Immune response and inflammation

Silent killer; TIME March,1,2004

Handono Kalim
Department of Internal Medicine
Faculty of Medicine, University of Brawijaya, Malang

The immune system

Infectious or inflammatory trigger

Innate or natural response

Same extent each time
Uses phagocytic cells
PMNs
Monocytes
Macrophages
Cells release mediators
Complement, APR,cytokines

Acquired or adaptive response

Involves proliferation of
antigen specific T and B cells
Antigen presenting cells
display antigen
T cells help B cells, assist
macrophages , and kill cells
Complement, APR, cytokines

Innate immune response

Intra vascular cells and connective tissue matrix and

cells involved in the inflammatory response
Mast cell

Fibroblast

Macrophage

CONNECTIVE
TISSUE
CELLS

Basophil
Platelets

VESSELS
Polymorphonuclear
Lymphocyte
leukocyte

CONNECTIVE
TISSUE
MATRIX

Monocyte

Eosinphil

Endothelium Basement membrane:

Collagen type IV
Laminin
Fibronectin
Proteoglycans
Elastic fibers Collagen fibers
Others

Proteoglycans

Recognition of danger by the innate immune system

B lipoproteins
B lipoarabinomannans
LPS (Lestospira, P. gingivalis)
Peptidoglycan (Gram-positive)
Zymosan (yeast)
GPI anchor (T. Cruzi)

LPS (Gram-negative)
Taxol (plant)
Viral proteins
Hsp60 (host)
Fibronectin (host)

MICA (host)

IgG1,
IgG3 (host)

Viral
dsRNA
TLR2/
TLR1 or 6
TLR3

Bacterial
flagelline

NKG2D/
DAP10

TLR4/
MD2

NK
cell
NKp46

CD16

DC/M
TLR5

HLA-E (host)

TLR9

KIR/
DAP12

Bacterial
CpG DNA

Viral
hemagglutinin

CD94
NKG2A or C

MHC class I (host)

Components of innate immunity

Humoral or cellular immune

response

Antigens
Foreigh
Bacteria
proteins Viruses
Parasites

HUMORAL RESPONSE

Fungi

CELL MEDIATED RESPON

Vertebrate body
T cell

B cell
TH cell
+

Antigen
Activated
TH cell

+Ag-class II
MHC molecule

Ab-secreting
Plasma cells

+Ag-classI
MHC molecule

CTL

Antibody
Antigen
elimination

Cytokine
secretion
Altered self cell

Killing of
Altered self-cell

Molecular interaction that mediate nave

T lymphocyte activation by APC
Pathogen
IL-4

Recognition

Th2
cell

Internalization
TLR

IL-4
IL-5
IL-10
IL-13

Antigen
presentation

APC

Nave
T cell

Tr1
cell

IL-10
TGF-

Co stimulation

IL-10
IL-12, IL-18

Th1
cell

IFN-
TNF-

Effector Mechanisms of
Humoral Immunity

Th2 effector functions

Mechanisms in Rheumatology 2001

Effector function of antibodies

Neutralization of
microbe and toxins
Antibodies
B cell

Opsonization and
phagocytosis of
microbe
Fc receptor

Microbe

Lysis of microbe
Phagocytosis of microbes
opsonized with complement
fragments ( e.g.,C3b)
Cb3 receptor

Complement
activation

Inflammation

Effector Mechanisms of
Cellular Immunity

Th1 effector functions

Click here to run the animation

Mechanisms in Rheumatology 2001

Types of cell-mediated immune responses

IFN- /
IFN- / receptor

2-5(A) synthase

ATP

Protein kinase
PKR (inactive)
PKR (activated)

2-5 (A)

Inactive
RNAse L

+ ATP and
dsRNA

Active
Phosphorylation
RNAse L
of elF-2
Degradation of
poly (A)mRNA

elF2-GDP
(nonfunctional)

INHIBITION OF PROTEIN SYNTHESIS

Induction of antiviral activity by IFN- and -

Immune Protection VS
Immunopathology

Immune pathologic : abnormalities in

physiology of adaptive immune responses
Specificity
Diversity
Memory
Specialization
Self limitation
Non reactivity to self

Mechanisms of the decline of normal immune responses

(homeostasis)

Tissue destruction
by mediators
derived from neutrophil activation

Major effect of IL-1 and TNF in inflammation:

physiologic or pathologic ?
Bacterial products, immune
complexes, toxins, physical
injury, other cytokines

MACROPHAGES (AND
OTHER CELL) ACTIVATION

IL-1/TNF

ACUTE-PHASE REACTIONS
Fever
Sleep
Appetite
Acute phase proteins
Hemodynamic effects (shock),
neutrophilia
ENDOTHELIAL EFFECTS
Leukocyte adherence
PGI synthesis
Procoagulant activity
Anticoagulant
IL-1, IL-8, IL-6,
FIBROBLAST EFFECTS
Proliferation
Collagen synthesis
Collagenase
Protease
PGE synthesis
LEUKOCYTES EFFECTS
Cytokine secretion , priming

Biologic effects of mediators in inflammation

Vasodilation
Prostaglandins, nitric oxide
Increased vascular permeability
Vasoactive amines, C3a and C5a (through liberating amines),
bradykinin, leukotrienes C4, D4, E4, PAF, substance P
Chemotaxis, leukocyte activation
C5a, leukotriene B4, chemokines, bacterial products
Fever
IL-1, IL-6, TNF, prostaglandin
Pain
Prostaglandin, bradykinin
Tissue damage
Neutrophil and macrophage lysozomal enzymes, oxygen
metabolites, nitric oxide

Balance between pro-inflammatory and antiinflammatory cytokines

Mechanisms in Rheumatology 2001

Oxygen Derived Free radicals

Oxygen-derived free radicals may be released extracellularly

from leukocytes after exposure to chemotactic factors, immune
complexes or phagocytic challenge

Low levels of these potent mediators can increase the

expression of chemokines ( e.g IL8 ), cytokines, and endothelial
leukocyte adhesion molecules

At higher levels can be damaging to the host :

Endothelial cell damage, with resultant increased vascular
permeability.
Inactivation of antiproteases , such as a1-antitrypsin.
Injury to other cell types ( tumor cells, red cells, parenchymal
cells )

Lipid-derived inflammatory mediators

Mechanisms in Rheumatology 2001

Changes of acute phase proteins

production by hepatocyte
Comprises a cascade of systemic responses
upon tissue injury or infection
Characterized by a variety of changes in
organ function such as fever, leucocytosis,
major laboratory changes
In response to mayor cytokines : IL-1,IL-6
and TNF-

Protein whose plasma concentrations increase

Complement system
Coagulation and fibrinolytic systems
Antiproteases
Transport protein
Participants in inflammatory responses
Others

Protein whose plasma concentrations decrease

Albumin
Transferrin
Insulin like growth factor
Etc

Other acute phase phenomena

Neuroendocrine changes
Hematopoietic changes
Metabolic changes
Hepatic changes
Changes in non protein plasma concentration

Influence of cytokines in hepatic protein ,

carbohydrate and lipid metabolism
Stimulates amino acid uptake : IL-1, IL-6, TNF , EGF
Inhibit liver amino acid up take : TGF and IGF-I
Enhance glucose up take : IL-6, IGF-I
Reduced gluconeogenesis : IL-1
Enhance glicolysis: EGF
Inhibit fatty acids synthesis : IL-4
Modulation of hepatic cholesterol synthesis : IL-1,
TNF, IFN, EGF, PDGF
Increased fatty acids synthesis : IFN, IL-1, IL-6

Neuro endocrine- immune

interaction

Hormonal signaling of the brain by immune

signals: routes of communication
Actively carried from the blood to the brain

across the blood-brain barrier

Cross passively at certain anatomically leaky

points in the blood-brain barrier

Some cytokine effects are indirectly mediated

through second messengers

Peripheral cytokines can signal the brain via

direct neuronal routes

Communication between the immune system

and the CNS (humoral and neuronal)
Behavior
IL-1 Neuronal Pathways

PVN
CRH
AVP

LC

es
Cytokin

ACTH AVP

Immune
System

C2
A2
C1
A1

Nucleus tr solitarius

Sympathetic

Sensory afferents

Physiologic role of neuro-endocrine-immune

communication

Extra cellular
insult

Proinflammatory
cytokines
Adhesion
molecules
Chemokines

Proinflammatory
cytokines
Adhesion
molecules
Chemokines
Glucocorticoids
Anti-inflammatory
cytokines

Neuro endocrine immune interaction represent an important physiologic

mechanism for modulation of the intensity of immune response, control of
susceptibility, and resistance to inflammatory disease

Behavioral effects cytokines on the CNS

Increased somnolence
Loss of appetite
Decreased mobility
Fever, pain
Depression, anxiety

Sickness behavior

Immune reactions,
Inflammation
Microbial toxins
Pyrogenic cytokines:
Il- 1,IL- 6,TNF,IFN

Glial cells : cAMP

Fever

Heat conservation
Heat production

Circulation

Hypothalamic
endothelium

PGE2

Thermoregulatory
set point

Chronology of events required for the

induction of fever

Inflammation ?

Chronic irritation and inflammation which

may lead to neoplastic transformation
Gastric adeno carcinoma
H. Pylori
infection

Intestinal
metaplasia

Reflux
disease

Barrets
metaplasia

Gastric
dysplasia

Gastric adenocarcinoma

Barrets
dysplasia

Oesophageal adeno carcinoma

Oesophageal
adenocarcinoma

Inflammatory markers and clinical progression of

Alzheimers disease dementia

IL-6, C1q mRNA

HLA-DR microglia
COX-2 protein
No dementia

Questionable

Mild

Moderate

Severe very severe

Amyloid plaque density

Atherosclerosis : an inflammatory

Evidence Supporting Involvement of Infectious

Agents in Atherosclerosis
Presence or absence of evidence for an
infectious agents
Cytomegalo
virus

Herpes virus
hominis

Clamidia
pneumoniae

Atherosclerosis

Transplantation
arteriosclerosis

Pathogen present in
atheroma

Can produce atheroma in

animals

Proof of casuality

Evidence
Seroepidemiology

Novel Risk Factors for Cardiovascular Events in Apparently

Healthy Woman

Similarities between Atherosclerosis and

Rheumatoid Arthritis
Atherosclerosis

RA

0 or

0 or

(UA)

Adhesion molecules (VCAM-1,

ICAM-1, E-selectin,P-selectin)

Endothelin

Neoangiogenesis

Possible antigens

HSP, OxLDL,
Infectious agents

Collagen II,
cartilage antigens ,
HSP, infectious
agents

B cell activation
Autoantibodies (oxLDL,
HSP)
Rheumatoid factor
C- reactive protein

Chronic inflammation

Chronic Inflammation
Chronic inflammation is an inflammation of prolonged
duration in which active inflammation, tissue destruction,
and attempts at repair are proceeding simultaneously
1. Persistent infections by certain microorganisms of low
toxicity and evoke DTH
2. Prolonged exposure to potentially toxic agents, either
exogenous or endogenous (e.g. silicosis, atherosclerosis,
Alzheimer dementia and cancer)
3. Autoimmunity and allergy
4. Idiopathic diseases : e.g. autism, idiopathic pulmonary
hypertension and myocardiopathy

RESOLUTION
INJURY

Mediators

Mediators
Persistent infection,
persistent toxin,
autoimmune disease

Acute
inflammation

Chronic
inflammation

ABSCESS FORMATION

HEALING
Regeneration,
scarring

Outcome of acute inflammation

Two stimuli for macrophage activation

Auto immunity

Anti-inflammatory cytokines: mechanisms of action

Mechanisms in Rheumatology 2001

MEDIATORS

CELLULAR
Preformed mediators
in secretary granules

Histamine
Serotin
Lysosomal enzymes

Newly synthesized

Prostaglandin
Leukotrienes
Platelet-activating factors
Activated oxygen species
Nitric oxide
Cytokines

Factor XII (Hageman

factor) activation

SOURCE
Mast cell, basophil, platelets
Platelets
Neutrphils, macrophage

All leukocytes, platelets, EC

All leukocytes
All leukocytes, EC
All leukocytes
Macrophages
Lymphocytes, macrophage, EC

Kinin system (bradykin)

Coagulation/ fibrinolysis system

PLASMA

LIVER
(major source)

Complement
activation

C3a
anaphylaxotins
C5a
C3b
C5b-9(membrane attack complex)

Chemical mediators of inflammation

Inhibition of antigen presentation by viruses

Mechanisms of how viruses may escape

immune surveillance
Negative selection of T cells if viral antigens in thymus
Exhaustive induction and deletion of all peripheral T
cells
Viral effects on lymphocytes ( limphotoxicity, effects on
function ) or interleukin production
Down modulation of class I or II MHC or viral
antigens
Residence in privileged site ( e.g epithelial cells )
T or B epitope escape mutant

Effector functions of antibodies

Inflammation and peripheral nerve

sensitization
Inflammation

COX-2

EP
Receptor

PGE2

PKA
PKC
P

SNS/PN3
TTX-Resistant
Sodium
Channel

Resting
Membrane
Potential
Increases
Neuron Firing
Threshold
Decreases

Samad TA et al. Nature. 2001;410:471-5. Woolf CJ et al. Science.

2000;288:1765-8.
Byers MR et al. In: Bonicas Management of Pain. 2001:26-72.

Inflammation and central sensitization

Cytokines

C-fibre terminal
PG

COX-1/2?

COX-2

Microglia

Glutamate

PG

Glutamate
COX-1/2?

SP

Receptors
NMDA
Non-NMDA
NK-1
EP

COX-1
COX-2

PLA2

Dorsal horn neuron

(Lamina V)

Ca2
+

Modulation of inflammatory response by neuro transmitter

peripheral and sympathetic nervous system

Sensory nerve fibers

For example
Norepinephrine
Adenosine

For example
Substance P

Synovial
tissue

Proinflammatory

Sympathetic nerve
fibers

At low
At high
neurotransmitter
neurotransmitter
concentrations concentrations (, A2)
(2 A1)

Antiinflammatory
Proinflammatory

Humoral Immunity

Pathogenic mechanism of autoimmunity

Pathogenesis of Autoimmune Disease

Triggering factors (probably
environmental)

Susceptibility genes
(usually multiple)

Abnormal Immune Response

Hyperactive T cells

Hyperactive B cells

Inadequate regulatory
mechanism

Persistent pathogenic auto antibodies

Persistent pathogenic immune complexes
(Persistent damaging auto reactive T cell)

Sick syndrome

Innate and adaptive immunity to intracellular bacteria

Phagocytosis

Killing of infected cells by NK cells

Antigens
Foreign
Bacteria
Viruses
proteins
Parasites

HUMORAL RESPONSE

Fungi

CELL MEDIATED RESPON

Vertebrate body

T cell

B cell
TH cell
+
Antigen
Activated
TH cell

+Ag-class II
MHC molecule

Ab-secreting
Plasma cells

CTL
Killing of
altered
self-cell

Antigen
elimination

Cytokine
secretion
Altered
Sel-cell

+Ag-classI
MHC molecule

Macrophages - lymphocytes interactions in

chronic inflammation

Biologic functions of the complement system

Increased of vascular permeability and dilation , mainly by

releasing histamin from mast cells ( C3a, C5a and C4a )

C5a activates the lipooxygenase pathway of AA in neutrophil and

monocytes

Leukocyte adhesion, chemotaxis and activation (C5a) for

neutrophils, monocytes, eosinophils, and basophils

Phagocytosis : C3b and C3b1 act as opsonins and favor

phagocytosis by neutrophil and macrophages which bear cell
surface receptors for C3b

C3 and C5 can be activated by several proteolytic enzymes

present within the inflammatory exudate ( plasmin, lyzosomal
enzymes )

Two stimuli for macrophage activation

IL-1,TNF

Present ag.to
lymphocyte

Interactions of macrophages with lymphocytes in chronic

inflammation

Induction of Th1 and Th2 immune responses

Innate and adaptive immunity

Microbe

Innate immunity

Adaptive immunity
B lymphocytes

Epithelial
barriers

Antibodies

T lymphocytes

Effector T cells

Phagocytes

Complement

NK cells

Hours
0

Days
12

Time after infection

Interaction of plasma protease in inflammation

Innate and adaptive immune responses to viruses

Protection against
infection

Eradication of established
infection

Mechanisms of how viruses may escape

immune surveillance
Negative selection of T cells if viral antigens in thymus
Exhaustive induction and deletion of all peripheral T
cells
Viral effects on lymphocytes ( limphotoxicity, effects on
function ) or interleukin production
Down modulation of class I or II MHC or viral
antigens
Residence in privileged site ( e.g epithelial cells )
T or B epitope escape mutant

IFN- /
IFN- / receptor

2-5(A) synthase

Protein kinase
PKR (inactive)

2-5 (A)

ATP
Inactive RNAse L

Active RNAse L

Degradation of poly (A)mRNA

PKR (activated)

+ ATP and
dsRNA

Phosphorylation of elF-2

elF2-GDP (nonfunctional)

INHIBITION OF PROTEIN SYNTHESIS

Induction of antiviral activity by IFN- and -

Inflammatory reaction

Innate
immunity

Adaptive
immunity

Stimulation of adaptive immunity by innate immune responses

INFECTIONS, TOXINS, IMMUNE COMPLEXES, NEOPLASIA

IL-1/TNF

IL-6

Hypothalamus
Prostaglandins (E)
Vasomotor center
Sympathetic nerves
Skin vasocontriction
Heart dissipation

Fever
Mechanism of fever

Vaso active amines

HISTAMIN. Causes dilation and increased vascular permeability
via H1 receptors . Mostly come from mast cell , but also found in
basophil and platelets, in response to:
Physical injury ( trauma, cold,or heat).
Immune reactions involving binding of Ab to mast cells.
Fragments of complement called anaphylatoxins ( C3a, C5a)
Histamin-releasing proteins derived from leucocytes.
Neuropeptides ( eg substance P).
Cytokines (IL-1,IL-8)
SEROTONIN. Present only in platelets and enterochromaffin cells.

The major local manifestations of acute inflammation

Margination of leukocytes

Chemotaxis
Chemotaxis : locomotion oriented along a chemical
gradient
Chemoattractans: bacterial products and endogenous
chemical mediators
Components of the complement system, particularly
C5a
Products of the lipoxygenase pathway mainly
leukotriene B4 (LTB4)
Cytokines, particularly those of the chemokine family
(eg, IL-8 )

Inhibitors ( regulators ) of Complement Activation

Regulation of C3 and C5 convertases by enhancing the

dissociation ( decay acceleration ) of convertase
complex ( e.g. decay accelerating factor _ DAF,and
Factor I )

Binding of active complement components : C1

inhibitor ( C1 INH )

Proteins that act at the level of MAC formation ( eg

CD59 : membrane inhibitor of reactive lysis )

Ultrastructure of neutrophil granules stained

for peroxidase activity and their constituents

Generation of lipoxin

General properties of cytokines and chemokines

Secretion of cytokines during immune and inflammatory

response is transient and closely regulated

Many cell types produce multiple cytokines

The proteins are pleotrophic in that they can act on

different cell types

Cytokine effects are often redundant, can influence the

synthesis or action of other cytokines

They are multifunction, an individual cytokine may have

both positive and negative regulatory actions

Cytokines mediate their effects by binding to specific

receptors on target cells

General pattern of intracellular signaling

Platelet activating factor

Antigen presentation

(a)

Cytokine receptor
Antigen

CD4

Co-stimulatory
signal

IL-2

TH activation
Effector
+
Memory
TH cells

APC
Class II
TH cell
(dendritic cell) MHC T cell
receptor

IL-2

IL-2

(b)
Antigen

IL-2

B cell

IL-2

Class I MHC

TH cell
Tc cell CD8 Altered self cell

Memory cell

Plasma cell

Memory Tc cell

Killing
CTL

Lysis

Cellular interactions involved in induction of immune responses

Perforin
monomers

Nukleus

Granule

Completed pore

Polymerized perforin

Schematic representation of apoptosis

Effector functions of Th1 cells

Molecular interaction that mediate nave

T lymphocyte activation by antigen
presenting cells (APC)
CD11a/
CD18 CD4/
CD8

CD3/
TCR

CTLA-4
CD 28

CD 2
CD154

T LYMPHOCYTE

CD58

CD54

peptide/
MHC

CD80/
CD86

CD40

ANTIGEN-PRESENTING
CELL

Two types oxide (NO) in endothelium (left) and macrophages (right)

Histologic pattern of acute inflammation

Pathways of reparative responses

after acute
inflammatory injury

Events in the resolution

of inflammation

Generation of diversity in T cell and B cell

antigen receptors
L

Germ line DNA

Rearranged DNA
Rearranged DNA

Primary RNA transcript

mRNA

Aktivasi komplemen
Mikroba
C3b

CR2
Sel B

C5a, C4a,
C3a

Inflamasi

Lisis mikroba Opsonisasi dan

fagositosis mikroba

Imunitas adaptif
(imunitas humoral)

Acute inflammation induced by complement activation

Bacteria

Toxin
1!! Toxin neutralization

2 Complement-mediated lysis
3

Opsonization and
phagocytosis

4 Anaphylatoxin mediate
mast cell degranulation.

C3b
C3b
C3b
C3b

C3a , C4a ,
C5a

Complement
activation
C3b
C3b
C3b
Macrophage

5 Chemotaxis

Mast cell
Mediator
Extravasation

Neutrophil

Lymphocyte

Macrophage

General functions of cytokines

Mechanisms in Rheumatology 2001

Overview of complement activation pathways

Antigen-antibody (IgG or IgM)

complex

CLASSIC PATHWAY

Classic pathway
Activated C1 C3 convertase

C1

Classic pathway
C5 convertase
C4b2a3b

C3b2a

C4 + C2

Also generated via plasmin

or lysosomal proteases
C5a

C3a
C3

C5

C6 C7 C8 C9
C5b

C3b

C3

C3b

C3bBb

Alternative pathway
C3 convertase
Factor Factor
Stabilized by
B
D
Microbial surfaces
properdin

Polysaccharides

C5-9
Membrane
attack complex

C3bBb3b
Alternative pathway
C5 convertase

ALTERNATIVE PATHWAY

Inhibition of antigen presentation by viruses

TERIMA KASIH