Chapter 21: Immune System

• “The Guardians of the Galaxy”

• Aka: The BEST SYSTEM EVER
 Immunity

• Resistance to disease
• The ability to resist damage by foreign
substances.
– Such as???
• Immune system
– Two intrinsic systems
• Innate (nonspecific) defense system
• Adaptive (specific) defense system

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Immune System

• Functional system rather than organ

system, although lymphatic organs are
essential as is bone marrow
• Innate and adaptive defenses intertwined
• Release and recognize many of same
defensive molecules
• Innate defenses do have specific pathways
for certain substances
• Innate responses release proteins that alert
cells of adaptive system to foreign
molecules
Innate Immunity

• What does innate mean?

• Function
– Recognize and destroy
• Response to a particular substance is the
SAME each exposure
• Innate defense system has two lines of
defense
– First - external body membranes (skin and
mucosae)
– Second - antimicrobial proteins, phagocytes,
and other cells
• Inhibit spread of invaders
• Inflammation most important mechanism
Immunity

• Adaptive defense system

– Third line of defense attacks particular foreign
substances
• Takes longer to react than innate system
Adaptive Immunity

• Function
– Recognizes and destroys foreign substances
• Response IMPROVES with subsequent
exposures

•S S M I
 Figure 21.1 Overview of innate and adaptive defenses.

Surface barriers
• Skin
• Mucous membranes

Innate
defenses Internal defenses
• Phagocytes
• Natural killer cells
• Inflammation
• Antimicrobial proteins
• Fever

Humoral immunity
• B cells
Adaptive
defenses

Cellular immunity
• T cells
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Innate Immunity: A closer look

• 3 components:

– Surface Barriers

– Cells

– Chemical mediators
Surface Barriers

• Function: ward off invading pathogens

• Don’t let them in…
– Skin, mucous membranes, and their
secretions ( and body fluids)
• Physical barrier to most microorganisms
• Keratin resistant to weak acids and bases,
bacterial enzymes, and toxins
• Mucosae provide similar mechanical barriers
Body Fluids

• Pathogens can be washed away by:

Surface Barriers

• Protective chemicals of these inhibit or destroy

microorganisms
– Acidity of skin and secretions – acid mantle –
inhibits growth
– Enzymes - lysozyme of saliva, respiratory
mucus, and lacrimal fluid – kill many
microorganisms
– Defensins – antimicrobial peptides – inhibit
growth
– Other chemicals - lipids in sebum, dermcidin
in sweat – toxic
Mucosae

• Line the body’s tracts:

–D
–U
–R
–R

• All are potential…..

• What kind of lymphatic tissue is present?

Surface Barriers

• Respiratory system modifications

– Mucus-coated hairs in nose
– Cilia of upper respiratory tract sweep dust-
and bacteria-laden mucus toward mouth
• What other respiratory events help expel
pathogens?
Internal Defenses: Cells and Chemicals

• Necessary if microorganisms invade

deeper tissues
– Phagocytes
– Natural killer (NK) cells
– Antimicrobial proteins (interferons and
complement proteins)
– Fever
– Inflammatory response (macrophages, mast
cells, WBCs, and inflammatory chemicals)
Phagocytes

• Neutrophils most abundant but die fighting

– Bacteria killers
– Become phagocytic on exposure to infectious material
• Macrophages develop from monocytes – chief
phagocytic cells – robust cells
• Free macrophages wander through tissue spaces,
e.g., alveolar macrophages
• Fixed macrophages permanent residents of some
organs; e.g., stellate macrophages (liver) and
microglia (brain)
 Mechanism of Phagocytosis
• Phagocyte must adhere to particle
– Some microorganisms evade adherence with capsule
• Opsonization marks pathogens—coating by complement
proteins or antibodies
• Cytoplasmic extensions bind to and engulf
particle in vesicle called phagosome
• Phagosome fuses with lysosome 
phagolysosome
• Digestion
• Exocytosis/Antigen Presentation (some cells)
 Figure 21.2a Phagocytosis.

Innate defenses Internal defenses

A macrophage (purple) uses its cytoplasmic

extensions to pull rod-shaped bacteria
(green) toward it. Scanning electron
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micrograph (4800x).
 Figure 21.2b Phagocytosis. Slide 1
1 Phagocyte
adheres to
pathogens or debris.

2 Phagocyte forms
pseudopods that
Phagosome eventually engulf the
(phagocytic particles, forming a
vesicle) phagosome.
Lysosome
3 Lysosome fuses
with the phagocytic
vesicle, forming a
phagolysosome.
Acid
hydrolase
enzymes 4 Lysosomal
enzymes digest the
particles, leaving a
residual body.

5 Exocytosis of the
vesicle removes
indigestible and
residual material.
Events of phagocytosis.
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Mechanism of Phagocytosis

• Pathogens killed by acidifying and digesting with

lysosomal enzymes
• Helper T cells cause release of enzymes of
respiratory burst, which kill pathogens resistant
to lysosomal enzymes by
– Releasing cell-killing free radicals
– Producing oxidizing chemicals (e.g., H2O2)
– Increasing pH and osmolarity of phagolysosome
• Defensins (in neutrophils) pierce membrane
Natural Killer (NK) Cells

• Nonphagocytic large granular lymphocytes

• Attack cells that lack "self" cell-surface
receptors
– Induce apoptosis in cancer cells and virus-
infected cells
• Secrete potent chemicals that enhance
inflammatory response
Inflammatory Response

• Triggered whenever body tissues injured

• Prevents spread of damaging agents
• Disposes of cell debris and pathogens
• Alerts adaptive immune system
• Sets the stage for repair
Inflammatory Response

• Cardinal signs of acute inflammation:

1. Redness
2. Heat
3. Swelling
4. Pain
(Sometimes 5. Impairment of function)
Inflammatory Response

• Begins with chemicals released into ECF

by injured tissues, immune cells, blood
proteins
• Macrophages and epithelial cells of
boundary tissues bear Toll-like receptors
(TLRs) recognize specific classes of
infecting microbes
• Activated TLRs trigger release of
cytokines that promote inflammation
Inflammatory Response

• Inflammatory mediators
– Kinins, prostaglandins (PGs), and
complement
• Dilate local arterioles (hyperemia)
– Causes redness and heat of inflamed region
• Make capillaries leaky
• Many attract leukocytes to area
• Some have inflammatory roles
Inflammatory Response

 Capillary permeability  exudate to

tissues
– Fluid containing clotting factors and
antibodies
– Causes local swelling (edema)
– Swelling pushes on nerve endings  pain
• Pain also from bacterial toxins, prostaglandins, and
kinins
– Moves foreign material into lymphatic vessels
– Delivers clotting proteins and complement
Inflammatory Response

• Clotting factors form fibrin mesh

– Scaffold for repair
– Isolates injured area so invaders cannot
spread
 Figure 21.3 Inflammation: flowchart of events.
Innate defenses Internal defenses

Initial stimulus
Physiological response
Signs of inflammation
Tissue injury Result

Release of inflammatory chemicals Release of leukocytosis-

(histamine, complement, inducing factor
kinins, prostaglandins, etc.)

Leukocytosis
(increased numbers of white
blood cells in bloodstream)

Arterioles Increased capillary Attract neutrophils,

dilate permeability monocytes, and
lymphocytes to Leukocytes migrate to
area (chemotaxis) injured area

Local hyperemia Capillaries

(increased blood leak fluid Margination
flow to area) (exudate formation) (leukocytes cling to
capillary walls)

Diapedesis
Leaked protein-rich Leaked clotting (leukocytes pass through
fluid in tissue spaces proteins form interstitial capillary walls)
clots that wall off area
to prevent injury to
surrounding tissue
Phagocytosis of pathogens
Heat Redness Pain Swelling and dead tissue cells
(by neutrophils, short-term;
by macrophages, long-term)

Locally increased Possible temporary Temporary fibrin Pus may form

temperature increases impairment of patch forms
metabolic rate of cells function scaffolding for repair Area cleared of debris

Healing

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Phagocyte Mobilization

• Neutrophils lead; macrophages follow

– As attack continues, monocytes arrive
• 12 hours after leaving bloodstream 
macrophages
• These "late-arrivers" replace dying neutrophils and
remain for clean up prior to repair
• If inflammation due to pathogens,
complement activated; adaptive immunity
elements arrive
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 walls of
capillaries in inflamed area in response to
CAMs
3. Diapedesis of neutrophils
4. Chemotaxis: inflammatory chemicals
(chemotactic agent) promote positive
chemotaxis of neutrophils
 Figure 21.4 Phagocyte mobilization. Slide 1
Innate defenses Internal defenses

Inflammatory
chemicals
diffusing 4 Chemotaxis.
from the Neutrophils follow
inflamed chemical trail.
site act as
chemotactic Capillary wall
agents. Basement
membrane
Endothelium

1 Leukocytosis. 2 Margination. 3 Diapedesis.

Neutrophils enter Neutrophils cling Neutrophils flatten
blood from bone to capillary wall. and squeeze out of
marrow. capillaries.
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Antimicrobial Proteins

• Include interferons and complement

proteins
• Some attack microorganisms directly
• Some hinder microorganisms' ability to
reproduce
Interferons

• Family of immune modulating proteins

– Have slightly different physiological effects
• Viral-infected cells secrete IFNs (e.g., IFN
alpha and beta) to "warn" neighboring
cells
– IFNs enter neighboring cells  produce
proteins that block viral reproduction and
degrade viral RNA
– IFN alpha and beta also activate NK cells
Interferons

resist virus
Interferons

• IFN gamma (immune interferon)

– Secreted by lymphocytes
– Widespread immune mobilizing effects
– Activates macrophages
• Since IFNs activate NK cells and
macrophages, indirectly fight cancer
• Artificial IFNs used to treat hepatitis C,
genital warts, multiple sclerosis, hairy cell
leukemia
Complement System (Complement)

• ~20 plasma proteins that circulate in

inactive form

• Major mechanism for destroying foreign

substances

• Our cells contain complement activation

inhibitors
Complement

• Unleashes inflammatory chemicals that

amplify all aspects of inflammatory
response
• Kills bacteria and certain other cell types
by cell lysis
• Enhances both innate and adaptive
defenses
Complement

• Major Effects

– Chemotaxis

– Opsonization

– Inflammation

– Lysis
Complement Activation

• Three pathways to activation

– Classical pathway
• Antibodies bind to invading organisms and to
complement components
• Called complement fixation
• First step in activation; more details later
Complement

• Lectin pathway
– Lectins - produced by innate system to
recognize foreign invaders
– When bound to foreign invaders can also bind
and activate complement
• Alternative pathway
– Activated spontaneously, lack of inhibitors
on microorganism's surface allows process
to proceed
Complement Activation

• Each pathway involves activation of

proteins in an orderly sequence
• Each step catalyzes the next
• Each pathway converges on C3, which
cleaves into C3a and C3b
• Common terminal pathway initiated that
– Enhances inflammation, promotes
phagocytosis, causes cell lysis
Complement Activation

• Cell lysis begins when

– C3b binds to target cell  insertion of complement
proteins called membrane attack complex (MAC)
into cell's membrane
– MAC forms and stabilizes hole in membrane  influx
of water  lysis of cell
• C3b also causes opsonization
• C3a and other cleavage products amplify
inflammation
– Stimulate mast cells and basophils to release
histamine
– Attract neutrophils and other inflammatory cells
 Figure 21.6 Complement activation.
Classical pathway Lectin pathway Alternative pathway
Activated by antibodies Activated by lectins Activated spontaneously. Lack of
coating target cell binding to specific sugars inhibitors on microorganism’s
on microorganism’s surface surface allows process to proceed

Together with other complement

proteins and factors

C3

C3a
C3b

C3b
Opsonization: Enhances inflammation:
C5b C5a Stimulates histamine
Coats pathogen
surfaces, which C6 release, increases blood

MAC
enhances phagocytosis vessel permeability,
C7 attracts phagocytes by
C8 chemotaxis, etc.
C9
MACs form from activated
complement components (C5b
and C6–C9) that insert into the
target cell membrane, creating
pores that can lyse the target cell.

Pore
Complement
proteins
(C5b–C9)

Membrane
of target cell

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Fever

• Abnormally high body temperature

• Systemic response to invading
microorganisms
• Leukocytes and macrophages exposed to
foreign substances secrete pyrogens
• Pyrogens act on body's thermostat in
hypothalamus, raising body temperature
Fever

• Benefits of moderate fever

– Causes liver and spleen to sequester iron and
zinc (needed by microorganisms)
– Increases metabolic rate  faster repair

• When is it bad?
– Why?
Adaptive Defenses

• Adaptive immune (specific defense)

system
– Protects against infectious agents and
abnormal body cells
– Amplifies inflammatory response
– Activates complement
– Must be primed by initial exposure to specific
foreign substance
• Priming takes time
Adaptive Defenses

• Specific – recognizes and targets specific

antigens
• Systemic – not restricted to initial site
• Have memory – stronger attacks to
"known" antigens
• Improvement- response strengthens on
next esposure
• Two separate, overlapping arms
– Humoral (antibody-mediated) immunity
– Cellular (cell-mediated) immunity
Humoral Immunity

• Antibodies, produced by lymphocytes,

circulating freely in body fluids
• Bind temporarily to target cell
– Temporarily inactivate
– Mark for destruction by phagocytes or
complement
• Humoral immunity has extracellular targets
Cellular Immunity

• Lymphocytes act against target cell

– Directly – by killing infected cells
– Indirectly – by releasing chemicals that
enhance inflammatory response; or activating
other lymphocytes or macrophages
• Cellular immunity has cellular targets
Antigens

• Substances that can mobilize adaptive

defenses and provoke an immune
response
• Targets of all adaptive immune responses
• Most are large, complex molecules not
normally found in body (nonself)
Complete Antigens

• Important functional properties

– Immunogenicity: ability to stimulate
proliferation of specific lymphocytes
– Reactivity: ability to react with activated
lymphocytes and antibodies released by
immunogenic reactions
• Examples: foreign protein,
polysaccharides, lipids, and nucleic acids
Haptens (Incomplete Antigens)

• Small molecules (haptens) not

immunogenic by themselves
– E.g., peptides, nucleotides, some hormones
• May be immunogenic if attached to body
proteins and combination is marked
foreign
• Cause immune system to mount harmful
attack
• Examples: poison ivy, animal dander,
detergents, and cosmetics
Antigenic Determinants

• Only certain parts (antigenic

determinants) of entire antigen are
immunogenic
• Antibodies and lymphocyte receptors bind
to them as enzyme binds substrate
Antigenic Determinants

• Most naturally occurring antigens have

numerous antigenic determinants that
– Mobilize several different lymphocyte
populations
– Form different kinds of antibodies against
them
• Large, chemically simple molecules (e.g.,
plastics) have little or no immunogenicity
 Figure 21.7 Most antigens have several different antigenic determinants.

Antigen-
Antigenic determinants
binding
sites
Antibody A

Antigen

Antibody B
Antibody C

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Self-antigens: MHC Proteins

• Protein molecules (self-antigens) on

surface of cells not antigenic to self but
antigenic to others in transfusions or grafts
• Example: MHC glycoproteins
– Coded by genes of major histocompatibility
complex (MHC) and unique to individual
– MCH I and MHC II
– Have groove holding self- or foreign antigen
• T lymphocytes can only recognize antigens that
are presented on MHC proteins
Cells of the Adaptive Immune System

• Three types of cells

– Two types of lymphocytes
• B lymphocytes (B cells)—humoral immunity
• T lymphocytes (T cells)—cellular immunity
– Antigen-presenting cells (APCs)
• Do not respond to specific antigens
• Play essential auxiliary roles in immunity
Lymphocyte Development, Maturation, and
Activation
• Five general steps
– Origin – all originate in red bone marrow
– Maturation
– Seeding secondary lymphoid organs and
circulation
– Antigen encounter and activation
– Proliferation and differentiation
 Figure 21.8 Lymphocyte development, maturation, and activation. Slide 1
Humoral immunity Primary lymphoid organs
Adaptive defenses (red bone marrow and thymus)
Cellular immunity
Secondary lymphoid organs
(lymph nodes, spleen, etc.)

Red bone marrow

1 Origin
• Both B and T lymphocyte precursors originate in red
bone marrow.

Lymphocyte
precursors

2 Maturation
• Lymphocyte precursors destined to become T cells migrate
(in blood) to the thymus and mature there.
• B cells mature in the bone marrow.
• During maturation lymphocytes develop immunocompetence
Thymus and self-tolerance.
Red bone marrow

3 Seeding secondary lymphoid organs and circulation

• Immunocompetent but still naive lymphocytes leave the
thymus and bone marrow.
• They “seed” the secondary lymphoid organs and circulate
through blood and lymph.
Antigen

4 Antigen encounter and activation

Lymph node • When a lymphocyte’s antigen receptors bind its antigen, that
lymphocyte can be activated.

5 Proliferation and differentiation

• Activated lymphocytes proliferate (multiply) and then
differentiate into effector cells and memory cells.
• Memory cells and effector T cells circulate continuously in
the blood and lymph and throughout the secondary
lymphoid organs.

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Maturation

• "Educated" to become mature; B cells in

bone marrow, T cells in thymus
– Immunocompetence – lymphocyte can
recognize one specific antigen by binding to it
• B or T cells display only one unique type of antigen
receptor on surface when achieve maturity – bind
only one antigen
– Self-tolerance
• Lymphocytes unresponsive to own antigens
T cells

• T cells mature in thymus under negative

and positive selection pressures ("tests")
– Positive selection
• Selects T cells capable of recognizing self-MHC
proteins (MHC restriction); failures destroyed by
apoptosis
– Negative selection
• Prompts apoptosis of T cells that bind to self-
antigens displayed by self-MHC
• Ensures self-tolerance
 Figure 21.9 T cell education in the thymus.
Adaptive defenses Cellular immunity
1. Positive Selection
T cells must recognize self major histocompatibility
proteins (self-MHC)
Antigen-
presenting Developing
thymic cell T cell

Failure to recognize self-

MHC results in apoptosis
(death by cell suicide).

Self-MHC T cell receptor

Self-antigen

Recognizing self-MHC
results in survival.
Survivors proceed
to negative selection.

2. 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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B cells

• B cells mature in red bone marrow

• Positively selected if successfully make
antigen receptors
• Those that are self-reactive
– Eliminated by apoptosis (clonal deletion)
Seeding Secondary Lymphoid Organs and
Circulation
• Immunocompetent B and T cells not yet
exposed to antigen called naive
• Exported from primary lymphoid organs
(bone marrow and thymus) to "seed"
secondary lymphoid organs (lymph nodes,
spleen, etc.)
– Increases chance of encounter with antigen
Antigen Encounter and Activation

• Clonal selection
– Naive lymphocyte's first encounter with
antigen  selected for further development
– If correct signals present, lymphocyte will
complete its differentiation
Proliferation and Differentiation

• Activated lymphocyte proliferates  exact

clones
• Most clones  effector cells that fight
infections
• Few remain as memory cells
– Able to respond to same antigen more quickly
second time
• B and T memory cells and effector T cells
circulate continuously
 Table 21.3 Overview of B and T Lymphocytes

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Antigen-presenting Cells (APCs)

• Engulf antigens
• Present fragments of antigens to T cells
for recognition
• Major types
– Dendritic cells in connective tissues and
epidermis
– Macrophages in connective tissues and
lymphoid organs
– B cells
APCs: Dendritic Cells and Macrophages

• Dendritic cells phagocytize pathogens,

enter lymphatics to present antigens to T
cells in lymph node
– Most effective antigen presenter known
– Key link between innate and adaptive
immunity
• Macrophages widespread in lymphoid
organs and connective tissues
– Present antigens to T cells to activate
themselves into voracious phagocytes that
secrete bactericidal chemicals
APCs: B lymphocytes

• Do not activate naive T cells

• Present antigens to helper T cell to assist
own activation
 Adaptive Immunity: Summary

• Uses lymphocytes, APCs, and specific

molecules to identify and destroy nonself
substances
• Depends upon ability of its cells to
– Recognize antigens by binding to them
– Communicate with one another so that whole
system mounts specific response

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Activation and Differentiation of B Cells

• B cell activated when antigens bind to its

surface receptors and cross-link them 
• Receptor-mediated endocytosis of cross-
linked antigen-receptor complexes (clonal
selection) 
• Proliferation and differentiation into
effector cells
Fate of the Clones

• Most clone cells become plasma cells

– Secrete specific antibodies at rate of 2000
molecules per second for four to five days,
then die
– Antibodies circulate in blood or lymph
• Bind to free antigens and mark for destruction by
innate or adaptive mechanisms
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 to same antigen
 Figure 21.11a Clonal selection of a B cell.

Adaptive defenses Humoral immunity

Primary response Antigen

(initial encounter Antigen binding
with antigen) to a receptor on a
specific B lymphocyte
(B lymphocytes with
Proliferation to noncomplementary
form a clone receptors remain
Activated B cells inactive)

Plasma cells Memory B cell—

(effector B cells) primed to respond
to same antigen
Secreted
antibody
molecules

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Immunological Memory

• Primary immune response

– Cell proliferation and differentiation upon first
antigen exposure
– Lag period: three to six days
– Peak levels of plasma antibody are reached in
10 days
– Antibody levels then decline
Immunological Memory

• Secondary immune response

– Re-exposure to same antigen gives faster,
more prolonged, more effective response
• 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
 Figure 21.11 Clonal selection of a B cell.
Adaptive defenses Humoral immunity

Primary response Antigen

(initial encounter Antigen binding
with antigen) to a receptor on a
specific B lymphocyte
(B lymphocytes with
noncomplementary
Proliferation to
receptors remain
form a clone
Activated B cells inactive)

Plasma cells Memory B cell—

(effector B cells) primed to respond
to same antigen
Secreted
antibody
molecules

Secondary response Subsequent

Clone of cells
(can be years later) challenge by same
identical to
antigen results in
ancestral cells
more rapid response

Plasma
cells

Secreted
antibody Memory
molecules B cells
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 Figure 21.12 Primary and secondary humoral responses.
Secondary immune response to
Primary immune antigen A is faster and larger; primary
response to antigen immune response to antigen B is
A occurs after a delay. similar to that for antigen A.

Antibody titer (antibody concentration)

104
in plasma (arbitrary units)

103

102

101 Anti-
Anti-
Bodies Bodies
to A to B
100
0 7 14 21 28 35 42 49 56

First exposure Second exposure to antigen A;

to antigen A first exposure to antigen B
Time (days)
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Active Humoral Immunity

• When B cells encounter antigens and

produce specific antibodies against them
• Two types of active humoral immunity:
– Naturally acquired—response to bacterial or
viral infection
– Artificially acquired—response to vaccine of
dead or attenuated pathogens
Active Humoral Immunity

• Vaccines
– Most of dead or attenuated pathogens
– Spare us symptoms of primary response
– Provide antigenic determinants that are
immunogenic and reactive
Passive Humoral Immunity

• Readymade antibodies introduced into

body
• B cells are not challenged by antigens
• Immunological memory does not occur
• Protection ends when antibodies degrade
Passive Humoral Immunity

• Two types
1. Naturally acquired—antibodies delivered to
fetus via placenta or to infant through milk
2. Artificially acquired—injection of serum,
such as gamma globulin
• Protection immediate but ends when antibodies
naturally degrade in body
 Figure 21.13 Active and passive humoral immunity.

Humoral
immunity

Active Passive

Naturally Artificially Naturally Artificially

acquired acquired acquired acquired
Infection; Vaccine; Antibodies Injection of
contact dead or passed from exogenous
with attenuated mother to antibodies
pathogen pathogens fetus via (gamma
placenta; or globulin)
to infant in
her milk
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Antibodies

• Immunoglobulins—gamma globulin portion

of blood
• Proteins secreted by plasma cells
• Capable of binding specifically with
antigen detected by B cells
• Grouped into one of five Ig classes
Basic Antibody Structure

• T- or Y-shaped antibody monomer of

four looping polypeptide chains linked by
disulfide bonds
• Two identical heavy (H) chains with hinge
region at "middles"
• Two identical light (L) chains
• Variable (V) regions at one end of each
arm combine to form two identical
antigen-binding sites
Basic Antibody Structure

• Constant (C) regions of stem

– Determine antibody class (IgM, IgA, IgD, IgG,
or IgE)
– Serve common functions in all antibodies by
dictating
• Cells and chemicals that antibody can bind
• How antibody class functions to eliminate
antigens
 Figure 21.14a Antibody structure.

Adaptive defenses Humoral immunity

H
ea
Antigen-binding vy
site ch
a in

Heavy chain Li
gh
variable region tc
Heavy chain ha
in Hinge region
constant region
Light chain
variable region Stem region
Light chain
constant region
Disulfide bond

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Classes of Antibodies

• IgM
– Pentamer (larger than others); first antibody
released
– Potent agglutinating agent
– Readily fixes and activates complement
• IgA (secretory IgA)
– Monomer or dimer; in mucus and other
secretions
– Helps prevent entry of pathogens
Classes of Antibodies

• IgD
– Monomer attached to surface of B cells
– Functions as B cell receptor
• IgG
– Monomer; 75–85% of antibodies in plasma
– From secondary and late primary responses
– Crosses placental barrier
Classes of Antibodies

• IgE
– Monomer active in some allergies and
parasitic infections
– Causes mast cells and basophils to release
histamine
• B cells can switch antibody classes but
retain antigen specificity
– IgM at first; then IgG
– Almost all secondary responses are IgG
 Table 21.4 Immunoglobulin Classes (1 of 2)

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 Table 21.4 Immunoglobulin Classes (2 of 2)

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Antibody Targets and Functions

• Antibodies inactivate and tag antigens; do

not destroy them
– Form antigen-antibody (immune)
complexes
• Defensive mechanisms used by antibodies
– Neutralization and agglutination (the two most
important)
– Precipitation and complement fixation
Neutralization

• Simplest defensive mechanism

• Antibodies block specific sites on viruses
or bacterial exotoxins
• Prevent these antigens from binding to
receptors on tissue cells
• Antigen-antibody complexes undergo
phagocytosis
Agglutination

• Antibodies bind same determinant on

more than one cell-bound antigen
• Cross-linked antigen-antibody complexes
agglutinate
– Example: clumping of mismatched blood cells
Precipitation

• Soluble molecules are cross-linked

• Complexes precipitate and are subject to
phagocytosis
Complement Fixation and Activation

• Main antibody defense against cellular

antigens (bacteria, mismatched RBCs)
• Several antibodies bind close together on
a cellular antigen  complement-binding
sites on stem regions align
– Triggers complement fixation into cell's
surface
  Cell lysis
 Figure 21.15 Mechanisms of antibody action.
Adaptive defenses Humoral immunity

Antigen-antibody
Antigen Antibody
complex

Inactivates by Fixes and activates

Neutralization Agglutination Precipitation Complement

(masks dangerous (cell-bound antigens) (soluble antigens)
parts of bacterial
exotoxins; viruses)

Enhances Enhances Leads to

Phagocytosis Inflammation Cell lysis

Chemotaxis

Histamine
release

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Summary of Antibody Actions

• Antigen-antibody complexes do not

destroy antigens; prepare them for
destruction by innate defenses
• Antibodies do not invade solid tissue
unless lesion present
• Can act intracellularly if attached to virus
before it enters cell
– Activate mechanisms that destroy virus
Cellular Immune Response

• T cells provide defense against

intracellular antigens
• Some T cells directly kill cells; others
release chemicals that regulate immune
response
Cellular Immune Response

• Two populations of T cells based on which

glycoprotein surface receptors displayed
– CD4 cells usually become helper T cells (TH);
activate B cells, other T cells, macrophages,
and direct adaptive immune response
• Some become regulatory T cells – which
moderate immune response
– Can also become memory T cells
Cellular Immune Response

– CD8 cells become cytotoxic T cells (TC)

• Destroy cells harboring foreign antigens
• Also become memory T cells
– Helper, cytotoxic, and regulatory T cells are
activated T cells
– Naive T cells simply termed CD4 or CD8 cells
 Figure 21.16 Major types of T cells.
Adaptive defenses Cellular immunity

Immature
lymphocyte
Red bone marrow

T cell T cell
receptor receptor
Maturation

Class II MHC CD8 Class I MHC

protein displaying CD4 protein displaying
cell cell
antigen Thymus antigen

Activation Activation

APC
(dendritic cell) Memory APC
cells (dendritic cell)

CD4 CD8

CD4 cells become Lymphoid

either helper T CD8 cells become
tissues and cytotoxic T
cells or organs
regulatory T cells cells

Effector
cells

Blood plasma

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MHC Proteins and Antigen Presentation

• T cells respond only to processed

fragments of antigens displayed on
surfaces of cells
• Antigen presentation vital for activation of
naive T cells and normal functioning of
effector T cells
MHC Proteins

• Two types of MHC proteins important to T

cell activation
– Class I MHC proteins – displayed by all
nucleated cells except RBCs
– Class II MHC proteins – displayed by APCs
(dendritic cells, macrophages, and B cells)
• Both types are synthesized at ER and bind
to peptide fragments
Class I MHC Proteins

• Bind with fragment of protein synthesized in the

cell (endogenous antigen)
• Endogenous antigen is self-antigen in normal
cell; a nonself antigen in infected or abnormal
cell
• Crucial for CD8 cell activation
• Inform cytotoxic T cells of microorganisms hiding
in cells (cytotoxic T cells ignore displayed self-
antigens)
• Act as antigen holders; form "self" part that T
cells recognize
Class II MHC Proteins

• Bind with fragments of exogenous

antigens that have been engulfed and
broken down in a phagolysosome
• Recognized by helper T cells
• Signal CD4 cells that help is required
MHC Restriction

• CD4 and CD8 cells have different

requirements for MHC protein that
presents antigens to them
– CD4 cells that become TH – bind only class II
MHC proteins typically on APC surfaces
– CD8 cells that become cytotoxic T cells – bind
only class I MHC proteins on APC surfaces
• Once activated, cytotoxic T cells seek same
antigen on class I MHC proteins on any cell
MHC Restriction

• CD8 cells activated by class I MHC

proteins
• How do APCs get endogenous antigens
from another cell and display them on
class I MHCs?
– Dendritic cells engulf dying virus-infected or
tumor cells, then display both class I and
class II MHCs
 Table 21.5 Role of MHC Proteins in Cellular Immunity

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T cell Activation

• T cell activation two-step process

– Antigen binding (MCH and TCR and CD
protien)
– Co-stimulation
• Both occur on surface of same APC
• Both required for clonal selection
T cell Activation: Co-stimulation

• Without co-stimulation, anergy occurs

– T cells
• Become tolerant to that antigen
• Are unable to divide
• Do not secrete cytokines
T cell Activation: Proliferation and
Differentiation
• T cells that are activated
– Enlarge and proliferate in response to
cytokines
– Differentiate and perform functions according
to their T cell class
 Figure 21.17 Clonal selection of T cells involves simultaneous recognition of self and nonself. Slide 1
Adaptive defenses Cellular immunity

Bacterial antigen 1 Antigen

presentation
Class lI MHC Dendritic cell engulfs
protein an exogenous
displaying antigen, processes it,
processed and displays its
bacterial antigen fragments on class II
Dendritic Co-stimulatory MHC protein.
cell molecule

CD4 protein 2 Double recognition

T cell 2a CD4 T cell
receptor recognizes antigen-
(TCR) MHC complex. Both
TCR and CD4 proteins
bind to antigen-MHC
Co-stimulatory CD4 T cell complex.
molecules
2b Co-stimulatory
Clone molecules bind
formation together.

3 Clone
formation Activated
CD4 T cells proliferate
(clone), and become
memory and effector
cells.
Memory
CD4 T cell Helper
T cells

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T cell Activation: Proliferation and
Differentiation
• Primary T cell response peaks within a week
• T cell apoptosis occurs between days 7 and 30
– Benefit of apoptosis: activated T cells are a hazard –
produce large amount inflammatory cytokines 
hyperplasia, cancer
• Effector activity wanes as amount of antigen
declines
• Memory T cells remain and mediate secondary
responses
Roles of Helper T (TH) cells

• Play central role in adaptive immune

response
– Activate both humoral and cellular arms
– Once primed by APC presentation of antigen,
they
• Help activate T and B cells
• Induce T and B cell proliferation
• Their cytokines recruit other immune cells
• Without TH, there is no immune
response
Helper T cells: Activation of B cells

• Interact directly with B cells displaying antigen

fragments bound to MHC II receptors
• Stimulate B cells to divide more rapidly and
begin antibody formation
• B cells may be activated without TH cells by
binding to T cell–independent antigens
– Response weak and short-lived
• Most antigens require TH co-stimulation to
activate B cells: T cell–dependent antigens
 Figure 21.18a The central role of helper T cells in mobilizing both humoral and cellular immunity. Slide
1
Helper T cells help in humoral immunity

Helper T cell
1 TH cell binds
T cell receptor (TCR) with the self-nonself
complexes of a B cell
that has encountered
Helper T cell its antigen and is
CD4 protein displaying it on
MHC II on its surface.
MHC II protein
of B cell displaying
processed antigen 2 TH cell releases
interleukins as co-
IL-4 and other stimulatory signals to
cytokines complete B cell
activation.

B cell (being activated)

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Helper T cells: Activation of CD8 cells

• CD8 cells require TH cell activation into

destructive cytotoxic T cells
• Cause dendritic cells to express co-
stimulatory molecules required for CD8
cell activation
 Figure 21.18b The central role of helper T cells in mobilizing both humoral and cellular immunity. Slide 1

Helper T cells help in cellular immunity

CD4 protein Helper T cell

1 TH cell binds
Class II MHC
protein dendritic cell.
APC (dendritic cell)
2 TH cell
IL-2 stimulates dendritic
cell to express
co-stimulatory
molecules.

3 Dendritic cell
can now activate
Class I CD8 CD8 cell with the
MHC protein protein help of interleukin 2
CD8 T cell secreted by TH cell.
(becomes TC cell
after activation)
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Helper T cells: Amplification of Innate
Defenses
• Amplify responses of innate immune
system
• Activate macrophages  more potent
killers
• Mobilize lymphocytes and macrophages
and attract other types of WBCs
Cytotoxic T (TC) cells

• Directly attack and kill other cells

• Activated TC cells circulate in blood and
lymph and lymphoid organs in search of
body cells displaying antigen they
recognize
Roles of Cytotoxic T (TC) cells

• Bind to a self-nonself complex

• Can destroy all infected or abnormal cells
• Targets
– Virus-infected cells
– Cells with intracellular bacteria or parasites
– Cancer cells
– Foreign cells (transfusions or transplants)
Cytotoxic T cells

• Lethal hit – two methods:

– TC cell releases perforins and granzymes by
exocytosis
• Perforins create pores through which granzymes
enter target cell
• Granzymes stimulate apoptosis
– TC cell binds specific membrane receptor on
target cell, and stimulates apoptosis
– “Vulcan Death Grip”
 Figure 21.19 Cytotoxic T cells attack infected and cancerous cells.

Adaptive defenses Cellular immunity

Cytotoxic 1 2 TC releases 3 Perforin molecules insert into

T cell (TC) TC identifies
perforin and the target cell membrane,
foreign antigens granzyme polymerize, and form transmembrane
on MHC I proteins molecules from its pores (cylindrical holes) similar to
and binds tightly granules by those produced by complement
to target cell. exocytosis. activation.

Granule
Perforin

TC cell
membrane Cytotoxic
T cell

Target
cell
membrane
Target Cancer cell
cell Perforin
pore
Granzymes

4 Granzymes enter the

5 The TC detaches target cell via the pores.
and searches for Once inside, granzymes
another prey. activate enzymes that
trigger apoptosis.
A mechanism of target cell killing by TC cells. Scanning electron micrograph of a
TC cell killing a cancer cell (2100x).

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Natural Killer cells

• Recognize other signs of abnormality

– Lack of class I MHC
– Antibody coating target cell
– Different surface markers of stressed cells
• Use same key mechanisms as TC cells for
killing their target cells
• Immune surveillance—NK and TC cells
prowl for markers they recognize
Regulatory T (TReg) cells

• Dampen immune response by direct

contact or by inhibitory cytokines
• Important in preventing autoimmune
reactions
– Suppress self-reactive lymphocytes in
periphery (outside lymphoid organs)
 Figure 21.20 Simplified summary of the primary immune response.
Cellular Humoral Antigen (Ag) intruder
immunity immunity

Inhibits Inhibits
Triggers

Adaptive defenses Innate defenses

Surface Internal
barriers defenses

Free Ags
may directly
activate B cell
Ag-infected
body cell engulfed
by dendritic cell Antigen-
activated
Becomes B cells

Clone and

Present Ag to activated helper T cells

Co-stimulate and release cytokines
give rise to
Ag-presenting cell
(APC) presents
self-Ag complex

Activates Activates Memory

B cells
Naive Naive
CD8 CD4
T cells T cells

Activated to clone Activated to clone

and give rise to Induce and give rise to Plasma cells
Memory Memory
co-stimulation CD4 (effector B cells)
CD8
T cells T cells

Secrete
Cytotoxic Helper
T cells T cells

Cytokines stimulate

Nonspecific killers
(macrophages and Antibodies (Igs)
Together the nonspecific killers
and cytotoxic T cells mount a NK cells of innate Circulating lgs along with complement
physical attack on the Ag immunity) mount a chemical attack on the Ag
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Organ Transplants

• Four varieties
– Autografts: from one body site to another in
same person
– Isografts: between identical twins
– Allografts: between individuals who are not
identical twins
– Xenografts: from another animal species
Organ Transplants

• Success depends on similarity of tissues

– Autografts and isografts ideal donor tissues
• Almost always successful if good blood supply and
no infection
– Research into successful xenografts from
genetically engineered animals
– Most common is allograft
• ABO, other blood antigens, MHC antigens
matched as closely as possible
Immunodeficiencies

• Congenital or acquired conditions that

impair function or production of immune
cells or molecules such as complement or
antibodies
Autoimmune Diseases

• Immune system loses ability to distinguish

self from foreign
• Production of autoantibodies and
sensitized TC cells that destroy body
tissues
• Examples include multiple sclerosis,
myasthenia gravis, Graves' disease, type
1 diabetes mellitus, systemic lupus
erythematosus (SLE), glomerulonephritis,
and rheumatoid arthritis
Mechanisms of Autoimmune Diseases

• Weakly self-reactive lymphocytes may be

activated by
– Foreign antigens may resemble self-antigens
• Antibodies against foreign antigen may cross-react
with self-antigen
– New self-antigens may appear, generated by
• Gene mutations
• Changes in self-antigens by hapten attachment or
infectious damage
• Release of novel self-antigens by trauma to barrier
Hypersensitivities

• Immune responses to perceived

(otherwise harmless) threat cause tissue
damage
• Different types distinguished by
– Their time course
– Whether antibodies or T cells involved
• Antibodies cause immediate and
subacute hypersensitivities
• T cells cause delayed hypersensitivity
Hypersensitivity

• Allergy
– Deleterious effects of hypersensitivity to
environmental (exogenous) antigens
• Autoimmunity
– Disturbance in the immunologic
tolerance of self-antigens
• Alloimmunity
– Immune reaction to tissues of another
individual
Hypersensitivity

• Characterized by the immune

mechanism
– Type I
• IgE mediated
– Type II
• Tissue-specific reactions
– Type III
• Immune complex mediated
– Type IV
• Cell mediated
Anaphylactic Shock

• Systemic response to allergen that directly

enters blood and circulates rapidly
• Basophils and mast cells enlisted throughout
body
• Systemic histamine release may cause
– Constriction of bronchioles; tongue may swell
– Sudden vasodilation and fluid loss from bloodstream
may 
– Circulatory collapse (hypotensive shock) and death
• Treatment: epinephrine
 Figure 21.21 Mechanism of an acute allergic (immediate hypersensitivity) response. Slide 1
Adaptive defenses Humoral immunity

Sensitization stage
Antigen
1 Antigen (allergen)
invades body.

2 Plasma cells
produce large amounts
of class
IgE antibodies against
allergen. Mast cell with
fixed IgE
antibodies

3 IgE antibodies IgE

attach to mast cells in
Granules
body tissues (and to
circulating basophils). containing
histamine

Subsequent (secondary)
responses

4 More of same
antigen invades body.

Mast cell granules

5 release contents
Antigen combines
with IgE attached after antigen binds
to mast cells (and with IgE antibodies
basophils), which triggers
degranulation and release
of histamine (and other chemicals).
Histamine

6
Histamine causes blood vessels to dilate and become
leaky, which promotes edema; stimulates secretion of large
amounts of mucus; and causes smooth muscles to contract. (If
respiratory system is site of antigen entry, asthma may ensue.)

Outpouring of Release of Constriction of

fluid from small respiratory
mucus passages
capillaries
(bronchioles)
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