Biochemical Markers in the inflammatory response

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Biochemical Markers in the inflammatory response

• Dr Claire Bethune
• Consultant Immunologist
• Derriford Hospital

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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

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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

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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

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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

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Figure 2-5
Pathogen recognition by macrophages resulting in
initiation of the inflammatory response
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Toll-like receptors

• Macrophages and mast cells.
• Recognition of microbial components by Toll-like
  receptor
• Leads to synthesis and secretion of
  proinflammatory cytokines and lipid mediators
• Recruitment of soluble immune components and
  immune cells from the blood.

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Figure 2-39
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Arachidonic acid-derived lipid mediators
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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

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Figure 2-18
The Complement Cascade
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Figure 2-19
Main components of the Complement Cascade
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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

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Interferons

• IFN-a and IFN-ß 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

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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

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Kinin

• Enzymatic cascade of plasma pro-enzymes that is
  triggered by tissue damage to produce
  inflammatory mediators including Bradykinin
• Bradykinin causes increase in vascular
  permeability and pain

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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

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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

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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 Il-6
  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

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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

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Figure 2-46
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Figure 2-47


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CRP

• Pentraxin protein family
• Binds phosphocholine of bacterial or fungal cell
  wall lipopolysaccharides
• Oposonisation
• Complement activation via C1q

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Mannose-binding lectin

• Normal low levels in serum, increased during
  acute-phase response
• Opsonisation
• Complement activation

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Figure 2-45
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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
• TGFß 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?)

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Summary

• Central role for macrophage
• Recognition, phagocytosis, cytokine production
• Local mediators of inflammation co-ordinated
• Local and systemic inflammation require tight
  regulation