Immune The System
PART A
1
Immunity: Two Intrinsic Defense
Systems
n
Innate (nonspecific) system responds quickly
and consists of:
First line of defense skin and mucosa
prevent entry of microorganisms
Second line of defense antimicrobial
proteins, phagocytes, and other cells
n Inhibit spread of invaders throughout the
body
n Inflammation is its most important
2
mechanism
Immunity: Two Intrinsic Defense
Systems
n
Adaptive (specific) defense system
Third line of defense mounts attack
against particular foreign substances
n Takes longer to react than the innate
system
n Works in conjunction with the innate
system
3
Innate and Adaptive Defenses
4
Innate Defense - First Line
n
n
n
n
Surface Barriers: skin and mucosa
Skin, mucous membranes, and their secretions
make up the first line of defense
Keratin in the skin:
Presents a physical barrier to most
microorganisms
Is resistant to weak acids and bases,
bacterial enzymes, and toxins
Mucosa provide similar mechanical barriers
5
Innate Defense
n
Epithelial membranes produce protective
chemicals that destroy microorganisms
Skin acidity (pH of 3 to 5) inhibits bacterial
growth
Sebum contains chemicals toxic to bacteria
Stomach mucosa secrete concentrated HCl
and protein-digesting enzymes
Saliva and lacrimal fluid contain lysozyme
6
Innate Defense
Mucus
n
traps microorganisms that enter the
digestive and respiratory systems
Respiratory Tract Mucosae:
Mucus-coated hairs in the nose trap inhaled
particles
Mucosa of the upper respiratory tract is
ciliated
Cilia sweep dust- and bacteria-laden mucus
away from lower respiratory passages
7
Innate Defense - Second Line
n
n
n
Internal Defenses: Cells and Chemicals
The body uses nonspecific cellular and
chemical devices to protect itself
Phagocytes and natural killer (NK) cells
Antimicrobial proteins and tissue fluid, fever
Inflammatory response enlists
macrophages, mast cells, WBCs, and
chemicals
Harmful substances are identified by surface
carbohydrates unique to infectious organisms
8
Innate Defense Second Line
n
n
n
n
n
Phagocytes
Macrophages are the chief phagocytic cells
Free macrophages wander throughout a
region in search of cellular debris
Kupffer cells (liver) and microglia (brain) are
fixed macrophages
They derive from
monocytes
9
Innate Defense Second Line
n
n
n
Neutrophils become phagocytic when
encountering infectious material
Eosinophils are weakly phagocytic. They are
important against parasitic worms
They degranulate their enzymes when
encountering the parasite
Mast cells release histamine and heparin
10
1 Microbe adheres to phagocyte.
2 Phagocyte forms pseudopods that
eventually engulf the particle.
Lysosome
Phagocytic vesicle
containing antigen
(phagosome).
3 Phagocytic vesicle is
fused with a lysosome.
Phagolysosome
Acid
hydrolase
enzymes
4 Microbe in fused vesicle
is killed and digested by
lysosomal enzymes within
the phagolysosome, leaving
a residual body.
Residual body
5 Indigestible and
residual material
is removed by
exocytosis.
(b)
11
Figure 21.2b
Innate Defense Second Line
n
n
n
Mechanism of phagocytosis:
First step for phagocytosis is adherence of the
pathogen to the phagocyte.
Adherence will be facilitated when the
pathogen is coated with complement or
antibodies:
Opsonization
12
Innate Defense Second Line
n
n
n
n
Respiratory burst
When the pathogen is resistant to common
digestive enzymes
Phagocytes will be stimulated by T helper cells
to release free radicals that have a potent
ability to kill cells
Neutrophils can also release defensins that
will perforate the pathogens membrane
13
Innate Defense Second Line
n
n
n
n
n
n
Natural Killer (NK) Cells
Can lyse and kill cancer cells and virus-infected
cells
Are a small, distinct group of large granular
lymphocytes
They lack specificity
They are not phagocytes
Kill their target cells by releasing perforins and
other cytolytic chemicals
14
Innate Defense Second Line
n
n
n
n
n
Secrete potent chemicals that enhance the
inflammatory response
They can recognize self cell receptors
They can also recognize sugars present on the
membrane of the pathogens
They destroy target cells coated with
antibodies
They destroy cells that lack self-antigens
15
Innate Defense Second Line
n
n
n
Inflammation: Tissue Response to Injury
The inflammatory response is triggered
whenever body tissues are injured
Prevents the spread of damaging agents to
nearby tissues
Disposes of cell debris and pathogens
Sets the stage for repair processes
The four cardinal signs of acute inflammation
are redness, heat, swelling, and pain
16
Innate Defense Second Line
n
n
Begins with a flood of inflammatory chemicals
released into the extracellular fluid
Inflammatory mediators:
Kinins, prostaglandins (PGs), complement,
and cytokines
Released by injured tissue, phagocytes,
lymphocytes, and mast cells
Cause local small blood vessels to dilate,
resulting in hyperemia
17
Innate Defense Second Line
n
n
Vasodilation and increased vascular
permeability
Chemicals liberated by the inflammatory
response will
Dilate small blood vessels
n Hyperemia
Increase the permeability of local capillaries
n Exsudate
18
Innate Defense Second Line
n
Exudatefluid containing proteins, clotting
factors, and antibodies
Exudate seeps into tissue spaces causing
local edema (swelling), which contributes to
the sensation of pain.
Also the bacterial toxins, prostaglandins and
kinins contribute for the pain
19
Innate Defense Second Line
n
The surge of protein-rich fluids into tissue
spaces (edema):
Helps dilute harmful substances
Brings in large quantities of oxygen and
nutrients needed for repair
Allows entry of clotting proteins, which
prevents the spread of bacteria by creating a
gel-like fibrin mesh
Inflammation will also release -defensins
that have antimicrobial properties
20
Innate Defense Second Line
n
Phagocyte mobilizes in four main phases:
Leukocytosis- the increase of WBC in the
blood. It is caused by factors released by
injured cells.
Margination neutrophils cling to the walls of
capillaries in the injured area
Diapedesis neutrophils squeeze through
capillary walls and begin phagocytosis
Chemotaxis WBC attraction to chemicals
that guide them to the site of injury or
inflammation after they leave the bloodstream.
21
Innate defenses
Internal defenses
4 Positive
chemotaxis
Inflammatory
chemicals diffusing
from the inflamed
site act as chemotactic
agents
1 Neutrophils enter blood
from bone marrow
2 Margination
Capillary wall
Endothelium
Basement membrane
3 Diapedesis
22
Figure 21.4
23
Innate Defense Second Line
n
n
n
Antimicrobial Proteins
Enhance the innate defenses by:
Attacking microorganisms directly
Hindering microorganisms ability to
reproduce
The most important antimicrobial proteins are:
Interferon
Complement proteins
24
Innate Defense Second Line
n
n
n
n
n
Interferon (IFN)
Genes that synthesize IFN are activated when
a host cell is invaded by a virus
Interferon molecules leave the infected cell and
enter neighboring cells
Interferon stimulates the healthy cells to
activate genes for an antiviral protein
production
This antiviral protein nonspecifically blocks
viral reproduction in the neighboring cell
25
Interferon
26
Innate Defense Second Line
n
IFNs family
Family of related proteins each with slightly
different physiological effects
Lymphocytes secrete gamma () interferon,
but most other WBCs secrete alpha ()
interferon
Fibroblasts secrete beta () interferon
Interferons also activate macrophages and
mobilize NKs
n Some anticancer property
27
Innate Defense Second Line
n
n
n
n
Complement
20 or so proteins that circulate in the blood in
an inactive form
Proteins include C1 through C9, factors B, D,
and P, and regulatory proteins
Provides a major mechanism for destroying
foreign substances in the body
28
Innate Defense Second Line
n
n
n
Amplifies all aspects of the inflammatory
response
Kills bacteria and certain other cell types (our
cells innactivate complement)
Enhances the effectiveness of both nonspecific
and specific defenses
29
Innate Defense Second Line
n
Complement Pathways:
Complement can be activated by two
pathways: classical and alternative
Classical pathway is linked to the immune
system
n Depends on the binding of antibodies to
invading organisms
n Subsequent binding of C1 to the antigenantibody complexes (complement fixation)
30
Innate Defense Second Line
n
n
n
Alternative pathway is triggered by interaction
among factors B, D, and P, and polysaccharide
molecules present on microorganisms
Each pathway involves a cascade in which
complement proteins are activated in a
sequence where each step catalyzes the next
Both pathways converge on C3, which cleaves
into C3a and C3b
31
Innate Defense Second Line
n
n
n
C3b initiates formation of a membrane attack
complex (MAC)
MAC causes cell lysis by creating pores in the
cell membranes
C3b also causes opsonization, and C3a
causes inflammation
32
Complement Pathways
33
Innate Defense Second Line
n
n
n
C-reactive Protein (CRP)
CRP is produced by the liver in response to
inflammatory molecules
CRP is a clinical marker used to assess:
The presence of an acute infection
An inflammatory condition and its response
to treatment
34
Innate Defense Second Line
n
n
n
Functions of C-reactive Protein:
Binds to receptor of pathogens and exposed
self-antigens of damaged body cells
Targets them for disposal by macrophages
and complements (classical pathway)
Activates complement by biding to C1
Cause deposit of C3 on the surface of the
bacterias
35
Innate Defense Second Line
n
n
n
Fever
Abnormally high body temperature in response
to invading microorganisms
The bodys thermostat is reset upwards in
response to pyrogens, chemicals secreted by
leukocytes and macrophages exposed to
bacteria and other foreign substances
36
Innate Defense Second Line
n
n
High fevers are dangerous because they can
denature enzymes
Moderate fever can be beneficial, as it causes:
The liver and spleen to sequester iron and
zinc (needed by microorganisms)
An increase in the metabolic rate, which
speeds up tissue repair
37
Adaptive Defenses Third Line
n
The adaptive (specific) immune system is a
functional system that:
Recognizes specific foreign substances
Acts to immobilize, neutralize, or destroy
foreign substances
Amplifies inflammatory response and
activates complement
38
Adaptive Immune Defenses
n
n
The adaptive immune system is antigenspecific, systemic, and has memory
It has two separate but overlapping arms:
Humoral, or antibody-mediated immunity
Cellular, or cell-mediated immunity
39
Self-Antigens
n
n
n
Our cells are dotted with a variety of protein
molecules (self-antigens) that are not antigenic
to us but are strongly antigenic to others
One type, MHC proteins, mark a cell as self
The two classes of MHC proteins are:
Class I MHC proteins found on virtually all
body cells
Class II MHC proteins found on certain
cells in the immune response
40
Nonself Antigens
n
n
n
Substances that can mobilize the immune
system and provoke an immune response
The ultimate targets of all immune responses
are mostly large, complex molecules not
normally found in the body (nonself)
They can be complete or incomplete
41
Complete Antigens
n
n
Important functional properties:
Immunogenicity ability to stimulate
proliferation of specific lymphocytes and
antibody production
Reactivity ability to react with products of
activated lymphocytes and the antibodies
released in response to them
Complete antigens include foreign protein,
nucleic acid, some lipids, and large
polysaccharides
42
Haptens (Incomplete Antigens)
n
n
n
Small molecules, such as peptides,
nucleotides, and many hormones, that are not
immunogenic but are reactive when attached
to protein carriers
If they link up with the bodys proteins, the
adaptive immune system may recognize them
as foreign and mount a harmful attack (allergy)
Haptens are found in poison ivy, dander, some
detergents, and cosmetics
43
n
n
n
n
Only certain parts of an entire antigen are
immunogenic
Antibodies and activated lymphocytes bind to
these 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) have little or no immunogenicity
44
Antigenic Determinants
45
Cells of the Adaptive Immune
System
n
n
Two types of lymphocytes
B lymphocytes oversee humoral
immunity
T lymphocytes non-antibody-producing
cells that constitute the cell-mediated arm of
immunity
Antigen-presenting cells (APCs):
Do not respond to specific antigens
Play essential auxiliary roles in immunity
46
Lymphocytes
n
n
Immature lymphocytes formed in the bone
marrow are essentially identical
Whether a lymphocyte matures into a B cell or
a T cell depends on where in the body it
becomes immunocompetent (ability to
recognize a specific antigen) and self-tolerant
B cells mature in the bone marrow
T cells mature in the thymus
47
T Cells
n
n
n
T cells mature in the thymus under negative
and positive selection pressures
Positive selection selects T cells that
recognize self-antigens,
Happens in the thymic cortex
Negative selection eliminates T cells that are
strongly anti-self
Happens in the inner thymic cortex
They become self-tolerant (ignore ones self
antigens)
48
T Cell Selection in the Thymus
49
B Cells
n
n
B cells become immunocompetent and selftolerant in bone marrow
Some self-reactive B cells:
Are killed (clonal deletion) in the bone
marrow
Other B cells undergo receptor editing in
which there is a rearrangement of their
receptors in the bone marrow
50
n
n
n
n
Display a unique type of receptor that responds
to a distinct antigen
Become immunocompetent before they
encounter antigens they may later attack
It is genes, not antigens, that determine
which foreign substances our immune
system will recognize and resist
Are exported to secondary lymphoid tissue
where encounters with antigens occur
Mature into fully functional antigen-activated
cells upon binding with their recognized antigen
51
Key:
Red bone
marrow
Immature
lymphocytes
Circulation
in blood
1
Thymus
1
Bone marrow
2
Immunocompetent,
but still naive,
lymphocyte migrates
via blood
3
Activated
Immunocompetent
B and T cells
recirculate in
blood and lymph
2
Lymph nodes,
spleen, and other
lymphoid tissues
3
= Site of lymphocyte origin
= Site of development of
immunocompetence as
B or T cells; primary
lymphoid organs
= Site of antigen challenge,
activation, and final
diff erentiation of B and
T cells
1 Lymphocytes destined
to become T cells
migrate to the thymus
and develop
immunocompetence
there. B cells develop
immunocompetence
in red bone marrow.
2 After leaving the thymus
or bone marrow as nave
immunocompetent cells,
lymphocytes seed the
lymph nodes, spleen, and
other lymphoid tissues
where the antigen
challenge occurs.
3 Antigen-activated
immunocompetent
lymphocytes circulate
continuously in the
bloodstream and lymph
and throughout the
lymphoid organs of
the body.
52
Antigen-Presenting Cells (APCs)
n
n
n
Major rolls in immunity are:
To engulf foreign particles
To present fragments of antigens on their
own surfaces, to be recognized by T cells
Major APCs are dendritic cells (DCs-in
epidermis and connective tissue),
macrophages, and B cells
The major initiators of adaptive immunity are
DCs, which migrate to the lymph nodes and
secondary lymphoid organs, and present
antigens to T and B cells
53
Macrophages and Dendritic
Cells
n
n
Secrete soluble proteins that activate T cells
Activated T cells in turn release chemicals that:
Stimulate the maturation and mobilization of
DCs
Cause macrophages to become activated
macrophages, which are insatiable
phagocytes that secrete bactericidal
chemicals
54
Adaptive Immunity: Summary
n
n
Two-fisted defensive system that uses
lymphocytes, APCs, and specific molecules to
identify and destroy nonself particles
Its response depends upon the ability of its
cells to:
Recognize foreign substances (antigens) by
binding to them
Communicate with one another so that the
whole system mounts a response specific to
55
those antigens
Humoral Immunity Response
n
n
n
Antigen challenge first encounter between an
antigen and a naive immunocompetent B or T
cell
Takes place in the spleen or any other
lymphoid organ
If the lymphocyte is a B cell:
The challenging antigen provokes a humoral
immune response
n Antibodies are produced against the
56
challenger
Clonal Selection
n
n
n
Stimulated B cell growth forms clones bearing
the same antigen-specific receptors
A naive, immunocompetent B cell is activated
when antigens bind to its surface receptors
These, plus T cell interactions, trigger clonal
selection
57
Primary Response
(initial encounter
with antigen)
B lymphoblasts
Proliferation to
form a clone
Plasma
cells
Antigen
Antigen binding
to a receptor on a
specific B lymphocyte
(B lymphocytes with
non-complementary
receptors remain
inactive)
Memory
B cell
Secreted
antibody
molecules
Secondary Response
(can be years later)
Clone of cells
identical to
ancestral cells
Subsequent
challenge by
same antigen
Plasma
cells
Secreted
antibody
molecules
Memory
B cells
58
Fate of the Clones
n
n
Most clone cells become antibody-secreting
plasma cells (short-lived cells)
Plasma cells secrete specific antibody at a
higher rate than B cells
59
Fate of the Clones
n
n
Secreted antibodies:
Bind to free antigens
Mark the antigens for destruction by specific
or nonspecific mechanisms
Clones that do not become plasma cells
become memory (long-lived) cells that can
mount an immediate response to subsequent
exposures of the same antigen
60
Immunological Memory
n
Primary immune response cellular
differentiation and proliferation, which occurs
on the first exposure to a specific antigen
Lag period: 3 to 6 days after antigen
challenge
Peak levels of plasma antibody are achieved
in 10 days
Antibody levels then decline
61
Immunological Memory
n
Secondary immune response re-exposure to
the same antigen
Sensitized memory cells respond within
hours
Antibody levels peak in 2 to 3 days at much
higher levels than in the primary response
Antibodies bind with greater affinity, and
their levels in the blood can remain high for
weeks to months
62
Primary and Secondary Humoral
Responses
63
Active Humoral Immunity
n
n
B cells encounter antigens and produce
antibodies against them
Naturally acquired response to a bacterial
or viral infection
Artificially acquired response to a vaccine
of dead or attenuated pathogens
Vaccines spare us the symptoms of disease,
and their weakened antigens provide antigenic
determinants that are immunogenic and
64
reactive
Passive Humoral Immunity
n
n
n
Differs from active immunity in the antibody
source and the degree of protection
B cells are not challenged by antigens
Immunological memory does not occur
Protection ends when antigens naturally
degrade in the body
Naturally acquired from the mother to her
fetus via the placenta
Artificially acquired from the injection of
serum, such as gamma globulin
65
Types of Acquired Immunity
66
The Immune System
PART B
67
Antibodies
n
n
Also called immunoglobulins
Constitute the gamma globulin portion of
blood proteins
Are soluble proteins secreted by activated B
cells and plasma cells in response to an
antigen
Are capable of binding specifically with that
antigen
There five are classes of antibodies: IgD, IgM,
IgG, IgA, and IgE
68
Classes of Antibodies
n
n
n
IgD monomer attached to the surface of B
cells, important in B cell activation
Function as antigen receptor of the B cell
IgM pentamer released by plasma cells
during the primary immune response
IgG monomer that is the most abundant and
diverse antibody in primary and secondary
response; crosses the placenta and confers
passive immunity
69
Classes of Antibodies
n
n
IgA dimer that helps prevent attachment of
pathogens to epithelial cell surfaces
IgE monomer that binds to mast cells and
basophils, causing histamine release when
activated
70
Basic Antibody Structure
n
n
n
n
Consists of four looping polypeptide chains
linked together with disulfide bonds
Two identical heavy (H) chains and two
identical light (L) chains
The four chains bound together form an
antibody monomer
Each chain has a variable (V) region at one
end and a constant (C) region at the other
Variable regions of the heavy and light chains
combine to form the antigen-binding site
71
Basic Antibody Structure
72
Antibody Structure
n
Antibodies responding to different antigens
have different V regions but the C region is the
same for all antibodies in a given class
73
Antibody Structure
n
C regions form the stem of the Y-shaped
antibody and:
Determine the class of the antibody
Determine how the antibody functions to
eliminate the antigens
Dictate the cells and chemicals that the
antibody can bind to
74
Mechanisms of Antibody Diversity
n
n
n
Plasma cells make over a billion types of
antibodies
However, each cell only contains 100,000
genes that code for these polypeptides
To code for this many antibodies, somatic
recombination takes place:
Gene segments are shuffled and combined
in different ways by each B cell as it
becomes immunocompetent
Information of the newly assembled genes is
expressed as B cell receptors and as
antibodies
75
Antibody Diversity
n
n
n
Random mixing of gene segments makes
unique antibody genes that:
Code for H and L chains
Account for part of the variability in
antibodies
V gene segments, called hypervariable
regions, mutate and increase antibody
variation
Plasma cells can switch H chains, making two
76
or more classes with the same V region
Antibody Targets
n
n
n
Antibodies themselves do not destroy antigen;
they inactivate and tag it for destruction
All antibodies form an antigen-antibody
(immune) complex
Defensive mechanisms used by antibodies are
neutralization, agglutination, precipitation, and
complement fixation
77
Complement Fixation and
Activation
n
Complement fixation:
Main mechanism used against cellular
antigens
Antibodies bound to cells change shape and
expose complement binding sites
This triggers complement fixation and cell
lysis
78
Complement Fixation and
Activation
Stimulates
inflammation (C3a)
n Enlists more and more defensive
elements
Promotes opsonization (C3b)
n Enhancing phagocytosis
79
Other Mechanisms of Antibody
Action
n
Neutralization antibodies bind to and block
specific sites on viruses or exotoxins, thus
preventing these antigens from binding to
receptors on tissue cells
80
Other Mechanisms of Antibody
Action
n
n
Agglutination antibodies bind the same
determinant on more than one antigen
Makes antigen-antibody complexes that are
cross-linked into large lattices
Cell-bound antigens are cross-linked,
causing clumping (agglutination)
Precipitation soluble molecules are crosslinked into large insoluble complexes
81
Mechanisms of Antibody Action
82
Figure 21.14
Monoclonal Antibodies
n
n
Commercially prepared antibodies are used:
To provide passive immunity
In research, clinical testing, and cancer
treatment
Monoclonal antibodies are pure antibody
preparations
Specific for a single antigenic determinant
Produced from descendents of a single cell
83
Monoclonal Antibodies
n
Hybridomas cell hybrids made from a fusion
of a tumor cell and a B cell
Have desirable properties of both parent
cells indefinite proliferation as well as the
ability to produce a single type of antibody
84
Cell-Mediated Immune
Response
n
n
Since antibodies are useless against
intracellular antigens, cell-mediated immunity is
needed
Two major populations of T cells - based on the
type of glycoprotein present on the T cell
membrane:
CD4 cells (T4 cells) are primarily helper T
cells (TH)
CD8 cells (T8 cells) are cytotoxic T cells
(TC) that destroy cells harboring foreign
antigens
85
Cell-Mediated Immune
Response
n
Other types of T cells are:
Regulatory T cells (Treg)
Memory T cells
86
Major Types of T Cells
87
Importance of Humoral
Response
n
Soluble antibodies
The simplest ammunition of the immune
response
Interact in extracellular environments such
as body secretions, tissue fluid, blood, and
lymph. Do not invade solid tissues.
Interact with free antigens or antigens in
their natural state
Do not destroy the antigens but prepare
them for destruction
88
Importance of Cellular
Response
n
n
T cells recognize and respond only to
processed fragments of antigen displayed on
the surface of body cells
T cells are best suited for cell-to-cell
interactions, and target:
Cells infected with viruses, bacteria, or
intracellular parasites
Abnormal or cancerous cells
Cells of infused or transplanted foreign
tissue
89
Antigen Recognition and MHC
Restriction
n
n
Immunocompetent T cells are activated when
the V regions of their surface receptors bind to
a recognized antigen
T cells must simultaneously recognize:
Nonself (the antigen)
Self (a MHC protein of a body cell)
90
MHC Proteins
n
n
n
Are coded for by genes of the major
histocompatibility complex (MHC) and are
unique to an individual
Each MHC molecule has a deep groove that
displays a peptide, which is a normal cellular
product of protein recycling
In infected cells, MHC proteins bind to
fragments of foreign antigens, which play a
crucial role in mobilizing the immune system
91
MHC Proteins
n
n
Both types of MHC proteins are important to T cell
activation
Class I MHC proteins
Present in almost all body cells (except RBCs)
Bound to fragments of self proteins
n Ignored by CD8 cells
Bound to nonself peptides
n Destroyed by CD8 cells
Always recognized by CD8 T cells
Display peptides from endogenous antigens
92
Class I MHC Proteins
n
Endogenous antigens are:
Degraded by proteases and enter the
endoplasmic reticulum ferried from the
cytosol by TAP
n Transporter associated with Antigen
Processing
Loaded onto class I MHC molecules
Displayed on the cell surface in association
with a class I MHC molecule
93
Class I MHC Proteins
Extracellular fluid
Antigenic peptide
Plasma membrane
of a tissue cell
Class I
MHC
4 Loaded MHC protein migrates
to the plasma membrane, where
it displays the antigenic peptide
Endoplasmic
reticulum (ER)
3 Endogenous antigen
peptide loaded onto
class I MHC
Endogenous antigen
(viral protein)
TAP
Class I
MHC
Cytoplasm of
virus-invaded
cell
2 Endogenous antigen
peptides enter ER via TAP
1 Endogenous antigen
degraded by protease
(a)
94
Class II MHC Proteins
n
n
n
Class II MHC proteins are found only on
mature B cells, and antigen-presenting
cells (monocyte-macrophage group and
dendritic cells)
A phagosome containing pathogens (with
exogenous antigens) merges with a
lysosome
Invariant protein prevents class II MHC
proteins from binding to peptides in the
endoplasmic reticulum
95
Class II MHC Proteins
Extracellular fluid
1 Extracellular antigen
Antigenic peptide
(bacterium) phagocytized
Plasma membrane
of an APC
Class
II
MH C
4 Loaded MHC protein
migrates to the plasma
membrane
3 After synthesis at the ER,
C
s
as
Cl II C
H
M
2 Lysosome
merges with
phagosome,
forming a
phagolysosome;
antigen
degraded
the class II MHC protein
migrates in a vesicle, which
fuses with the phagolysosome; C
la
invariant chain removed,
II ss
M
antigen loaded
H
Class
II
MHC
Invariant chain
prevents class II
MHC binding to
peptides in the ER
Endoplasmic
reticulum (ER)
Cytoplasm of APC
(b)
96
Antigen Recognition
n
n
Provides the key for the immune system to
recognize the presence of intracellular
microorganisms
MHC proteins are ignored by T cells if they are
complexed with self protein fragments
97
Antigen Recognition
n
If MHC proteins are complexed with
endogenous or exogenous antigenic peptides,
they:
Indicate the presence of intracellular
infectious microorganisms
Act as antigen holders
Form the self part of the self-antiself
complexes recognized by T cells
98
T Cell Activation: Step One
Antigen Binding
n
Instead of MHC T cells have T cell antigen
receptors (TCRs):
Bind to an antigen-MHC protein complex
T cells recognize only antigens they are
programmed to detect
99
T Cell Activation: Step One
Antigen Binding
n
n
MHC restriction TH and TC bind to different
classes of MHC proteins
TH cells bind only to antigen linked to class II
MHC proteins
Mobile APCs (dendritic cells) quickly alert
the body to the presence of antigen by
migrating to the lymph nodes and presenting
antigen
100
T Cell Activation: Step One
Antigen Binding
n
n
TC cells are activated by antigen fragments
complexed with class I MHC proteins
APCs produce co-stimulatory molecules that
are required for TC activation
101
T Cell Activation: Step One
Antigen Binding
102
T Cell Activation: Step Two Costimulation
n
n
Before a T cell can undergo clonal expansion, it
must bind to other surface receptors on the
APC cells
Ex: APC cells sprout B7 proteins when
nonspecific defenses are mobilized
B7 binds to T cell receptors (co-stimulation)
Other co-stimulatory signals include
cytokines and interleukin 1 and 2
T cell now will clone
103
T Cell Activation: Step Two
Co-stimulation
n
n
Depending on receptor type, co-stimulators
can cause T cells to complete their activation
or abort activation
Without co-stimulation, T cells display anergy:
Become tolerant to that antigen
Are unable to divide
Do not secrete cytokines
104
T Cell Activation: Step Two
Co-stimulation
n
T cells that are activated:
Enlarge, proliferate, and form clones
Differentiate and perform functions
according to their T cell class
105
T Cell Activation: Step Two Costimulation
n
n
n
n
n
Primary T cell response peaks within a week
after signal exposure
T cells then undergo apoptosis between days 7
and 30
Effector activity wanes as the amount of
antigen declines
The disposal of activated effector cells is a
protective mechanism for the body
Memory T cells remain and mediate secondary
responses to the same antigen
106
T Cell Activation: Step Two Costimulation
n
n
n
Primary T cell response peaks within a week
after signal exposure
T cells then undergo apoptosis between days 7
and 30
A protective mechanism for the body
As T cell dies, the effectors activity wanes
as the amount of antigen declines
Memory T cells remain and mediate secondary
responses to the same antigen
107
Cytokines
n
Mediators involved in cellular immunity,
including hormone-like or paracrine-like
glycoproteins released by activated T cells and
macrophages
n
Some are co-stimulators of T cells and some
promote T cell proliferation
108
Cytokines
n
Examples include:
Perforin and lymphotoxin cell toxins
Gamma interferon enhances the killing
power of macrophages
Inflammatory factors
109
Specific T Cells
n
n
n
Helper T cells (TH)
Cytotoxic T cells (TC)
Regulatory T cells (TREG)
110
Specific T Cell Roles
n
n
n
n
Helper T Cells (TH)
Regulatory cells that play a central role in the
immune response
Once primed by APC presentation of antigen,
they:
Chemically or directly stimulate proliferation of
other T cells
Stimulate B cells that have already become
bound to antigen
Without TH, there is no immune response
111
Helper T Cell
n
n
n
n
n
TH cells interact directly with B cells that have
antigen fragments on their surfaces bound to
MHC II receptors
TH cells stimulate B cells to divide more rapidly
and begin antibody formation
B cells may be activated without TH cells by
binding to T cellindependent antigens
Most antigens, however, require TH costimulation to activate B cells: T cell
dependent antigens
Cytokines released by TH amplify nonspecific
defenses
112
13
Cytotoxic T Cell (Tc)
n
n
n
TC cells, or killer T cells, are the only T cells
that can directly attack and kill other cells
They circulate throughout the body in search of
body cells that display the antigen to which
they have been sensitized
Their targets include:
Virus-infected cells
Cells with intracellular bacteria or parasites
Cancer cells
Foreign cells from blood transfusions or
transplants
114
Mechanisms of Tc Action
n
n
In some cases, TC cells:
Bind to the target cell and release perforin
into its membrane
n In the presence of Ca2+ perforin causes
cell lysis by creating transmembrane
pores
Other TC cells induce cell death by:
Secreting lymphotoxin, which fragments the
target cells DNA
Secreting gamma interferon, which
stimulates phagocytosis by macrophages
115
Mechanisms of Tc Action
116
Regulatory T Cells (TREG)
n
n
Regulatory T cells (TREG) regulatory cells
that release cytokines, which suppress the
activity of both T cells and B cells
They act either by direct contact or by
releasing cytokines
117
118
Figure 21.20
Organ Transplants
n
The four major types of grafts are:
Autografts graft transplanted from one site
on the body to another in the same person
Isografts grafts between identical twins
Allografts transplants between individuals
that are not identical twins, but belong to
same species
Xenografts grafts taken from another
animal species
119
Prevention of Rejection
n
n
Prevention of tissue rejection is accomplished
by using immunosuppressive drugs
However, these drugs depress patients
immune system so it cannot fight off foreign
agents
120
Immunodeficiencies
n
Diseases in which the function or production of
immune cells, phagocytes, or complement is
abnormal
Congenital (genetic)
n Severe Combined Immunodeficiency
Syndromes (SCID)
Deficits of B and T cells
Acquired
121
Acquired Immunodeficiencies
n
Hodgkins disease cancer of the lymph nodes
n
Acquired immune deficiency syndrome (AIDS)
cripples the immune system by destroying
helper T (CD4) cells
122
Autoimmune Diseases
n
n
n
Loss of the immune systems ability to
distinguish self from nonself
The body produces autoantibodies and
sensitized TC cells that destroy its own tissues
Examples include multiple sclerosis,
myasthenia gravis, Graves disease, Type I
(juvenile) diabetes mellitus, systemic lupus
erythematosus (SLE), glomerulonephritis, and
rheumatoid arthritis
123
Mechanisms of Autoimmune
Diseases
n
n
Ineffective lymphocyte programming selfreactive T and B cells that should have been
eliminated in the thymus and bone marrow
escape into the circulation
New self-antigens appear, generated by:
Gene mutations that cause new proteins to
appear
Changes in self-antigens by hapten
attachment or as a result of infectious
124
damage
Mechanisms of Autoimmune
Diseases
n
If the determinants on foreign antigens
resemble self-antigens:
Antibodies made against foreign antigens
cross-react with self-antigens
125
Hypersensitivity
n
n
n
n
Immune responses that cause tissue damage
Different types of hypersensitivity reactions are
distinguished by:
Their time course
Whether antibodies or T cells are the
principle immune elements involved
Antibody-mediated allergies are immediate
and subacute hypersensitivities
T cell-mediated allergic condition causes
delayed hypersensitivity
126
Immediate Hypersensitivity
n
n
n
n
Acute (type I) hypersensitivities begin in
seconds after contact with allergen
Initial allergen contact is asymptomatic but
sensitizes the person
Subsequent exposures to allergen cause:
Release of histamine and inflammatory
chemicals
Systemic or local responses
Anaphylaxis
127
Immediate Hypersensitivity
The
mechanism involves IL-4 secreted by
TH cells
n Increased in susceptible persons
IL-4 stimulates B cells to produce IgE
IgE binds to mast cells and basophils
causing them to degranulate, resulting in a
flood of histamine release and inducing the
inflammatory response
128
Sensitization stage
1 Antigen (allergen)
invades body.
2 Plasma cells
produce large
amounts of class
IgE antibodies
against allergen.
3 IgE antibodies
attach to mast
cells in body tissues
(and to circulating
basophils).
Mast cell with
fixed IgE
antibodies
IgE
Granules
containing
histamine
Subsequent (secondary)
responses
4 More of
same antigen
invades body.
Antigen
5 Antigen combines
with IgE attached
to mast cells (and
basophils), which
triggers degranulation
and release of histamine
(and other chemicals).
Mast cell granules
release contents
after antigen binds
with IgE antibodies
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
fluid from
capillaries
Release
of mucus
Constriction of small
respiratory passages
(bronchioles)
129
Anaphylaxis
n
n
n
n
Reactions include runny nose, itching
reddened skin, and watery eyes
If allergen is inhaled, asthmatic symptoms
appear constriction of bronchioles and
restricted airflow
If allergen is ingested, cramping, vomiting, or
diarrhea occur
Antihistamines counteract these effects
130
Anaphylactic Shock
n
n
n
n
Response to allergen that directly enters the
blood (e.g., insect bite, injection)
Basophils and mast cells are enlisted
throughout the body
Systemic histamine releases may result in:
Constriction of bronchioles
Sudden vasodilation and fluid loss from the
bloodstream
Hypotensive shock and death
Treatment epinephrine is the drug of choice
131
Subacute Hypersensitivities
n
Caused by IgM and IgG, and transferred via
blood plasma or serum
Onset is slow (13 hours) after antigen
exposure
Duration is long lasting (1015 hours)
132
Subacute Hypersensitivities
n
Cytotoxic (type II) reactions
Antibodies bind to antigens on specific body
cells, stimulating phagocytosis and
complement-mediated lysis of the cellular
antigens
Example: mismatched blood transfusion
reaction
133
Subacute Hypersensitivities
n
Immune complex (type III) hypersensitivity
Antigens are widely distributed through the
body or blood
Insoluble antigen-antibody complexes form
Complexes cannot be cleared from a
particular area of the body
Intense inflammation, local cell lysis, and
death may result
Example: systemic lupus erythematosus
(SLE)
134
Delayed Hypersensitivities
(Type IV)
n
n
n
n
Onset is slow (13 days)
Mediated by mechanisms involving delayed
hypersensitivity T cells and cytotoxic T cells
Cytokines from activated TC are the mediators
of the inflammatory response
Antihistamines are ineffective and
corticosteroid drugs are used to provide relief
135
Delayed Hypersensitivities
(Type IV)
n
n
Example: allergic contact dermatitis (e.g.,
poison ivy)
Involved in protective reactions against
viruses, bacteria, fungi, protozoa, cancer, and
rejection of foreign grafts or transplants
136
Developmental Aspects
n
n
n
Immune system stem cells develop in the liver
and spleen by the ninth week
Later, bone marrow becomes the primary
source of stem cells
Lymphocyte development continues in the
bone marrow and thymus system begins to
wane
137
Developmental Aspects
n
n
The immune system is impaired by stress and
depression
With age, the immune system begins to wane
138