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