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prepared by
Janice Meeking,
Mount Royal College
CHAPTER
21
The Immune
System:
Innate and
Adaptive:Body
Defenses:
Part A
Copyright © 2010 Pearson Education, Inc.
Immunity
• Resistance to disease
• Immune system has two intrinsic systems
• Innate (nonspecific) defense system
• Adaptive (specific) defense system
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Immunity
1. Innate defense system has two lines of
defense
• First line of defense is external body
membranes (skin and mucosae)
• Second line of defense is antimicrobial
proteins, phagocytes, and other cells
• Inhibit spread of invaders
• Inflammation is its most important
mechanism
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Immunity
2. Adaptive defense system
• Third line of defense attacks particular
foreign substances
• Takes longer to react than the innate
system
• Innate and adaptive defenses are deeply
intertwined
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Surface barriers
• Skin
• Mucous membranes
Innate
defenses
Internal defenses
• Phagocytes
• NK cells
• Inflammation
• Antimicrobial proteins
• Fever
Humoral immunity
• B cells
Adaptive
defenses
Cellular immunity
• T cells
Copyright © 2010 Pearson Education, Inc.
Figure 21.1
Innate Defenses
• Surface barriers
• Skin, mucous membranes, and their
secretions
• Physical barrier to most microorganisms
• Keratin is resistant to weak acids and bases,
bacterial enzymes, and toxins
• Mucosae provide similar mechanical barriers
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Surface Barriers
• Protective chemicals inhibit or destroy
microorganisms
• Skin acidity (pH of 3 – 5)
• Lipids in sebum and Dermcidin in eccrine
sweat glands
• HCl and protein-digesting enzymes of stomach
mucosae
• Lysozyme of saliva and lacrimal fluid
• Mucus
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Surface Barriers
• Respiratory system modifications
• Mucus-coated hairs in the nose
• Cilia of upper respiratory tract sweep dust- and
bacteria-laden mucus from lower respiratory
passages
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Internal Defenses: Cells and Chemicals
• Necessary if microorganisms invade deeper
tissues
• Phagocytes
• Natural killer (NK) cells
• Inflammatory response (macrophages, mast
cells, WBCs, and inflammatory chemicals)
• Antimicrobial proteins (interferons and
complement proteins)
• Fever
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Phagocytes: Macrophages
• Macrophages develop from monocytes to
become the chief phagocytic cells
• Free macrophages wander through tissue
spaces
• E.g., alveolar macrophages
• Fixed macrophages are permanent
residents of some organs
• E.g., Kupffer cells (liver) and microglia
(brain)
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Phagocytes: Neutrophils
• Neutrophils
• Become phagocytic on encountering infectious
material in tissues
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Mechanism of Phagocytosis
Step 1: Adherence of phagocyte to pathogen
• Facilitated by opsonization—coating of
pathogen by complement proteins or
antibodies
• In order to adhere the phagocytic cell must
recognize and be able to bind to something on
the outside of the organism-generally the
carbohydrate. Some organisms cannot be
bound to like the pneumococcus unless it is
already coated – opsonization.
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Innate defenses
Internal defenses
(a) A macrophage (purple) uses its cytoplasmic
extensions to pull spherical bacteria (green)
toward it. Scanning electron micrograph (1750x).
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Figure 21.2a
1 Phagocyte
adheres to
pathogens or debris.
Lysosome
Phagosome
(phagocytic
vesicle)
Acid
hydrolase
enzymes
(b) Events of phagocytosis.
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2 Phagocyte forms
pseudopods that
eventually engulf the
particles forming a
phagosome.
3 Lysosome fuses
with the phagocytic
vesicle, forming a
phagolysosome.
4 Lysosomal
enzymes digest the
particles, leaving a
residual body.
5 Exocytosis of the
vesicle removes
indigestible and
residual material.
Figure 21.2b
Mechanism of Phagocytosis
• Destruction of pathogens
• Acidification and digestion by lysosomal enzymes –
Some organisms cannot be destroyed by the
lysosome enzymes – like TB – so a granuloma
formed.
• Respiratory burst
• Release of cell-killing free radicals
• Activation of additional enzymes – generally by
changes in pH (becomes more basic) and
osmolarity in the lysosome
• Oxidizing chemicals (e.g. H2O2)
• Defensins (in neutrophils) – pierce membrane
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Respiratory Burst
• Respiratory burst (is sometimes called oxidative burst) is
the rapid release of reactive oxygen species (superoxide
radical and hydrogen peroxide) from different types of cells.
• Usually it denotes the release of these chemicals from immune
cells, e.g., neutrophils and monocytes, as they come into
contact with different bacteria or fungi.
• To maximally activate the respiratory burst – T-helper cells
stimulate phagocytes
• The respiratory burst also increases the pH and osmolarity in
the phagolysosome – thus activating other protein-digesting
enzymes that digest the invader.
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Chronic granulomatous disease
• a diverse group of hereditary diseases in which certain cells of
the immune system have difficulty forming the reactive oxygen
compounds (most importantly, the superoxide radical) used to
kill certain ingested pathogens. This leads to the formation of
granulomata in many organs. CGD affects about 1 in 200,000
people in the United States, with about 20 new cases diagnosed
each year
• There are over 410 known possible defects in the PHOX
enzyme complex that can lead to chronic granulomatous
disease
• There are currently no studies detailing the long term outcome
of chronic granulomatous disease with modern treatment.
Without treatment children often die in the first decade of life.
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Granuloma
Granuloma is a medical term for a roughly spherical
mass of immune cells that forms when the immune
system attempts to wall off substances that it perceives
as foreign but is unable to eliminate. Such substances
include infectious organisms such as and bacteria and
fungi as well as other materials such as keratin and
suture fragments. A granuloma is therefore a special
type of inflammation that can occur in a wide variety of
diseases.
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Natural Killer (NK) Cells (CD 16 & CD 56)
• Large granular lymphocytes - larger lymphocytes with
small granules (stained vesicles)
• Target cells that lack “self” cell-surface receptors or
cells that display wrong MHCI or MICA
• NK cell will not attack if a cell’s LY49 receptor is
displayed and can be recognized by the NK cell’s
MHCI
• Secrete perforans and granzyme
• Induce apoptosis in cancer cells and virus-infected
cells
• Secrete potent chemicals that enhance the
inflammatory response
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Inflammatory Response
• Triggered whenever body tissues are injured
or infected
1. Prevents the spread of damaging agents
2. Disposes of cell debris and pathogens
3. Sets the stage for repair
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Inflammatory Response
•
Cardinal signs of acute inflammation:
1. Redness
2. Heat
3. Swelling
4. Pain
(And sometimes 5. Impairment of function)
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Inflammatory Response
• Macrophages and epithelial cells of boundary
tissues bear Toll-like receptors (TLRs)
• Eleven recognized TLR
• TLRs recognize specific classes of infecting
microbes – like Salmonella and TB
• Activated TLRs trigger the release of
cytokines that promote inflammation and
attract WBCs
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Inflammatory Response
• Inflammatory mediators
• Histamine (from mast cells and Basophils)
• Blood proteins
• Kinins, prostaglandins (PGs), leukotrienes,
and complement
• Singulair is a leukotriene inhibitor
• Released by injured tissue, phagocytes,
lymphocytes, basophils, and mast cells
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Vasodilation and Increased Vascular
Permeability
• Inflammatory chemicals cause
• Dilation of arterioles, resulting in hyperemia
• Increased permeability of local capillaries and
edema (leakage of exudate) – edema helps
with sweep of organisms and chemicals into
capillaries of the lymphatics
• Exudate contains proteins, clotting factors,
and antibodies
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Inflammatory Response: Edema
• Functions of the surge of exudate
• Moves foreign material into lymphatic vessels
• Delivers clotting proteins to form a scaffold for
repair and to isolate the area – by walling off
the infected area
• Streptococcus can produce Streptokinase to
break down clot and open the walled off area
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Anti-inflammatory agents
• NSAID – Non-steroidal antiinflammatory drugs
– which are anti-prostaglandins
• SAID – Steroidal anti-inflammatory drugs –
which are natural and synthetic
glucocorticoids
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NSAID
• drugs with analgesic and antipyretic (feverreducing) effects and which have, in higher
doses, anti-inflammatory effects (reducing
inflammation).
• There are two main types of NSAIDs,
nonselective and selective. The terms
nonselective and selective refer to different
NSAIDs ability to inhibit specific types of
cyclooxygenase (COX) enzymes.
• Nonselective NSAIDs — Nonselective NSAIDs
inhibit both COX-1 and COX-2 enzymes to a
similar degree.
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• Nonselective NSAIDs — Nonselective
NSAIDs inhibit both COX-1 and COX-2
enzymes to a similar degree.
• Selective NSAIDs — Selective NSAIDs inhibit
COX enzymes found at sites of inflammation
(COX-2) more than the type that is normally
found in the stomach, blood platelets, and
blood vessels (COX-1).
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• Nonselective NSAIDs — Nonselective
NSAIDs include commonly available drugs
such as aspirin, ibuprofen (Advil®, Motrin®,
Nuprin®), and naproxen (Aleve®), as well as
some prescription-strength NSAIDs
• Selective NSAIDs — Selective NSAIDs (also
called COX-2 inhibitors) are as effective in
relieving pain and inflammation as
nonselective NSAIDs and are less likely to
cause gastrointestinal injury.
Celecoxib (Celebrex®) is the only selective
NSAID currently available in the United
States.
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SAID (Glucocorticoids)
• Glucocorticoids influence all types of inflammatory
events, no matter their cause. They induce the lipocortin1 (annexin-1) synthesis, which then binds to cell
membranes preventing the phospholipase A2 from
coming into contact with its substrate arachidonic acid.
This leads to diminished eicosanoid production. The
cyclooxygenase (both COX-1 and COX-2) expression is
also suppressed, potentiating the effect.
• Glucocorticoids also stimulate the lipocortin-1 escaping to
the extracellular space, where it binds to the leukocyte
membrane receptors and inhibits various inflammatory
events: epithelial adhesion, emigration, chemotaxis,
phagocytosis, respiratory burst, and the release of
various inflammatory mediators (lysosomal enzymes,
cytokines, tissue plasminogen activator, chemokines,
etc.) from neutrophils, macrophages, and mastocytes.
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Beta Defensins
• Beta defensins are a family of mammalian
defensins. The beta defensins are antimicrobial
peptides implicated in the resistance of epithelial
surfaces to microbial colonization.
• Present in epithelial mucosal cells – and released
when the epithelial cells are damaged
• Most defensins function by binding to the
microbial cell membrane, and, once embedded,
forming pore-like membrane defects that allow
efflux of essential ions and nutrients.
• Alpha defensins are produced by neutrophils
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Innate defenses
Tissue injury
Internal defenses
Release of chemical mediators
(histamine, complement,
kinins, prostaglandins, etc.)
Release of leukocytosisinducing factor
Leukocytosis
(increased numbers of white
blood cells in bloodstream)
Initial stimulus
Vasodilation
of arterioles
Increased capillary
permeability
Local hyperemia
(increased blood
flow to area)
Capillaries
leak fluid
(exudate formation)
Attract neutrophils,
monocytes, and
lymphocytes to
area (chemotaxis)
Leukocytes migrate to
injured area
Margination
(leukocytes cling to
capillary walls)
Physiological response
Signs of inflammation
Leaked protein-rich
fluid in tissue spaces
Result
Heat
Redness
Locally increased
temperature increases
metabolic rate of cells
Pain
Swelling
Possible temporary
limitation of
joint movement
Leaked clotting
proteins form interstitial
clots that wall off area
to prevent injury to
surrounding tissue
Temporary fibrin
patch forms
scaffolding for repair
Diapedesis
(leukocytes pass through
capillary walls)
Phagocytosis of pathogens
and dead tissue cells
(by neutrophils, short-term;
by macrophages, long-term)
Pus may form
Area cleared of debris
Healing
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Figure 21.3
Phagocyte Mobilization
• Neutrophils, then phagocytes flood to
inflamed sites
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Phagocyte Mobilization
•
Steps for phagocyte mobilization
1. Leukocytosis: release of neutrophils from bone
marrow in response to leukocytosis-inducing factors
from injured cells
2. Margination: neutrophils cling to the walls of
capillaries in the inflamed area (selectins)
3. Diapedesis of neutrophils
4. Chemotaxis: inflammatory chemicals (chemotactic
agent) promote positive chemotaxis of neutrophils
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Innate
defenses
Internal
defenses
Inflammatory
chemicals
diffusing
from the
inflamed site
act as chemotactic
agents.
Leukocytosis.
Neutrophils enter blood
from bone marrow.
1
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Margination.
Neutrophils cling
to capillary wall.
2
Chemotaxis.
Neutrophils
follow chemical
trail.
4
Capillary wall
Basement
membrane
Endothelium
Diapedesis.
Neutrophils flatten and
squeeze out of capillaries.
3
Figure 21.4
Innate
defenses
Internal
defenses
Inflammatory
chemicals
diffusing
from the
inflamed site
act as chemotactic
agents.
Capillary wall
Basement
membrane
Endothelium
Leukocytosis.
Neutrophils enter blood
from bone marrow.
1
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Figure 21.4, step 1
Innate
defenses
Internal
defenses
Inflammatory
chemicals
diffusing
from the
inflamed site
act as chemotactic
agents.
Leukocytosis.
Neutrophils enter blood
from bone marrow.
1
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Capillary wall
Basement
membrane
Endothelium
Margination.
Neutrophils cling
to capillary wall.
2
Figure 21.4, step 2
Innate
defenses
Internal
defenses
Inflammatory
chemicals
diffusing
from the
inflamed site
act as chemotactic
agents.
Leukocytosis.
Neutrophils enter blood
from bone marrow.
1
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Margination.
Neutrophils cling
to capillary wall.
2
Capillary wall
Basement
membrane
Endothelium
Diapedesis.
Neutrophils flatten and
squeeze out of capillaries.
3
Figure 21.4, step 3
Innate
defenses
Internal
defenses
Inflammatory
chemicals
diffusing
from the
inflamed site
act as chemotactic
agents.
Leukocytosis.
Neutrophils enter blood
from bone marrow.
1
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Margination.
Neutrophils cling
to capillary wall.
2
Chemotaxis.
Neutrophils
follow chemical
trail.
4
Capillary wall
Basement
membrane
Endothelium
Diapedesis.
Neutrophils flatten and
squeeze out of capillaries.
3
Figure 21.4, step 4
Antimicrobial Proteins
• Interferons (IFNs) and complement proteins
• Attack microorganisms directly
• Hinder microorganisms’ ability to reproduce
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Interferons
• Viral-infected cells are activated to secrete
IFNs
• IFNs enter neighboring cells
• Neighboring cells produce antiviral proteins
that block viral reproduction
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Innate defenses
Virus
Viral nucleic acid
1 Virus
enters cell.
Internal defenses
New viruses
5 Antiviral
proteins block
viral
reproduction.
2 Interferon
genes switch on.
DNA
Nucleus
mRNA
4 Interferon
3 Cell produces
interferon
molecules.
Interferon
Host cell 2
Host cell 1
Binds interferon
Infected by virus; from cell 1; interferon
makes interferon; induces synthesis of
is killed by virus
protective proteins
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binding
stimulates cell to
turn on genes for
antiviral proteins.
Figure 21.5
Innate defenses
Virus
Viral nucleic acid
Internal defenses
1 Virus
enters cell.
Nucleus
Host cell 1
Infected by virus;
makes interferon;
is killed by virus
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Host cell 2
Binds interferon
from cell 1; interferon
induces synthesis of
protective proteins
Figure 21.5, step 1
Innate defenses
Virus
Viral nucleic acid
Internal defenses
1 Virus
enters cell.
2 Interferon
genes switch on.
DNA
Nucleus
Host cell 1
Infected by virus;
makes interferon;
is killed by virus
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Host cell 2
Binds interferon
from cell 1; interferon
induces synthesis of
protective proteins
Figure 21.5, step 2
Innate defenses
Virus
Viral nucleic acid
Internal defenses
1 Virus
enters cell.
2 Interferon
genes switch on.
DNA
Nucleus
mRNA
3 Cell produces
interferon
molecules.
Interferon
Host cell 2
Host cell 1
Binds interferon
Infected by virus; from cell 1; interferon
makes interferon; induces synthesis of
is killed by virus
protective proteins
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Figure 21.5, step 3
Innate defenses
Virus
Viral nucleic acid
Internal defenses
1 Virus
enters cell.
2 Interferon
genes switch on.
DNA
Nucleus
mRNA
4 Interferon
3 Cell produces
interferon
molecules.
Interferon
Host cell 2
Host cell 1
Binds interferon
Infected by virus; from cell 1; interferon
makes interferon; induces synthesis of
is killed by virus
protective proteins
Copyright © 2010 Pearson Education, Inc.
binding
stimulates cell to
turn on genes for
antiviral proteins.
Figure 21.5, step 4
Innate defenses
Virus
Viral nucleic acid
1 Virus
Internal defenses
New viruses
enters cell.
5 Antiviral
proteins block
viral
reproduction.
2 Interferon
genes switch on.
DNA
Nucleus
mRNA
4 Interferon
3 Cell produces
interferon
molecules.
Host cell 1
Infected by virus;
makes interferon;
is killed by virus
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Interferon
Host cell 2
Binds interferon
from cell 1; interferon
induces synthesis of
protective proteins
binding
stimulates cell to
turn on genes for
antiviral proteins.
Figure 21.5, step 5
Interferons
• Produced by a variety of body cells
• Lymphocytes produce gamma (), or immune,
interferon – stimulates macrophages to killer
status
• Most other WBCs produce alpha () interferon
– reduce inflammation
• Fibroblasts produce beta () interferon –
reduce inflammation
• Interferons also activate macrophages and
mobilize NKs
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Interferons
• Functions
• Anti-viral – in the cell being defended the cell
produces PKR ( Protein Kinase RNA) – this
blocks the virus from making new proteins in
the host cell – blocks at the ribosome
• Reduce inflammation
• Activate macrophages and mobilize NK cells
• Genetically engineered IFNs for
• Antiviral agents against hepatitis and genital
warts virus – alpha and Beta Interferons
• Multiple sclerosis treatment – Beta Interferon
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Complement
• ~20 blood proteins that circulate in an
inactive form
• Include C1–C9, factors B, D, and P, and
regulatory proteins
• Major mechanism for destroying foreign
substances
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Complement
• Amplifies all aspects of the inflammatory
response
• Kills bacteria and certain other cell types by
cell lysis
• Enhances both nonspecific and specific
defenses
• Opsonization – Inflammation and Lysis
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Complement Activation
• Two pathways
1. Classical pathway
• Antibodies bind to invading organisms or
CRP
Note: only two antibodies bind compliment
–IgG and IgM
• C1 binds to the antigen-antibody
complexes (complement fixation)
2. Alternative pathway
• Triggered when activated C3, B, D, and
P interact on the surface of
microorganisms
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Complement Activation
• Each pathway involves activation of proteins
in an orderly sequence
• Each step catalyzes the next
• Both pathways converge on C3, which
cleaves into C3a and C3b
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Complement Activation
• Activated complement
• Enhances inflammation
• Promotes phagocytosis
• Causes cell lysis
• C3b initiates formation of a membrane attack
complex (MAC)
• MAC causes cell lysis by inducing a massive influx
of water
• C3b also causes opsonization, and C3a causes
inflammation
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Two IgG or CRP or 1 IgM
Classical pathway
Antigen-antibody complex
+
complex
Opsonization:
coats pathogen
surfaces, which
enhances phagocytosis
Insertion of MAC and cell lysis
(holes in target cell’s membrane)
Surface not protected by sialic acid
Alternative pathway
Spontaneous activation
+
Stabilizing factors (B, D, and P)
+
No inhibitors on pathogen
surface
Enhances inflammation:
stimulates histamine release,
increases blood vessel
permeability, attracts
phagocytes by chemotaxis,
etc.
Pore
Complement
proteins
(C5b–C9)
Membrane
of target cell
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Figure 21.6
C-Reactive Protein (CRP)
• C-reactive protein (CRP) is a protein found
in the blood, the levels of which rise in
response to inflammation (an acute-phase
protein). Its physiological role is to bind to
phosphocholine expressed on the surface of
dead or dying cells (and some types of
bacteria) in order to activate the complement
system via the C1Q complex.
• CRP is synthesized by the liver in response to
factors released by fat cells.
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C-Reactive Protein (CRP)
• CRP was originally discovered by Tillett and
Francis in 1930 as a substance in the serum of
patients with acute inflammation that reacted with
the C polysaccharide of pneumococcus.
• CRP is a member of the class of acute-phase
reactants, as its levels rise dramatically during
inflammation processes occurring in the body.
• CRP rises up to 50,000-fold in acute inflammation,
such as infection. It rises above normal limits
within 6 hours, and peaks at 48 hours. Its halflife is constant, and therefore its level is mainly
determined by the rate of production
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CRP versus ESR
• The erythrocyte sedimentation rate (ESR is
the rate at which red blood cells precipitate in
a period of 1 hour. It is a common hematology
test which is a non-specific measure of
inflammation. To perform the test,
anticoagulated blood is placed in an upright
tube, known as a Westergren tube, and the
rate at which the red blood cells fall is
measured and reported in mm/h.
• ESR – slower and more prolonged sign of
inflammation than the CRP
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Fever
• Systemic response to invading
microorganisms
• Leukocytes and macrophages exposed to
foreign substances secrete pyrogens
• Pyrogens reset the body’s thermostat upward
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Fever
• Pyrogens generally microorganisms cause the
release of fever inducing cytokines from cells such
as WBC , smooth muscle cells, glial cells and some
others
• The cytokines are IL1, TNF, Interferon alpha, and
IL6
• These travel in the circulation causing certain blood
vessel endothelial cells in the thermal control center
(Pre-optic nucleus) in the hypothalamus to produce
PGE2 – which causes cyclic AMP to produced
subsequently causing the cells of the pre-optic
nucleus to raise the body temperature
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Fever
• High fevers are dangerous because heat
denatures enzymes
• Benefits of moderate fever
• Causes the liver and spleen to sequester iron
and zinc (needed by microorganisms)
• Increases metabolic rate, which speeds up
repair
• Kills certain organisms like syphilis
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Fever versus Hyperthermia
• A fever is when the temperature set point in
the hypothalamus is changed
• Hyperthermia is a condition when normal
metabolic heat cannot be dissipated – thus
raising the body temperature
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Adaptive Defenses
• The adaptive immune (specific defense)
system
• Protects against infectious agents and
abnormal body cells
• Amplifies the inflammatory response
• Activates complement
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Adaptive Defenses
•
•
Adaptive immune response
•
Is specific
•
Is systemic
•
Has memory
Two separate overlapping arms
1. Humoral (antibody-mediated) immunity
2. Cellular (cell-mediated) immunity
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Antigens (Antibody Generating)
• Antigen – substance that be recognized by the
adaptive immune system (can be partial or complete)
• Isoantigens (self MHC 1) and hetero-antigens
• Immunogen – special type of antigen that can
stimulate the 3rd line (adaptive immune system) by
itself (complete antigen)
• Substances that can mobilize the adaptive
defenses and provoke an immune response
• Most are large, complex organic molecules not
normally found in the body (nonself) –proteins are
generally the most antigenic
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Complete Antigens (Immunogenicity)
• Important functional properties
• Immunogenicity: ability to stimulate
proliferation of specific lymphocytes and
antibodies (complete antigen)
• Reactivity: ability to react with products of
activated lymphocytes and antibodies released
(partial antigen if only can do reactivity and not
immunogenicity)
Examples: foreign protein, polysaccharides,
lipids, and nucleic acids
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Haptens (Incomplete Antigens)
Antigenicity
• Small molecules (peptides, nucleotides, and
hormones) – less than 1,000 AMU (Daltons)
• Not immunogenic by themselves
• Are immunogenic when attached to body
proteins
• Cause the immune system to mount a harmful
attack
• Examples: poison ivy, animal dander,
detergents, and cosmetics
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Antigenic Determinants (Epitopes)
• Certain parts of an entire antigen that are
immunogenic
• Antibodies and lymphocyte receptors bind to
them
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Antigenic Determinants
• Most naturally occurring antigens have
numerous antigenic determinants that
• Mobilize several different lymphocyte
populations
• Form different kinds of antibodies against it
• Large, chemically simple molecules (e.g.,
plastics or metals – like a prosthesis) have
little or no immunogenicity
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Multiple antigenic determinants on surface of the bacteria
If each antigenic determinant is different – then a different antibody and
/or T cell can attach to it. cell will attach
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Antibody A
Antigenbinding
sites
Antigenic determinants
Antigen
Antibody B
Antibody C
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Figure 21.7
Self-Antigens (Isoantigens) : MHC Proteins
• Protein molecules (self-antigens) on the
surface of cells
• Antigenic to others in transfusions or grafts
• Example: MHC proteins
• Coded for by genes of the major
histocompatibility complex (MHC) and are
unique to an individual
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MHC Proteins
• In humans, the 3.6-Mb (3,600,000 base pairs) MHC
region on chromosome 6 contains 140 genes
• Classes of MHC proteins
• Class I MHC proteins, found on virtually all body cells
• Class II MHC proteins, found on certain cells in the
immune response
• Class MHC III – code for immune components such as
complement, and some cytokines like TNF
• MHC proteins display peptides (usually self-antigens)
• In infected cells, MHC proteins display fragments of
foreign antigens- MICA, which help mobilize
• MICA – MHC Class I Chain – related Gene A
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MHC I and II
• The MHC surface markers are proteins that have
a groove in their surfaces exposed to the outside
of the cell
• The groove is filled with some substance – if the
MHC I – it is filled with a piece of a protein
formed from the inside of the cells (endogenous
antigens) – proteins formed on the inside of the
cell could be normal or abnormal (virus or tumor)
• If MHC II – it is filled with some coming from the
outside of the cell (exogenous antigens)
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Cells of the Adaptive Immune System
• Two types of lymphocytes
• B lymphocytes (B cells)—humoral immunity
• T lymphocytes (T cells)—cell-mediated
immunity
• Antigen-presenting cells (APCs)
• Do not respond to specific antigens
• Play essential auxiliary roles in immunity
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Lymphocytes
• Originate in red bone marrow
• B cells mature in the red bone marrow (B
originally came from the studies done in the
Bursa of Fabricius of the chicken)
• T cells mature in the thymus
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Proportions of Lymphocytes
• Natural Killer -
7% (2-13%)
• T helper – T4 –
46% (28 – 59%)
• T cytotoxic T8 –
19% (13-32%)
• T gamma –delta – no number
• B – cells -
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23% (18 – 47%)
• When Lymphocytes are mature, they have
• Immunocompetence; they are able to recognize
and bind to a specific antigen (recognize where to
look for an antigen and bind tight if foreign)
• Self-tolerance – unresponsive to self antigens
• Naive (unexposed) B and T cells are exported from the
primary lymphoid organs (Thymus and Bone marrow)
to lymph nodes, spleen, and other lymphoid organs
• Terminology - before immunocompetence – immature
– after immunocompetence but have not met an
antigen – naïve – after meeting antigen but no
costimulation- active idling – after costimulation –
fully active
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Adaptive defenses
Immature
lymphocytes
Red bone marrow: site of lymphocyte origin
Humoral immunity
Cellular immunity
Primary lymphoid organs: site of
development of immunocompetence as B or
T cells
Secondary lymphoid organs: site of
antigen encounter, and activation to become
effector and memory B or T cells
Red
bone marrow
1 Lymphocytes destined to become T cells
migrate (in blood) to the thymus and develop
immunocompetence there. B cells develop
immunocompetence in red bone marrow.
Thymus
Bone marrow
2 Immunocompetent but still naive
Lymph nodes,
spleen, and other
lymphoid tissues
lymphocytes leave the thymus and bone
marrow. They “seed” the lymph nodes,
spleen, and other lymphoid tissues where
they encounter their antigen.
3 Antigen-activated immunocompetent
lymphocytes (effector cells and memory
cells) circulate continuously in the
bloodstream and lymph and throughout
the lymphoid organs of the body.
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Figure 21.8
T Cells (Have TCR – T cell receptor –CD3)
• In the thymus under the influence of thymic hormones
(Thymosins) get educated and get CDs (CD3 and other
specific CD like 4, 8, 10 or gamma delta) on cell surface have
104 to 105
• Thymic education process involves two processes – positive
and negative selection (no outsiders – Blood-Thymic barrier)
• Positive selection
• Selects T cells capable of loosely binding to the self-MHC
proteins themselves (MHC restriction) –– This is a
recognition and restriction process
• Negative selection
• Prompts apoptosis of T cells that bind too tightly to selfthe self antigens displayed by self-MHC proteins
• Ensures self-tolerance
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MHC restriction further clarified
• 1. Good T-lymphocytes should be restricted to only view
antigens associated with an MHC I or MHC II
• 2. If the cell is a T helper cell it should be restricted to
only view antigens (foreign) on an MHC II
• 3. If the T cell is any other variety like the T-cytotoxic –
then it should only be restricted to view antigens
(endogenously produced) on MHC I – and only view it if
the antigen presented is endogenous. Some
endogenous antigens (proteins) are cut up proteins
displaying trouble (virus, intracellular parasite or tumor)
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T-cells
• When a cell enters the thymus gland it receives many
T cell receptors (CD 3) – the T cell receptors are of
different varieties (variety determines whether it can
view only MHC I or MHC II) – but each cell has one
variety with somewhere between 100,000 – 1,000,000
copies of the receptors on the cell membrane
• During positive selection – only the variety of T-cells having a
T cell receptor that recognizes our own MHC isoantigen proteins
(only the MHC itself – not anything bound to it) displayed on the
epithelial cells in the Thymus outer cortex are retained – those
that do not undergo apoptosis – MHC restriction – T cells should
only view MHC receptors
• During positive selection T helper cells should be directed to
only view MHC II and all the others MHC I (like the T cytotoxic)
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Negative Selection
• Occurs in inner thymic cortex as cells move
downward from the outer cortical area where
positive selection occurred.
• In negative selection – non T helper –cells
that bind to (especially too tightly) MHC I
receptors with one of our own proteins in its
groove are eliminated (apoptosis) – this is
how we develop tolerance
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Types of T cells
• While positive and negative selection is occurring in the
thymus the immature T cells are also expressing CD4 or
CD8 antigens on their surface. Initially the pre-T cell that
enters the thymus is CD4-CD8-. In the thymus it becomes
CD4+CD8+ and as positive and negative selection
proceeds a cell becomes either a CD4+ or CD8+ cell.
• The commitment to become either a CD4+ or CD8+ cells
depends on which class of MHC molecule the cell
encounters. If a CD4+CD8+ cell is presented with a class
I molecule it will down regulate CD4 and become a CD8+
cell. If a cell is presented with a class II MHC molecule it
will down regulate CD8 and become a CD4+ cell
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Thymic education occurs in cortex
• Outer cortex – Positive Selection
• Inner cortex – Negative Selection
Thymic education is a 2 -3 day
process.
Only 2% graduate – 98% undergo
apoptosis
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Adaptive defenses
Cellular immunity
Positive selection: T cells must recognize self major
histocompatibility proteins (self-MHC).
AntigenDeveloping
presenting
T cell
thymic cell
Failure to recognize self-MHC
results in apoptosis (death
by cell suicide).
MHC
T cell receptor
Self-antigen
Recognizing self-MHC results in
MHC restriction—survivors are
restricted to recognizing antigen
on self-MHC. Survivors proceed
to negative selection.
Negative selection: T cells must not recognize self-antigens.
Recognizing self-antigen results
in apoptosis. This eliminates
self-reactive T cells that could
cause autoimmune diseases.
Failure to recognize (bind tightly
to) self-antigen results in survival
and continued maturation.
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Figure 21.9
B Cells (B-cell receptors are surface
antibodies – CD 19 and 21)
• B cells mature in red bone marrow
• Self-reactive B cells
• Are eliminated by apoptosis (clonal deletion) or
• Undergo receptor editing – rearrangement of
their receptors
• Are inactivated (anergy) if they escape from
the bone marrow
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B cells should only recognize foreign substances – not self at all!
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Antigen Receptor Diversity
• Lymphocytes make up to a billion different types of antigen
receptors
• Coded for by only ~20,000 - 25,000 genes (Domain genes)
• The haploid human genome contains 23,000 protein-coding
genes, far fewer than had been expected before its
sequencing. In fact, only about 1.5% of the genome codes for
proteins, while the rest consists of non-coding RNA genes,
regulatory sequences, introns, and (controversially named)
"junk" DNA
• Gene segments are shuffled by somatic
recombination
• Genes determine which foreign substances the
immune system will recognize and resist
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Karyotype
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Introns act as spacers for genetic recombination of domains (exons)
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Antigen-Presenting Cells (APCs)
• Have MHC II on their cell surfaces
• Engulf antigens
• Present fragments of antigens to be recognized by T
cells
• Major types
• Dendritic cells in connective tissues and epidermis
• Macrophages in connective tissues and lymphoid
organs
• Some B cells
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Dendritic cell like the Langerhans cell
Figure 21.10
Macrophages and Dendritic Cells
• Present antigens and activate T cells
• Macrophages mostly remain fixed in the lymphoid
organs
• Dendritic cells internalize pathogens and enter
lymphatics to present the antigens to T cells in
lymphoid organs
• Activated T cells release chemicals that
• Prod macrophages to become insatiable phagocytes
and to secrete bactericidal chemicals
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Adaptive Immunity: Summary
• Uses lymphocytes, APCs, and specific
molecules to identify and destroy nonself
substances
• Depends upon the ability of its cells to
• Recognize antigens by binding to them
• Communicate with one another so that the
whole system mounts a specific response
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Humoral Immunity Response
• Antigen challenge
• First encounter between an antigen and a
naive immunocompetent lymphocyte
• Usually occurs in the spleen or a lymph node
• If the lymphocyte is a B cell
• The antigen provokes a humoral immune
response
• Antibodies are produced
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Clonal Selection
1. B cell is activated when antigens bind to its
surface receptors and cross-link them
2. Receptor-mediated endocytosis of crosslinked antigen-receptor complexes occurs
3. Stimulated B cell grows to form a clone of
identical cells bearing the same antigenspecific receptors
(T cells are usually required to help B cells
achieve full activation)
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Fate of the Clones
• Most clone cells become plasma cells
• secrete specific antibodies at the rate of 2000
molecules per second for four to five days
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Fate of the Clones
• Secreted antibodies
• Circulate in blood or lymph
• Bind to free antigens
• Mark the antigens for destruction
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Fate of the Clones
• Clone cells that do not become plasma cells
become memory cells
• Provide immunological memory
• Mount an immediate response to future
exposures of the same antigen
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Adaptive defenses
Humoral immunity
Primary response
(initial encounter
with antigen)
Activated B cells
Plasma cells
(effector B cells)
Secreted
antibody
molecules
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Antigen
Proliferation to
form a clone
Antigen binding
to a receptor on a
specific B lymphocyte
(B lymphocytes with
non-complementary
receptors remain
inactive)
Memory B cell—
primed to
respond to same
antigen
Figure 21.11 (1 of 2)
Immunological Memory
• Primary immune response
• Occurs on the first exposure to a specific
antigen
• Lag period: three to six days
• Note – the lag period is the time it takes for the
selected B cells to proliferate to approximately 12
generations and to differentiate into plasma cells
• Peak levels of plasma antibody are reached in
10 days
• Antibody levels then decline quickly
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Immunological Memory
• Secondary immune response
• Occurs on re-exposure to the same antigen
• Sensitized memory cells respond within hours
• Antibody levels peak in two to three days at
much higher levels
• Antibodies bind with greater affinity
• Antibody level can remain high for weeks to
months
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Adaptive defenses
Humoral immunity
Primary response
(initial encounter
with antigen)
Activated B cells
Proliferation to
form a clone
Plasma cells
(effector B cells)
Memory B cell—
primed to respond
to same antigen
Secreted
antibody
molecules
Secondary response
(can be years later)
Antigen
Antigen binding
to a receptor on a
specific B lymphocyte
(B lymphocytes with
non-complementary
receptors remain
inactive)
Clone of cells
identical to
ancestral cells
Subsequent
challenge by
same antigen
results in more
rapid response
Plasma
cells
Secreted
antibody
molecules
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Memory
B cells
Figure 21.11
Secondary immune response to
antigen A is faster and larger; primary
immune response to antigen B is
similar to that for antigen A.
Primary immune
response to antigen
A occurs after a delay.
Antibodies
to B
Antibodies
to A
First exposure
to antigen A
Second exposure to antigen A;
first exposure to antigen B
Time (days)
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Figure 21.12
Active Humoral Immunity
• Occurs when B cells encounter antigens and
produce specific antibodies against them
• Two types
• Naturally acquired—response to a bacterial
or viral infection
• Artificially acquired—response to a vaccine
of dead or attenuated pathogens
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Active Immunity (Artificially Acquired) - Vaccines
See Vaccine PowerPoint
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Passive Humoral Immunity
• B cells are not challenged by antigens
• Immunological memory does not occur
• Passive immunization is used when there is
a high risk of infection and insufficient time for
the body to develop its own immune
response, or to reduce the symptoms of
ongoing or immunosuppressive diseases
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Passive Humoral Immunity
• Two types
1. Naturally acquired—antibodies delivered to
a fetus via the placenta or to infant through
milk
2. Artificially acquired—injection of serum,
such as gamma globulin
• Protection is immediate but ends when
antibodies naturally degrade in the body
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• Artificially acquired passive immunity
(termed Gamma Globulin injection) is a
short-term immunization achieved by the
transfer of antibodies, which can be
administered in several forms; as 1. human or
animal blood plasma or serum, as 2. pooled
human immunoglobulin for intravenous (IVIG)
or intramuscular (IG) use, as 3. high-titer
human IVIG or IG from immunized or from
donors recovering from the disease, and as 4.
monoclonal antibodies (MAb).
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Humoral
immunity
Active
Passive
Naturally
acquired
Artificially
acquired
Naturally
acquired
Artificially
acquired
Infection;
contact
with
pathogen
Vaccine;
dead or
attenuated
pathogens
Antibodies
pass from
mother to
fetus via
placenta;
or to infant
in her milk
Injection of
immune
serum
(gamma
globulin)
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Figure 21.13