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The Immune System
Chapter 51
Introduction
Vertebrates have three levels of defenses
-1. The Integumentary System
-Skin and mucous membranes provide
first line of defense
-2. Nonspecific (innate) Immune System
-Acts very rapidly after onset of infection
-3. Specific Immune System
-Eliminates microbes that escaped the
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second line of defense
Skin
The skin is the largest organ of the body
-Provides a nearly impenetrable barrier,
reinforced with chemical weapons
-Oil & sweat glands give skin a pH of 3-5
-Lysozyme breaks bacterial cell walls
-Also contains many normal flora
-Non-pathogenic microorganisms that
out-compete pathogenic ones
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Skin
The skin is composed of three layers
-Epidermis = 10-30 cells thick
-Stratum corneum – Outermost layer;
cells shed continuously
-Stratum spinosum – Middle layer
-Stratum basale – Innermost layer;
cells actively dividing
-Contains keratin, which makes
skin tough and water-resistant
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Skin
-Dermis = Contains connective tissue and
is 15-40 times thicker than epidermis
-Provides structural support for
epidermis, and matrix for blood vessels,
muscles and nerve endings
-Subcutaneous layer = Contains mainly
adipose (fat) cells
-Acts as shock absorbers and insulators
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Mucosal Epithelial Surfaces
The digestive, respiratory and urogenital
tracts are lined by mucous membranes
-Cells secrete mucus which traps microbes
Digestive tract
-Salivary lysozyme; acidic stomach
Respiratory tract
-Ciliary action
Urogenital tract
-Acidic urine
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Nonspecific Immunity
The nonspecific or innate immune system
consists of cellular and chemical devices
that respond to any microbial infection
-The response is quite rapid
Among the most important defenses are three
types of leukocytes (white blood cells)
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Leukocytes
Macrophages
-Large, irregularly
shaped cells
-Kill microbes by
phagocytosis
-Mature from
monocytes that
enter tissues from
the blood
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Leukocytes
Neutrophils
-The most abundant circulating leukocytes
-First to appear at site of damage/infection
-Kill microbes by phagocytosis
Natural killer (NK) cells
-Destroy pathogen-infected and cancer cells
by programmed cell death or apoptosis
-Produce perforins and granzymes
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Leukocytes
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Leukocytes (Cont.)
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The Inflammatory Response
Inflammation involves several body systems
-Injured cells release chemical alarms,
including histamine and prostaglandins
-Cause nearby blood vessels to dilate
and increase in permeability
-Promote phagocyte accumulation
-Hallmark signs = Redness, warmth,
swelling, pain, and potential loss of function
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The Inflammatory Response
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The Inflammatory Response
Inflammation is accompanied by an acute
phase response, manifested by fever
-Macrophages release interleukin-1
-Causes hypothalamus to raise body
temperature
-Promotes activity of phagocytes,
while impeding microbial growth
-However, very high fevers are hazardous
as they may denature critical enzymes 14
Complement
The complement system consists of about
30 different proteins that circulate in the
blood in an inactive form
-Upon pathogen encounter, a cascade of
activation occurs
-Some proteins aggregate to form a
membrane attack complex (MAC) on
surface of pathogen
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Complement
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Complement
Other functions of complement proteins
-C3b coats surface of invading pathogens,
thereby enhancing their phagocytosis
-Some stimulate the release of histamine
from mast cells and basophils
-Some attract more phagocytes to the area
of infection
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Interferon
Interferons (IFN) are proteins that play a key
role in body defense
-Three major types: IFN-a, IFN-b, IFN-g
-IFN-a and IFN-b are produced by almost all
body cells in response to viral infection
-Induce degradation of viral RNA
-IFN-g is produced only by T-lymphocytes
and natural killer cells
-Protects from infection and cancer
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The Specific Immune System
The scientific study of immunity began with
Edward Jenner in 1796
-Observed that milkmaids who had cowpox
rarely experienced smallpox
-Inoculated individuals with fluid from
cowpox vesicles to protect them from
smallpox
-Vaccination
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The Specific Immune System
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The Specific Immune System
The four characteristics of the specific, or
adaptive, immune response are:
-1. Specificity
-2. Diversity
-3. Memory
-4. Ability to distinguish self from non-self
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Antigens
An antigen is a molecule that provokes a
specific immune response
-May be components of microorganisms or
proteins/glycoproteins found on surface of
red blood cells or transplanted tissue cells
A single protein may have many different
antigenic determinants or epitopes
-Each can stimulate a distinct immune
response
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Antigens
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Lymphocytes
Lymphocytes are leukocytes with surface
receptors for antigenic determinants
-Direct an immune response against either
the antigen or the cell that carries it
When a naïve lymphocyte binds a specific
antigen for the first time, it gets activated by
a process called clonal selection
-Produces a clone of cells: some respond
immediately, others are memory cells
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Lymphocytes
B lymphocytes or B cells
-Respond to antigens by secreting
antibodies or immunoglobulins (Ig)
-Participate in humoral immunity
T lymphocytes or T cells
-Regulate other immune cells or directly
attack cells that carry specific antigens
-Participate in cell-mediated immunity
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Acquisition of Specific Immunity
Immunity can be acquired in two ways
-Active immunity results from activation of
an individual’s own lymphocytes
-Pathogen infection or vaccination
-Passive immunity results from obtaining
another individual’s antibodies
-Transfer of maternal antibodies across
placenta
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Hematopoiesis
All blood cells are derived from hematopoietic
stem cells through hematopoiesis
-A lymphoid progenitor gives rise to
lymphocytes and natural killer cells
-A myeloid progenitor gives rise to all other
white blood cells, plus RBCs and platelets
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Organs of the Immune System
Organs of the immune system consist of the:
-Primary lymphoid organs
-Bone marrow and thymus
-Secondary lymphoid organs
-Lymph nodes, spleen, and mucosalassociated lymphoid tissue (MALT)
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Primary Lymphoid Organs
The bone marrow is site of B cell maturation
-Each B cell has about 105 Ig molecules on
its surface, all with the same specificity
-However, different B cells will have
different specificities
-B cells recognize epitopes directly
-Any lymphocytes that are likely to bind to
self-antigens undergo apoptosis
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Primary Lymphoid Organs
The thymus is the site of T cell maturation
-Each T cell has about 105 identical T-cell
receptors, or TCRs on its surface
-Recognize epitopes only if they are
combined with major histocompatibility
complex (MHC) peptides
-Lymphocytes that cannot bind MHCs, or
that bind self-MHC/self-peptide too tightly
undergo apoptosis
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Secondary Lymphoid Organs
The locations of these organs promote the
filtering of antigens that enter any part of an
individual’s body
-Mature but naïve B and T cells become
activated in the lymph nodes
-The spleen is site of immune responses to
antigens found mainly in the blood
-Mucosal-associated lymphoid tissue
(MALT) include the tonsils and appendix
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T Cells
T lymphocytes are of two types:
-Cytotoxic T cells (Tc)
-CD8+ cells
-Helper T cells (TH)
-CD4+ cells
-Distinguished by type of MHC markers
recognized and roles after activation
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T Cells
In humans, the MHC complex is also termed
human leukocyte antigens (HLAs)
-Markers that distinguish self from nonself
-MHC class I = Found on all nucleated cells
-Recognized by Tc cells
-MHC class II = Found only on antigenpresenting cells
-Recognized by TH cells
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T Cells
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T Cells
Cytotoxic T cells
-Naïve TC cells are activated upon TCR
recognition of foreign peptide displayed on
self-MHC class I protein on dendritic cells
-Clonal expansion and differentiation into
activated cells and memory cells
-Activated cells induce apoptosis in cells
with same specificity as first cell
-Likely a viral-infected or cancer cell 39
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T Cells
Helper T cells
-TH cells respond to exogenous antigen that
is taken up by an antigen presenting cell
-Antigen is partially digested, then
complexed with MHC class II proteins
-Complex is transported to and
displayed on the cell surface
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T Cells
Helper T cells
-Activated TH cell gives rise to a clone of TH
cells including both effector cells and
memory cells
-Most effector TH cells leave the lymphoid
organs and circulate around the body
-Secrete proteins called cytokines
-Promote humoral and cell-mediated
immune responses
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B Cells
Humoral immunity begins when naïve B cells
in secondary lymph organs meet antigens
-B cells are activated when their surface Igs
bind to a specific epitope on an antigen
-TH cytokines may also be required
-Activation results in clonal expansion and
differentiation into plasma and memory cells
-Plasma cells produce soluble antibodies
against the same epitope
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Immunoglobulins
An immunoglobulin consists of two identical
short polypeptides, light chains, and two
identical longer polypeptides, heavy chains
-Four chains are held by disulfide bonds,
forming a Y-shaped molecule
-Fab regions = Two “arms”
-Fc region = “Stem”
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Immunoglobulins
Each chain has a variable region (amino acid
sequence differs between Igs) and a
constant region
-The variable regions fold together to form a
cleft, the antigen-binding site
Each Ig can bind two identical epitopes
-Allows formation of antigen-antibody
complexes
-Indeed, Igs can agglutinate, precipitate
or neutralize antigens
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Immunoglobulins
There are five classes of immunoglobulins
-IgM = First type of antibody produced
during an immune response
-Monomer on B cells, but secreted as
pentamer
-IgD = Present on mature naïve B cells
-Not secreted in normal situations
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Immunoglobulins
-IgG = Major form of antibody in blood
-Main component of secondary response
-Can cross placenta
-IgA = Major form of antibody in secretions
-Usually produced as a dimer
-Can pass to nursing infant in mom’s milk
-IgE = Present at very low levels in blood
-Plays a role in allergic reactions
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Immunoglobulin Diversity
Human B cells can generate antibodies with
over 1010 different antigen-binding sites
-This diversity is generated through a
process called DNA rearrangement
An Ig protein is encoded by different
segments of DNA
-V (variable), D (diversity), J (joining)
-Plus a constant region
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Immunoglobulin Diversity
These segments are joined during maturation
in the bone marrow
-First, a D and a J segment are joined
-Then, DJ is combined with a V segment
-Transcription and RNA processing follow,
linking variable region to a constant region
-Translation occurs in the rough ER, where
heavy and light chains are joined together
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T Cell Receptors
The structure of a TCR is similar to an
immunoglobulin Fab
-Unlike Igs, TCRs
are not secreted
-TCR diversity is
also caused by
DNA
rearrangements
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Immune Responses
The first encounter with a foreign antigen is
called the primary immune response
-Only few B or T cells can recognize antigen
The second encounter is called the
secondary immune response
-This time there is a large clone of memory
cells that can recognize the antigen
-Immune response is more effective
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Autoimmunity
The acceptance of self cells is known as
immune tolerance
Autoimmune diseases are caused by the
failure of immune tolerance
-Result in activation of autoreactive T cells,
and production of autoantibodies by B cells
-Cause inflammation and organ damage
-Alleviated by corticosteroids and
NSAIDs, including aspirin
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Allergy
Allergy refers to a greatly heightened
response to a foreign antigen, or allergen
-The most common type is known as
immediate hypersensitivity
-Results from excessive IgE production
-Seasonal hay fever
-Provoked by ragweed or other pollen
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Allergy
On initial exposure to allergen, B cells are
activated to secrete IgE antibodies
-Bind to FC receptors on mast cells or
basophils
On subsequent exposure to allergen,
allergen cross-links bound IgEs
-Cells are induced to release histamine and
other inflammatory mediators
-Produce symptoms of allergy
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Allergy
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Allergy (Cont.)
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Allergy
In systemic anaphylaxis, the allergic reaction
is severe and potentially life-threatening
-Anaphylactic shock = Blood pressure
drop, and bronchial constriction
-Death within 20-30 minutes
Most people, however, experience local
anaphylaxis
-Hives or mild asthma
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Allergy
Delayed-type hypersensitivity produces
symptoms within about 48 hours of a
second exposure to an allergen
-Mediated by TH cells and macrophages
-Contact dermatitis
-Caused by varied materials, such as
poison ivy, nickel in jewelry and
cosmetics
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Antibodies in Medicine
A person’s blood type is determined by
antigens found on surface of red blood cells
-ABO blood types = Types A, B, AB and O
-Rh factor = Rh positive and Rh negative
The immune system is tolerant of its own
RBC antigens, but makes antibodies that
bind to those that differ
-For example, people with type A blood
make antibodies against the B antigen
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Antibodies in Medicine
In blood transfusions, the antigens of the
donor have to be matched to the antibodies
of the recipient
-For instance, a type A person cannot
donate to a type B or type O
-These would have anti-A antibodies
Blood is typed by agglutination reactions,
using circulating IgM antibodies
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Antibodies in Medicine
A mismatched blood transfusion may be
deadly
-Within 5-8 hours, tremendous hemolysis of
the transfused RBCs is detected
-Due to formation of complement MACs
-The released hemoglobin is converted to
bilirubin
-Can cause severe organ damage,
especially to kidneys
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Monoclonal Antibodies
Monoclonal antibodies exhibit specificity for
one epitope only
Animal is immunized with antigen then killed
-B cells are obtained from animal’s spleen
-Fused with a myeloma cell – a B-cell
tumor that no longer produces Igs
-A clonal hybrid or hybridoma
-Divides indefinitely and produces
monoclonal antibodies
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Monoclonal Antibodies
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Monoclonal Antibodies
Availability of large quantities of pure
monoclonal antibodies has allowed the
development of very sensitive clinical tests
-Some pregnancy tests use a monoclonal
antibody against the hormone human
chorionic gonadotropin (HCG)
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Monoclonal Antibodies
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Monoclonal Antibodies (Cont.)
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Monoclonal Antibodies
Monoclonal antibodies against CD4, a TH
marker, are used to monitor AIDS
Monoclonal antibodies have also been used
in the treatment of cancer
-Formation of tumor-specific
immunotoxins
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Monoclonal Antibodies
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Monoclonal Antibodies (Cont.)
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Evading the Immune System
Some pathogens can alter their surface
antigens to avoid immune system detection
Influenza virus expresses 2 surface proteins:
hemaglutinin (HA) and neuraminidase (NA)
-Antigenic drift = Point mutations to the HA
and NA genes
-Antigenic shift = Sudden appearance of a
new virus subtype where HA and/or NA
proteins are completely different
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Evading the Immune System
Salmonella typhimurium
-Can alternate between expression of two
different flagellar proteins
Mycobacterium tuberculosis
-Once phagocytosed, inhibits fusion of the
phagosome with lysosomes
Neisseria gonorrhoeae
-Secrete proteases that degrade IgA
antibodies
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Evading the Immune System
HIV, human immunodeficiency virus,
mounts a direct attack on TH cells
-Binds to CD4 proteins, and is endocytosed
An individual is considered to have AIDS
when their TH cell level has dropped
significantly
-Immunosuppression results in an increase
in opportunistic infections and cancers
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Evading the Immune System
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