNF induce the shedding of TNF receptors
• Decreases sensitivity of that cell
• Binds free TNF reducing availability to surrounding cells
• Glucocorticoids stimulated via hypothalamus inhibit
inflammation
• Inhibition of inflammatory cytokine production
• Antiinflammatory cytokines from macrophages
• IL-10 produced following TLR stimulation of macrophages
• TGFβ produced by macrophages (particularly those ingesting
apoptotic cells)
• Acetylcholine released by neurones of the vagus nerve
act via nicotinic acetylcholine receptors on tissue
macrophages to inhibit TNF and IL-1 production
(explaination for action of acupuncture?)
Summary
• Central role for macrophage
– Recognition, phagocytosis, cytokine
production
• Local mediators of inflammation coordinated
• Local and systemic inflammation require
tight regulation