Cells Mediator5hoouhohu

This lecture contains many points of information which may at
first appear overwhelming to the student. Remember that in one

hour I need to give an overview of the inflammatory response,
something which is still evolving after millions of years!
By the end of this lecture students should be able to :

Discuss the differences between acute and chronic
inflammation.
Give the key processes of both.

Explain the process whereby cells leave the bloodstream
into infected tissue.
Discuss how neutrophils and macrophages are important in
inflammation.
Describe the processes of chemotaxis and phagocytosis.

Give clinical examples of inflammation and the processes
involved.
Inflammation
Level 2, Immunology (13a) 10/10/05
Dr J. Alastair Gracie
CRD
III
University of Glasgow
j.a.gracie@clinmed.gla.ac.uk
Definition
Is a complex response of the body to damage
to its cells and vascularised tissue.
this can be due to:- infectious agent
antigen challenge
physical/chemical
AIM
Isolate/Destroy/Expel foreign body

Initiate structural and functional repair
HEAT
REDNESS
SWELLING
Calor
Rubor
Tumor
PAIN
Dolor
LOSS OF
FUNCTION
Functio
laesa
net effects.
increased blood flow to the tissue causing:
increased temperature,
redness,
swelling, and
pain.
two types of inflammation

Acute Inflammation
short duration-few minutes to days

protein exudate
neutrophils predominate
Chronic Inflammation
days to years
mainly macrophages and lymphocytes
fewer neutrophils
Inflammation is good?
isolating the damaged area,
mobilizing effector cells and
molecules to the site, and in the
later stages
promoting healing and tissue repair,
inflammation protects the body.
Inflammation is bad?
Inflammatory response out of
proportion to the threat it is dealing
with.
More damage to the body than the
agent itself would have produced.
Allergies and Autoimmune Diseases
Soluble Mediators of Inflammation

PLASMA :Complement/Antibody
Coagulation
Fibrinolytic
Kinin
cytokines and chemokines
Soluble Factors
Mediator
Histamine
Source
Preformed in mast cells,
basophils, platelets
Effect
Arteriolar dilation , increased
vascular permeability
Serotonin
platelets
As above
Prostaglandins
From arachidonic acid by

cyclooxygenase pathway
Inhibits platelet aggregation

vasodilator
Leukotrienes
From leucocytes by
lipoxygenase pathway
Chemotaxis of neutrophils (LTB4)

Vasoconstriction,bronchospasm
increased permeability
Vasodilation, directly toxic
Nitric Oxide
Macrophages and EC
induced by TNF/IFN
PAF
Mast cells, eosinophils
TNF/IL-6/IL-1
Macrophages
Acute phase response Activates

EC, fever, NO synthesis
Lysozyme
Macrophages/neutrophils
Causes lysis of bacterial cell wall
Vasoconstriction
Vasodialation
Bradykinin
Liver/plasma
Pain, vasodilation increases

permeability
Hageman
Factor
Liver/plasma
Initiator of Kinin, clotting,

fibrinolytic,complement cascade
Complement
Liver/plasma
MAC, chemotactic and

degranulation factors
Coagulation
fibrinolytic
pathways
Lactoferrin
Transferrin
Plasma proteins
Coagulation/thrombosis
macrophages
Binds iron to deprive pathogen
Cellular Mediators of Inflammation

CELLS :Neutrophils
Monocytes/macrophages
Basophils
Eosinophils
Mast cells
Lymphocytes
Vascular endothelium
Epithelium
Vasodilatation and early

cellular events
Leads to calor and rubor
results in increased permeability of
vessels (tumor)
allows emigration of both
plasma components
cells
caused by :Release of vasoactive mediators :Prostaglandin

E.C.
histamine
mast cells
Bradykinin
plasma
C3a, C5a
C
Cytokines
Various
Increased permeability allows
proteins and fluids to leak out
Cell sludging and slowing down
acute response
over next few hours (to days)
mobilisation and recruitment of
circulating inflammatory cells
appearance of neutrophils in area of tissue
damage
monocytes/macrophages and lymphocytes
later
Destruction and removal of infectious agent

Involves:
CHEMOTAXIS
PHAGOCYTOSIS
if persists can become

CHRONIC
neutrophils down
monocytes/macrophages and lymphocytes up
Chemotaxis
Orientate and move along a gradient of
increasing stimulus
Exogenous mediators:
N-formyl methionine terminal a.a.from bacteria
Lipids from destroyed or damaged membranes
(including LPS)
Endogenous mediators:
Complement proteins (C5a)

Chemokines, particularly IL-8
Arachidonic acid products (LTB4)
Phagocytosis
Recognise, attach and engulf target
surround with plasma membrane
fuses to produce phagosome
this fuses with intracellular granules
keeps internal
Neutrophils
50-60% of circulating
leukocytes
short lived
1st line of defence
Several bacteriostatic
and toxic factors
Phagocytose and
release soluble
mediators
Neutrophils (2)
Have granules :Primary - serine proteases, lysozyme and
phospholipase A2
Secondary - similar to 1ry plus lactoferrin
and collagenase
Tertiary - at leading edge of migrating
PMNs, contain gelatinasescapable of degrading b.m.
RO products and respiratory burst
Neutrophils - the process

Roll along vessel wall
attracted by
chemotactic factors
migrate out of vessel
into tissue
engulf organisms
degranulate
Extravasation
(Margination and Diapedesis)
Cells move to outside of vessel
attach to endothelium by specific
receptors
move through between EC-EC junctions
migrate into surrounding tissue
Margination
Cell flow slows
leucocytes marginate to vessel walls
cells cover area of wall
pavementing
Rolling Adhesion
P and E-selectin on endothelial
surfaces interact with carbohydrate
epitopes on leucocytes [sialyl-Lewisx]
selectins induced by LTB4, C5a,
histamine
adherence reversible roll
Tight Binding
Stronger interactions between:
LFA-1, MAC-1 [integrins] on leucocyte

and
ICAM-1 on EC -induced by cytokines
Interaction strengthened by IL-8 and

other chemoattractants
Rolling arrested!
Diapedesis
Cells cross EC wall
Involves integrins PLUS
CD31(PECAM)
leucocyte and EC
junction (Zipper effect)
Move under effect of
chemoattractants e.g.
IL-8, C5a,
penetrates bm by
proteolytic enzymes
Multi-step process of cell

infiltration to an Inflammatory Site
Immunobiology, Garland Press
Outcome of acute ?
Resolution
normal architecture
with little damage
removal of dead
tissue
Failed Resolution
scar formation with
loss of original
architecture,
fibrosis
Chronic
inflammation
Chronic Inflammation
Prolonged inflammatory response
persistence of causative agent
Tissue damage with attempts at
healing/repair usually with fibrosis/scarring
When do we get?
-Progression from acute
-after repeated acute
-de novo
What causes ?
- M Tuberculosis
-fungi, protozoa
- inert particles e.g .silica
-self tissue
Type of infiltrate?
-mixed
-more macrophages and lymphocytes
less neutrophils.
Examples
RA, TB,
Granulomatous Inflammation
Inflammation dominated by macrophages
substances resist lysosomal degradation
dense accumulation of macrophages +/lymphocytes.
RA as a chronic inflammatory
disease
RA
Scheme for chronic inflammation
Neutrophil
Macrophage
Morphology
Smaller cells with multi-lobed

nucleus and neutral cytoplasmic
granules
Large mononuclear cells with

granular cytoplasm
Location
Blood requires recruitment to

site of infection
Often resident in tissues

(remove routine cell debris)
Activated during recruitment,

then able to kill internalised
bacteria automatically
Require activation by bacterial

molecules IFN-
Die at site by apoptosis

(then taken up by macrophages)
Migrate to local lymph nodes
Killing ability
After killing
Antigen
presentation
Dogma says they cannot present Can present antigen

antigen
(Class II upregulated by IFN-)
(dont normally express Class II)
Borrowed from Dr Brewer!
Bactericidal products of phagocytes

Class of Mechanism
One or two examples:
Acid
Lysosomes have highly

acidic conditions
Toxic oxygen
Superoxide, hydrogen
peroxide (bleach!).
Neutrophils also make
hypochlorite
Toxic nitrogen
Nitric oxide
Antimicrobial peptides
Enzymes
Lysozyme dissolves cell wall

of gram positive bacteria
Competitors
Iron binding proteins,

Vitamin scavengers
Borrowed from Dr Brewer!
Macrophages
Janeway, (2000), NEJM
Immunobiology, Garland Press

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This lecture contains many points of information which may at

first appear overwhelming to the student. Remember that in one

By the end of this lecture students should be able to :

Give the key processes of both.

into infected tissue.

Discuss how neutrophils and macrophages are important in

Describe the processes of chemotaxis and phagocytosis.

Isolate/Destroy/Expel foreign body

two types of inflammation

short duration-few minutes to days

Soluble Mediators of Inflammation

From arachidonic acid by

Inhibits platelet aggregation

Chemotaxis of neutrophils (LTB4)

Mast cells, eosinophils

Acute phase response Activates

Causes lysis of bacterial cell wall

Pain, vasodilation increases

Initiator of Kinin, clotting,

MAC, chemotactic and

Binds iron to deprive pathogen

Cellular Mediators of Inflammation

Vasodilatation and early

caused by :Release of vasoactive mediators :Prostaglandin

Destruction and removal of infectious agent

if persists can become

Complement proteins (C5a)

RO products and respiratory burst

Neutrophils - the process

LFA-1, MAC-1 [integrins] on leucocyte

Interaction strengthened by IL-8 and

Multi-step process of cell

Immunobiology, Garland Press

Scheme for chronic inflammation

Smaller cells with multi-lobed

Large mononuclear cells with

Blood requires recruitment to

Often resident in tissues

Activated during recruitment,

Require activation by bacterial

Die at site by apoptosis

Migrate to local lymph nodes

Dogma says they cannot present Can present antigen

Borrowed from Dr Brewer!

Bactericidal products of phagocytes

One or two examples:

Lysosomes have highly

Lysozyme dissolves cell wall

Iron binding proteins,

Borrowed from Dr Brewer!

Janeway, (2000), NEJM

Immunobiology, Garland Press

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