CHAPTER 21

THE IMMUNE SYSTEM

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OBJECTIVES:
The student should be able to:
1. Differentiate between innate (non-specific) and adaptive (specific)
body defenses.
2. Describe the general contributions of surface barriers, phagocytes,
NK cells, antimicrobial proteins, and fever to the functioning of innate
defenses.
3. Describe in detail the events that occur in inflammation and relate
these events to the four cardinal signs of inflammation. (See Figure
21.3.)
4. Define immunocompetence and self-tolerance and explain their
importance to the functions of T cells and B cells.
5. Compare the processes of activation and clonal selection of B cells and
T cells.
6. Describe the general structure of an antibody, and relate it to the
general functions of an antibody. Describe four mechanisms by which
antibodies facilitate the inactivation and destruction of foreign
antigens.
OBJECTIVES:
The student should be able to:
7. Describe the roles of plasma cells, memory cells, helper T (TH) cells,
and cytotoxic T (TC) cells in humoral and cellular immunity. (See Figure
21.20.)
8. Compare and contrast active and passive humoral immunity, naturally
and artificially acquired immunity, as well as primary and secondary
immune responses.
Key Terms:
• immunity, innate (nonspecific) defense system, adaptive (specific)
defense system, pathogens

• macrophages (free and fixed), neutrophils, phagosome, phagolysosome,

opsonization, natural killer (NK) cells

• inflammatory response, cardinal signs of inflammation, mast cells,

histamine, kinins, prostaglandins, cytokines, margination, diapedesis,
chemotactic agents

• interferons (IFNs), complement, MAC (membrane attack complex),

fever, pyrogens
Key Terms:
• humoral (antibody-mediated) immunity, cellular (cell-mediated)
immunity, antigen, nonself, complete antigen, immunogenicity,
reactivity, hapten (incomplete antigen), antigenic determinants, self-
antigens, MHC (major histocompatibility complex) proteins, T cells (T
lymphocytes), B cells (B lymphocytes), immunocompetence, self-
tolerance, antigen-presenting cells (APCs), dendritic cells

• humoral immune response: clonal selection, clone, plasma cells, memory

cells, primary immune response, secondary immune response,
immunological memory, active humoral immunity, passive humoral
immunity, antibodies (immunoglobulins or Igs), antigen-binding sites,
antigen-antibody (immune) complexes, neutralization, agglutination,
precipitation, complement fixation and activation, monoclonal
antibodies

• cellular immune response: CD4 cells, helper T (TH) cells, CD8 cells,
cytotoxic T (TC) cells, regulatory T cells (Treg cells), class I and class
II MHC proteins, antigen binding, T cell antigen receptors (TCRs), co-
stimulation, cytokines, interleukins, perforin, immune surveillance
 CHAPTER 21
THE IMMUNE SYSTEM
PART I

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 The Immune System

• provides resistance to potentially harmful

pathogens (=disease causing microorganisms)
• Two types:
I. Innate (nonspecific) defense system
– First line of defense (surface barriers)
– Second line of defense (internal defenses)
II. Adaptive (specific) defense system
• Third line of defense (humoral and cellular immunity)
• Takes longer to react than innate

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Figure 21.1 Simplified overview of innate and adaptive defenses.

1st line Surface barriers

• Skin
• Mucous membranes

Innate
defenses Internal defenses
• Phagocytes
2nd line • Natural killer cells
• Inflammation
• Antimicrobial proteins
• Fever

Humoral immunity
• B cells
Adaptive
defenses 3rd line
Cellular immunity
• T cells
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 Part I – INNATE DEFENSES

• first line of defense: surface barriers

• Second line of defense: innate internal defenses

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 First Line of Defense: Surface Barriers

• skin and 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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• Skin and mucous membranes produce protective
chemicals that inhibit or destroy microorganisms
– Acid: acidity of skin and some mucous secretions
inhibits growth
– Enzymes: lysozyme of saliva, respiratory mucus,
and lacrimal fluid kills many microorganisms;
enzymes in stomach kill many microorganisms
– Mucin: sticky mucus that lines digestive and
respiratory tract traps microorganisms
– Defensins: antimicrobial peptides that inhibit
microbial growth
– Other chemicals: lipids in sebum and dermicidin in
sweat are toxic to some bacteria
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 Surface Barriers (con’t)

• Respiratory system also has modifications to

stop pathogens
– Mucus-coated hairs in nose trap inhaled particles
– Cilia of upper respiratory tract sweep dust- and
bacteria-laden mucus toward mouth

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Table 21.1 The First Line of Defense: Surface Membrane Barriers

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 Second Line of Defense: Cells and Chemicals
• mobilized if microorganisms invade deeper
tissues
• Various cells and chemicals protect against
pathogens that breach the surface barriers:
1. Phagocytes
2. Natural killer (NK) cells
3. Inflammatory response (macrophages, mast
cells, WBCs, and inflammatory chemicals)
4. Antimicrobial proteins (interferons and
complement proteins)
5. Fever

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 1. Phagocytes
• white blood cells that ingest and digest (eat) foreign
invaders
• Neutrophils: most abundant, but die fighting
– become phagocytic on exposure to infectious material
• Macrophages: develop from monocytes, chief
phagocytic cells; most robust phagocytic cell
– 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)
• Opsonization: antibodies or complement proteins
are opsonins that coat pathogens
• Act as “handles” for phagocytes to grab on to, enhancing
phagocytosis
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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 micrograph (4800×).

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Figure 21.2 Phagocytosis. Slide 6

1 Phagocyte adheres
to pathogens or debris.

2 Phagocyte forms
pseudopods that
eventually engulf the
Phagosome
particles, forming a
(phagocytic
phagosome.
vesicle)
Lysosome
3 Lysosome fuses
with the phagocytic
vesicle, forming a
phagolysosome.

Acid
hydrolase
enzymes 4 Toxic compounds
and lysosomal
enzymes destroy
pathogens.

5 Sometimes
exocytosis of the
vesicle removes
indigestible and
residual material.
Events of phagocytosis.

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Phagocytes – killing mechanisms:

• Phagocytosis  digestion via lysosomal

enzymes
• Activated phagocytes may release a series of
antimicrobial agents:
– Antimicrobial enzymes, e.g. defensins (in
PMNs)- pierce pathogen’s membrane
– Free radicals (e.g. NO, superoxides) and
oxidizing chemicals (e.g H2O2, bleach)
generated via “respiratory burst”
 2. Natural Killer (NK) Cells
• Nonphagocytic, large granular lymphocytes that
police blood and lymph
– Can kill cancer and virus-infected cells before
adaptive immune system is activated
• React nonspecifically; recognize target cells that lack
certain identity molecules on cell membrane (e.g.
“self” cell surface proteins)
• Kill via direct contact by inducing apoptosis in
cancer cells and virus-infected cells
– Secrete perforins and other cytolytic chemicals (e.g.
granzymes)
– Secrete potent chemicals that enhance inflammatory
response
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 3. Inflammation
• Nonspecific response to tissue injury/infection
• Benefits include:
– prevents the spread of injurious agents to nearby
tissues
– disposes of pathogens and dead cells
– Alerts the adaptive immune system
– sets the stage for repair

Four cardinal signs of acute inflammation:

– redness, heat, swelling, and pain
– (+ impaired fxn) –> 5th cardinal sign
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Inflammatory Response

• Begins with chemicals released into ECF by

injured tissues, immune cells, blood proteins
(see Table 21.2)
• Macrophages and epithelial cells of boundary
tissues bear Toll-like receptors (TLRs)
– 11 types of TLRs recognize specific classes of
infecting microbes
– Activated TLRs trigger release of inflammatory
chemicals that promote inflammation
Table 21.2 Inflammatory Chemicals

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Inflammatory Mediators & effects:
– histamine released from mast cells (&
basophils)
– kinins, prostaglandins (PGs), complement
and cytokines from injured tissue, phagocytes
and lymphocytes
– All cause vasodilation (dilate BV in injured area
& blood, resulting in hyperemia)  redness and
heat
– Also increase capillary permeability  exudate
(fluid with proteins, clotting factors, AB’s from
blood to tissue spaces)  local edema (swelling)
 may contribute to pain sensation as fluid
presses on adjacent nerve endings
– Kinins & PGs may also induce pain
• The surge of protein-rich exudate into tissue:
– contributes to swelling and pain
– helps dilute harmful substances, moving
foreign material into lymphatic vessels
– allows entry of clotting proteins to form a
scaffold for repair and prevents the spread of
bacteria
Figure 21.3 Events of acute inflammation.

Innate defenses Internal defenses Initial stimulus

Physiological response
Signs of inflammation
Tissue injury
Result

Release of inflammatory chemicals Release of leukocytosis-

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

Leukocytosis
(increased numbers of white
blood cells in bloodstream)
Arterioles Increased capillary Attract neutrophils,
dilate permeability monocytes, and
Leukocytes migrate to
lymphocytes to
injured area
area (chemotaxis)

Local hyperemia Capillaries

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

Heat Redness
Locally increased
temperature increases
metabolic rate of cells
Diapedesis
Leaked protein-rich Leaked clotting
(leukocytes pass through
fluid in tissue spaces proteins form
capillary walls)
interstitial clots
that wall off area
to prevent injury to Phagocytosis of pathogens
Pain Swelling surrounding tissue and dead tissue cells
(by neutrophils, short-term;
by macrophages, long-term)
Possible temporary Temporary fibrin Pus may form
impairment of patch forms
function scaffolding Area cleared of debris
for repair

Healing

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 Phagocyte Mobilization
• Neutrophils first flood the inflamed sites (monocytes to
follow)
• Four main steps:
• Leukocytosis - neutrophils are released from the bone
marrow in response to leukocytosis-inducing factors
released by injured cells
• Margination - neutrophils cling to the walls of
capillaries in the injured/inflamed area
• Diapedesis (emigration) – neutrophils squeeze
through capillary walls
• Chemotaxis – inflammatory chemicals (chemotactic
agents) attract neutrophils (& other leukocytes) to the
injury site
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Figure 21.4 Phagocyte mobilization. Slide 5

Innate defenses Internal defenses

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

• enhance innate defense by:

– Attacking microorganisms directly, or
– Hindering microorganisms’ ability to reproduce
• Most important antimicrobial proteins
– Interferons
– Complement proteins

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 Interferons (IFN)

– family of immune modulating proteins released

from virus-infected cells and other cells (e.g
WBCs, fibroblasts)
– Cells infected with viruses can secrete IFNs
that “warn” healthy neighboring cells
• IFNs enter neighboring cells, stimulating production
of proteins that block viral reproduction and degrade
viral RNA

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Figure 21.5 The interferon mechanism against viruses. Slide 6

Innate defenses Internal defenses

Virus
Viral nucleic acid
1 Virus
New
enters cell.
viruses 5 Antiviral
proteins block
viral reproduction.

2 Interferon
genes
switch on.

Antiviral
mRNA
DNA

Nucleus

mRNA for
interferon

4 Interferon
3 Cell binding stimulates
produces cell to turn on genes
interferon for antiviral proteins.
molecules. Interferon
receptor
Interferon
Host cell 1 Host cell 2
Infected by virus; Binds interferon
makes interferon; from cell 1; interferon
is killed by virus induces synthesis of
protective proteins
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 Complement System (complement)
– consists of ~20 blood proteins that circulate in
blood in inactive state
– Includes proteins C1–C9, factors B, D, and P,
and regulatory proteins
– Provides major mechanism for destroying foreign
substances
– Activation enhances inflammation and also
directly destroys bacteria
• Enhances both innate and adaptive defenses

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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.
MACs form from activated
C9
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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• 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
 5. Fever
– Abnormally high body temperature that is systemic
response to invading microorganisms
– Leukocytes and macrophages exposed to foreign
substances secrete pyrogens
– Pyrogens reset body’s thermostat in
hypothalamus, raising body temperature
• Not the same as localized heat in inflammation
– Benefits of mild- moderate fever:
• Causes liver and spleen to sequester iron and zinc (less
available to microorganisms)
• Increases metabolic rate, which increases rate
of repair
– High fever: can be dangerous
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 Table 21.3 The Second Line of Defense: Innate
Cellular and Chemical Defenses

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 CHAPTER 21
THE IMMUNE SYSTEM
PART 2

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 Part 2 – ADAPTIVE DEFENSES
- Protects against infectious agents and abnormal body
cells
- Amplifies the inflammatory response
- Activates complement
• Characteristics of adaptive immunity
– It is specific: recognizes and targets specific antigens
– It is systemic: not restricted to initial site
– It has memory: mounts an even stronger attack to
“known” antigens (second and subsequent exposures)
• Two main branches of adaptive system
1. Humoral (antibody-mediated) immunity
2. Cellular (cell-mediated) immunity

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 Adaptive Defenses

1. Humoral immunity
– Antibodies, produced by lymphocytes, circulate freely in
body fluids
– Bind temporarily to target cell
• Temporarily inactivate
• Mark for destruction by phagocytes or complement
– Humoral immunity has extracellular targets
2. 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
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 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)
• Characteristics of antigens
– Can be a complete antigen or hapten (incomplete)
– Contain antigenic determinants
– Can be a self-antigen

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 Complete Antigens
• have two 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 proteins, polysaccharides,
lipids, and nucleic acids on microorganisms

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 Haptens (incomplete antigens)

• molecules too small to be seen so are not

immunogenic by themselves
• Have reactivity BUT not immunogenicity
– Examples: small peptides, nucleotides, some hormones,
penicillin, poison ivy, animal dander, detergents,
cosmetics, etc.
• May become immunogenic if hapten attaches to
body’s own proteins
– Combination of protein and hapten is then seen as
foreign  adaptive immune system and mounts a
harmful attack (hypersensitivity)

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 Antigenic Determinants

• parts of antigen that antibodies or lymphocyte

receptors bind to
• 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 (such as
plastics) have little or no immunogenicity

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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
• all cells are covered with variety of proteins
located on surface that are not antigenic to
self, but may be antigenic to others in
transfusions or grafts
• One set of important self-proteins are group
of glycoproteins called MHC proteins
– Coded by genes of major histocompatibility
complex (MHC) and unique to each individual
– Contain groove that can hold piece of self-
antigen or foreign antigen
• T lymphocytes can recognize only antigens that are
presented on MHC proteins
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 Lymphocytes and Antigen-Presenting Cells

• Adaptive immune system involves three crucial

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

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 Lymphocyte Development, Maturation, and
Activation
• Five general steps:
– Origin – all originate in red bone marrow
– Maturation – in primary lymphoid organs (bone
marrow or thymus)
• Immunocompetent
• Self-tolerant
• Naive cells
– Seeding secondary lymphoid organs and
circulation
– Antigen encounter and activation
– Proliferation and differentiation
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 Figure 21.8 Lymphocyte development, maturation, and activation. Slide 6
Primary lymphoid organs
Humoral immunity
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 2 Maturation
precursors • 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
Thymus
immunocompetence 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
Antigen circulate through blood and lymph.

Lymph node 4 Antigen encounter and activation

• 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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Lymphocytes

• Originate in red bone marrow

– B cells mature in the red bone marrow
– T cells mature in the thymus
• When mature, they have
– Immunocompetence – they are able to recognize
and bind to a specific antigen
– Self-tolerance – unresponsive to self antigens

• Naive (unexposed) B and T cells are exported to

lymph nodes, spleen, and other lymphoid organs
• Increases chance of encounter with specific antigen
LYMPHOCYTE MATURATION
T cells Maturation

• 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. Immunocompetence
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 Self-tolerance
continued maturation.

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B cells Maturation

• B cells mature in red bone marrow

• Positively selected if successfully make antigen
receptors
• Those that are self-reactive
– Eliminated by apoptosis (clonal deletion)
 LYMPHOCYTE ACTIVATION,
PROLIFERATION & DIFFERENTIATION

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Antigen Encounter and Activation

• Clonal selection
– Naive lymphocyte's first encounter with antigen
via antigen receptors  selected for further
development
– If correct signals present, lymphocyte will
complete its activation
Antigen receptors:

– Specific shape “fits” one specific 3-D shape of

Antigen
– Are what makes adaptive immunity “specific”
– In T cells are called T cell antigen receptors
(TCRs)
– In B cells are called antibodies – the same
antibodies that are released from that cell if it
becomes activated
– Each clone of B or T cell is specific for one
specific antigen, i.e. has receptor for that
antigen on cell surface
 B and T cell antigen receptor

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Proliferation and Differentiation

• Activated lymphocyte proliferates  form exact

copies of itself (clones)
• Most clones become effector cells that fight
infections
• Few remain as memory cells
– Able to respond to same antigen more quickly
second time it is encountered
• B and T memory cells and effector T cells
circulate continuously
 Table 21.4 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  T cell activation
• Major types:
– Dendritic cells in connective tissues and
epidermis
– Macrophages in connective tissues and
lymphoid organs
– B cells
 • Dendritic cells
– Found in connective tissues and epidermis
– Phagocytize pathogens that enter tissues, then
enter lymphatics to present antigens to T cells in
lymph node
• Most effective antigen presenter known
• Key link between innate and adaptive immunity

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Figure 21.10 Dendritic cell.

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 • Macrophages
– Widely distributed in connective tissues and
lymphoid organs
– Present antigens to T cells, which not only
activates T cell, but also further activates
macrophage
• Activated macrophage becomes voracious phagocytic
killer
• Also trigger powerful inflammatory responses and
recruit additional defenses
• B lymphocytes
– Do not activate naive T cells
– Present antigens to helper T cell to assist their
own activation
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 1. HUMORAL IMMUNITY

• Antigen challenge:
– First encounter between an antigen and a naive
immunocompetent B lymphocyte
– Usually occurs in the lymphoid organs (e.g.
spleen or a lymph node)
– The antigen provokes a humoral immune
response:
• Antibodies are produced
• Activation and differentiation of B cells:

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 Fate of the clones:
• Most clone cells become plasma cells
– antibody-secreting effector cells
– Secrete specific antibodies for 4-5 days, then die
– Antibodies circulate in blood or lymph
• binding to free antigens, marking them for destruction
by innate or other adaptive mechanisms
• Clone cells that do not become plasma cells
become memory cells
– Provide immunological memory
– Mount an immediate response to future
exposures to same antigen
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B Cell Clonal Selection
Ag binds to B cell surface receptors and cross-links
adjacent receptors

receptor-mediated endocytosis of cross-linked antigen-
receptor complexes occurs
 requires co-stimulation
 by helper T cells for full activation
Clonal selection
B cell grows & proliferates to form a clone (many
identical cells able to bear the same antigen-specific
receptors)

Plasma cells & memory cells
 Figure 21.11-1 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 receptors remain
Activated B cells to form a inactive)
clone

Plasma cells Memory B cell—

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

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 Figure 21.11-2 Clonal selection of a B cell.

Memory B cell—
primed to respond
to same antigen

Secondary response Clone of cells

Subsequent
(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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 Immunological Memory

1. Primary immune response

– cell proliferation and differentiation upon
exposure to antigen for the first time
– Lag period: 3 to 6 days
– Peak levels of plasma antibody are reached in
10 days
– Antibody levels then decline

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 2. Secondary immune response
– Re-exposure to same antigen gives faster, more
prolonged, more effective response
• Sensitized memory cells provide immunological
memory
• Respond within hours, not days
• Antibody levels peak in 2 to 3 days at much higher
levels
• Antibodies bind with greater affinity
• Antibody level can remain high for weeks to months

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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 vs. Passive Humoral Immunity

- Natural acquired
- Artificially acquired
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 with dead or passed from exogenous
pathogen attenuated mother to antibodies
pathogens fetus via (gamma
placenta; or globulin)
to infant in
her milk
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 Active Humoral Immunity
• occurs when B cells encounter antigens and
produce specific antibodies against them
• Two types of active humoral immunity:
1. Naturally acquired: formed in response to
actual bacterial or viral infection
2. Artificially acquired: formed in response to
vaccine of dead or attenuated pathogens
• Provide antigenic determinants that are immunogenic
and reactive
• Spare us symptoms of primary response

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 Passive Humoral Immunity
• occurs when ready-made antibodies are
introduced into body
– B cells are not challenged by antigens
– Immunological memory does not occur
– Protection ends when antibodies degrade

• Two types of passive humoral immunity:

1. Naturally acquired: antibodies delivered to fetus
via placenta or to infant through milk
2. Artificially acquired: injection of serum, such as
gamma globulin
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Antibodies

• Immunoglobulins—gamma globulin portion of

blood
• Proteins secreted by plasma cells
• Capable of binding specific antigen detected by
B cells
• Grouped into one of five Ig classes
 Basic antibody structure
• T- or Y-shaped antibody monomer consists of four
polypeptide chains linked by disulfide bonds:
– Two identical heavy (H) chains
– Two identical light (L) chains
• Variable (V) regions of each arm combine to form
two identical antigen-binding sites
• Stems makeup constant (C) regions
– Area that determines antibody class
– Considered effector region of antibody
– Serves common functions in all antibodies by dictating:
1. Type of cells and/or chemicals that antibody can bind
2. How antibody class functions to eliminate antigens

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 Figure 21.14a Antibody
Adaptive defenses structure.
Humoral immunity

Antigen-binding site

Hinge region

Stem region

Heavy chain Light chain

variable region variable region
Heavy chain Light chain
constant region constant region
Disulfide bond
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 Table 21.5-1 Immunoglobulin Classes

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 Table 21.5-2 Immunoglobulin Classes (continued)

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 Antibody targets and functions

• Antibodies do not destroy antigens; they

inactivate and tag them
– Form antigen-antibody (immune) complexes
• Defensive mechanisms used by antibodies:
– Neutralization
– Agglutination
– Precipitation
– Complement fixation

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 Neutralization

– Simplest, but one of most important defensive

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

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 Agglutination

– Antibodies can bind same determinant on more

than one-bound antigen at the same time
– Allows for antigen-antibody complexes to
become cross-linked into large lattice-like clumps
• Example: clumping of mismatched blood cells

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 Precipitation

– Soluble molecules are cross-linked into large

insoluble complexes
– Complexes precipitate out of solution
– Precipated complexes are easier for phagocytes
to engulf

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 Complement fixation and activation

– Main antibody defense against cellular antigens

(bacteria, mismatched RBCs)
– When several antibodies are bound close
together on same antigen, complement-binding
sites on their stem regions are exposed
• triggers complement fixation
– Complement fixation and activation leads to:
– cell lysis
– Amplification of the inflammatory response
– enhanced phagocytosis (through opsonization)

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 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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 Monoclonal antibodies:
- commercially prepared pure antibodies that are
specific for a single antigenic determinant
– Produced by hybridomas, cell hybrids formed
from fusion of tumor cell and B cell
• Tumor cell portion allows cells to proliferate
indefinitely, while B cell portion allows production of
single type of antibody
– Used in research, clinical testing, and cancer
treatment

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 2. CELLULAR IMMUNITY
• Mediated by T cells
• T cells provide defense against intracellular
antigens (e.g. virus infected cells), tumor or
abnormal cells, graft tissues
• Some T cells directly kill cells; others release
chemicals that regulate immune response
• Each T cell displays:
1. T cell receptors (TCRs): antigen-specific
receptors
2. Cell Differentiation molecules (e.g. CD4 and
CD8 gylcoproteins):
• assist in T cell interactions with other cells
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TYPES OF T CELLS
2 major populations:
• CD8 cells (when activated become cytotoxic T
cells)
– Bind target cell, convey lethal hit
– Secrete perforins punch hole in cell membrane
– Secrete granzymes into target cells  destruction

• CD4 cells (when activated become helper T

cells)
– 60-80% of T cells
– Secrete cytokines
– Crucial help for ALL aspects of adaptive immunity
– Orchestrated both B and T cell responses
– Destroyed by HIV
– Some become regulatory T cells (moderate immune
response)
Other types of T cells:
– Regulatory T cells (TREG)
• May result from CD4 T cell activation
• Dampen the immune response by direct
contact or by inhibitory cytokines (e.g. IL-10
and TGFb)
• Important in preventing autoimmune reactions
– Memory T cells (from activation of CD4 and
CD8 T 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 I MHC
Class II MHC CD8 protein displaying
CD4
protein displaying cell antigen
antigen
cell Thymus

Activation Activation

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

CD4 CD8

CD4 cells Lymphoid CD8 cells

become either tissues and become
helper cytotoxic
organs
T cells or T cells
regulatory
T cells Effector
cells
Blood plasma

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ANTIGEN RECOGNITION BY T CELLS
- Immunocompetent T cells are activated when
their surface receptors bind to a recognized
antigen (nonself) displayed by MHC proteins
- Antigen presentation vital for activation of
naive T cells and normal functioning of effector
T cells
- T cells must simultaneously recognize:
•Nonself (the antigen)
•Self (an MHC protein of a body cell)
 MHC Proteins and Antigen Presentation

• Two classes of MHC proteins important to T cell

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

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 Class I MHC Proteins

– Bind with short fragment of endogenous antigen,

protein synthesized inside cell
• Endogenous antigen can be:
– Self-antigen: normal proteins of cell
– Nonself antigen: abnormal proteins found in infected or
abnormal cell
– crucial for CD8 cell activation
• Act as antigen holders; form “self” part that T cells
recognize
• Inform cytotoxic T cells of microorganisms hiding in
cells (cytotoxic T cells ignore displayed self-antigens)

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 Class II MHC Proteins

– Bind with fragments of exogenous (extracellular)

antigens that have been engulfed and broken
down in a phagolysosome by antigen-presenting
cell
– recognized by helper T cells
• Signal CD4 cells that help is required

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 MHC Restriction
• CD4 and CD8 cells have different requirements
for MHC protein that presents antigens to them
– CD4 cells that become TH are restricted to
binding to only class II MHC proteins typically
on APC surfaces
– CD8 cells that become cytotoxic T cells are
restricted to binding only class I MHC proteins
found on every cell surface, including APC
surfaces (Note: RBCs do not express MHC
proteins)
• Once activated, cytotoxic T cells seek out same
antigen on class I MHC proteins on any cell
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 Table 21.6 Role of MHC Proteins in Cellular Immunity

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T CELL ACTIVATION

• T cell activation is a two-step process:

1. Antigen binding
2. Co-stimulation
• Both occur on surface of same APC
• Both are required for clonal selection of cell
• T cells that are activated:
– Enlarge and proliferate in response to
cytokines
– Differentiate and perform functions according
to their T cell class
 1. Antigen binding

– T cell antigen receptors (TCRs) bind to antigen-

MHC complex on APC surface
– TCR must perform double recognition by
recognizing both MHC and foreign antigen it
displays
– Binding of TCR to complex triggers multiple
intracellular signaling pathways that start T cell
activation
– Other T cell surface proteins are involved in T
cell activation (e.g., CD4 and CD8 help maintain
coupling during antigen recognition)

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 2. Co-stimulation

– Complete T cell activation requires T cell to also

bind to one or more co-stimulatory signals on
surface of APC
– Without co-stimulation, anergy occurs, in which
T cells:
• Become tolerant to that antigen
• Are unable to divide
• Do not secrete cytokines
– Two-step process is a safeguard against
unwanted T cell activation

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 Proliferation & differentiation of T cells
– T cells that are activated enlarge and proliferate in
response to cytokines
• Differentiate and perform functions according to their T cell
class
– Primary T cell response peaks within a week
– T cell apoptosis occurs between days 7 and 30
• Activated T cells are a hazard because they produce large
amounts of inflammatory cytokines
• Could result in hyperplasia or cancer if not cleared from
system
– Effector activity wanes as amount of antigen
declines
– Memory T cells remain and mediate secondary
responses
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 Figure 21.17 Clonal selection of T cells involves simultaneous recognition of self and nonself. Slide 4

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.
molecule receptor
2b Co-stimulatory
Clone molecules bind their
formation receptors.

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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 Cytokines

– Chemical messengers of immune system

– Mediate cell development, differentiation, and
responses in immune system
– Include interferons and interleukins
– May amplify and regulate innate and adaptive
responses
• e.g. - Interleukin-2
» Encourages activated T cells to divide rapidly
- Gamma interferon
» enhances killing power of macrophages

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 Table 21.7 Selected Cytokines

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 Roles of Specific Effector T Cells

• Helper T (TH) cells

– Play central role in adaptive immune response
– Activate both humoral and cellular arms
– Once primed by APC presentation of antigen,
helper T cells:
• Help activate B cells and other T cells
• Induce T and B cell proliferation
• Secrete cytokines that recruit other immune cells
– Without TH, there is no immune response

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 Slide 6
Figure 21.18 The central role of helper T cells in mobilizing both humoral and
cellular immunity.

Humoral immunity
Adaptive defenses
Cellular immunity

Helper T cells help in humoral immunity Helper T cells help in cellular immunity

Helper T cell CD4 protein Helper T cell

Class II MHC 1 TH cell binds
1 TH cell binds with
dendritic cell.
T cell receptor (TCR) the self-nonself protein
complexes of a B cell APC (dendritic
that has encountered
Helper T cell cell)
its antigen and is 2 TH cell
CD4 protein displaying it on
IL-2 stimulates dendritic
MHC II on its surface. cell to express
MHC II protein
of B cell displaying co-stimulatory
processed antigen molecules.
2 TH cell releases
interleukins as co-
stimulatory signals to 3 Dendritic cell
IL-4 and other
complete B cell can now activate
cytokines Class I CD8
activation. CD8 cell with the
MHC protein protein help of interleukin 2
CD8 T cell secreted by TH cell.
B cell (being activated) (becomes TC cell
after activation)

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 • 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
– Activated TC cells target:
• Virus-infected cells, cells with intracellular bacteria or parasites,
cancer cells, foreign cells (transfusions or transplants)
– deliver lethal hit using two mechanisms:
1. TC cell releases perforins and granzymes by exocytosis
– Perforins create pores through which granzymes enter target
cell
– Granzymes stimulate apoptosis
2. TC cell binds specific membrane receptor on target cell and
stimulates apoptosis

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 Figure 21.19a Cytotoxic T cells attack infected and cancerous cells.
Adaptive defenses Cellular immunity

Cytotoxic
T cell (TC) 1 TC identifies 2 TC releases 3 Perforin molecules insert into
foreign antigens perforin and the target cell membrane,
on MHC I granzyme polymerize, and form
proteins and molecules from transmembrane pores (cylindrical
binds tightly to its granules by holes) similar to those produced
target cell. exocytosis. by complement activation.

Granule
Perforin

TC cell
membrane

Target
cell
membrane
Target
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.
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 • Cytotoxic T (TC) cells vs. NK cells
– Natural killer cells recognize other signs of
abnormality that cytotoxic T cells do not look for,
such as:
• Cells that lack class I MHC proteins
• Antibodies coating target cell
• Different surface markers seen on stressed cells
– NK cells use same key mechanisms as TC cells
for killing their target cells
– Immune surveillance: NK and TC cells prowl
body looking for markers they each recognize

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 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
Ag-infected activate B cell
body cell engulfed
by dendritic cell Antigen-
activated
Becomes B cells

Co-stimulate and release cytokines

Clone and
Ag-presenting cell

Present Ag to helper T cells

give rise to
(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 and give rise to
Induce Plasma cells
co-stimulation (effector B cells)

Memory
Memory
CD4 T cells
CD8 T cells Secrete
Cytotoxic Helper
T cells T cells

Cytokines stimulate

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

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 Table 21.8 Cells and Molecules of the Adaptive Immune Response

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Test your knowledge:

Do the following Review Questions

at the end of Chapter 21:
1-3, 6-20, and 24-27