Transcript CH 18: powerpoint

Natural Defenses
against Disease
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Natural Defenses against Disease
• Animal Defense Systems
• Nonspecific Defenses
• Specific Defenses: The Immune System
• B Cells: The Humoral Immune Response
• T Cells: The Cellular Immune Response
• The Genetic Basis of Antibody Diversity
• Disorders of the Immune System
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Animal Defense Systems
• Animal defense systems are based on the
distinction between self and nonself.
• There are two general types of defense
mechanisms:
 Nonspecific defenses, or innate defenses,
are inherited mechanisms that protect the
body from many different pathogens.
 Specific defenses are adaptive mechanisms
that protect against specific targets.
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Animal Defense Systems
• Components of the defense system are
distributed throughout the body.
• Lymphoid tissues (thymus, bone marrow,
spleen, lymph nodes) are essential parts of the
defense system.
• Blood plasma suspends red and white blood cells
and platelets.
• Red blood cells are found in the closed circulatory
system.
• White blood cells and platelets are found in the
closed circulatory system and in the lymphatic
system.
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Animal Defense Systems
• Lymph consists of fluids that accumulate outside
of the closed circulatory system in the lymphatic
system.
• The lymphatic system is a branching system of
tiny capillaries connecting larger vessels.
• These lymph ducts eventually lead to a large
lymph duct that connects to a major vein near the
heart.
• At sites along lymph vessels are small, roundish
lymph nodes.
• Lymph nodes contain a variety of white blood
cells.
Figure 18.1 The Human Lymphatic system
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Animal Defense Systems
• White blood cells are important in defense.
• All blood cells originate from stem cells in the bone
marrow.
• White blood cells (leukocytes) are clear and have
a nucleus and organelles.
• Red blood cells are smaller and lose their nuclei
before they become functional.
• White blood cells can leave the circulatory system.
• The number of white blood cells sometimes rises in
response to invading pathogens.
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Animal Defense Systems
• There are two main groups of white blood cells:
phagocytes and lymphocytes.
• Phagocytes engulf and digest foreign materials.
• Lymphocytes are most abundant. There are two
types: B and T cells.
• T cells migrate from the circulation to the thymus,
where they mature.
• B cells circulate and also collect in lymph
vessels, and make antibodies.
Figure 18.2 Blood Cells (Part 1)
Figure 18.2 Blood Cells (Part 2)
Figure 18.2 Blood Cells (Part 3)
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Animal Defense Systems
• Four groups of proteins play key roles in defending
against disease:
 Antibodies, secreted by B cells, bind
specifically to certain substances.
 T cell receptors are cell surface receptors that
bind nonself substances on the surface of other
cells.
 Major histocompatibility complex (MHC)
proteins are exposed outside cells of mammals.
These proteins help to distinguish self from
nonself.
 Cytokines are soluble signal proteins released
by T cells. They bind and alter the behavior of
their target cells.
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Nonspecific Defenses
• The skin acts as a physical barrier to pathogens.
• Bacteria and fungi on the surface of the body
(normal flora) compete for space and nutrients
against pathogens.
• Tears, nasal mucus, and saliva contain the enzyme
lysozyme that attacks the cell walls of many
bacteria.
• Mucus and cilia in the respiratory system trap
pathogens and remove them.
• Ingested pathogens can be destroyed by the
hydrochloric acid and proteases in the stomach.
• In the small intestine, bile salts kill some pathogens.
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Nonspecific Defenses
• Vertebrate blood contains about 20 antimicrobial
complement proteins.
• Complement proteins provide three types of
defenses:
 They attach to microbes, helping phagocytes
recognize and destroy them.
 They activate the inflammation response and
attract phagocytes to the site of infection.
 They lyse invading cells.
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Nonspecific Defenses
• Interferons are produced by cells that are
infected by a virus.
• All interferons are glycoproteins consisting of
about 160 amino acids.
• They increase resistance of neighboring cells to
infections by the same or other viruses.
• Each vertebrate species produces at least three
different interferons.
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Nonspecific Defenses
• Phagocytes ingest pathogens. There are several
types of phagocytes:
 Neutrophils attack pathogens in infected
tissue.
 Monocytes mature into macrophages. They
live longer and consume larger numbers of
pathogens than do neutrophils. Some roam
and others are stationary in lymph nodes and
lymphoid tissue.
 Eosinophils kill parasites, such as worms,
that have been coated with antibodies.
 Dendritic cells have highly folded plasma
membranes that can capture invading
pathogens.
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Nonspecific Defenses
• Natural killer cells are a class of nonphagocytic
white blood cells
• They can initiate the lysis of virus-infected cells
and some tumor cells.
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Nonspecific Defenses
• The inflammation response is used in dealing
with infection or tissue damage.
• Mast cells and white blood cells called basophils
release histamine, which triggers inflammation.
• Histamine causes capillaries to become leaky,
allowing plasma and phagocytes to escape into
the tissue.
• Complement proteins and other chemical signals
attract phagocytes. Neutrophils arrive first, then
monocytes (which become macrophages).
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Nonspecific Defenses
• The macrophages engulf invaders and debris and
are responsible for most of the healing.
• They produce several cytokines, which may signal
the brain to produce a fever.
• Pus, composed of dead cells and leaked fluid,
may accumulate.
Figure 18.4 Interactions of Cells and Chemical Signals in Inflammation (Part 1)
Figure 18.4 Interactions of Cells and Chemical Signals in Inflammation (Part 2)
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Nonspecific Defenses
• An invading pathogen is a signal that triggers the
body’s defense mechanisms.
• A signal transduction pathway acts as the link
between a signal and the immune response.
• The membrane protein toll is the receptor.
• Toll is part of a protein kinase cascade that results
in the transcription of at least 40 genes involved in
both specific and nonspecific defenses.
• The signal molecules are made only by microbes.
Figure 18.5 Cell Signaling and Defense
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Specific Defenses: The Immune System
• Four characteristics of the immune system:
 1. Specificity: Antigens are organisms or
molecules that are specifically recognized by T
cell receptors and antibodies.
 The sites on antigens that the immune
system recognizes are the antigenic
determinants (or epitopes).
 Each antigen typically has several different
antigenic determinants.
 The host creates T cells and/or antibodies
that are specific to the antigenic
determinants.
Figure 18.6 Each Antibody Matches an Antigenic Determinant
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Specific Defenses: The Immune System
 2. Diversity:
It is estimated that the human immune
system can distinguish and respond to 10
million different antigenic determinants.
 3. Distinguishing self from nonself:

Each normal cell in the body bears a
tremendous number of antigenic
determinants. It is crucial that the immune
system leave these alone.
 4. Immunological memory:


Once exposed to a pathogen, the immune
system remembers it and mounts future
responses much more rapidly.
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Specific Defenses: The Immune System
• The immune system has two responses against
invaders: The humoral immune response and the
cellular immune response.
• The two responses operate in concert and share
mechanisms.
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Specific Defenses: The Immune System
• The humoral immune response involves
antibodies that recognize antigenic determinants
by shape and composition.
• Some antibodies are soluble proteins that travel
free in blood and lymph. Others are integral
membrane proteins on B cells.
• When a pathogen invades the body, it may be
detected by and bound by a B cell whose
membrane antibody fits one of its potential
antigenic determinants.
• This binding activates the B cell, which makes
multiple soluble copies of an antibody with the
same specificity as its membrane antibody.
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Specific Defenses: The Immune System
• The cellular immune response is able to detect
antigens that reside within cells.
• It destroys virus-infected or mutated cells.
• Its main component consists of T cells.
• T cells have T cell receptors that can recognize
and bind specific antigenic determinants.
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Specific Defenses: The Immune System
• Several questions arise that are fundamental to
understanding the immune system.
 How does the enormous diversity of B cells and T
cells arise?
 How do B and T cells specific to antigens
proliferate?
 Why don’t antibodies and T cells attack and
destroy our own bodies?
 How can the memory of postexposure be
explained?
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Specific Defenses: The Immune System
• Clonal selection explains much of this.
• The healthy body contains a great variety of B
cells and T cells, each of which is specific for only
one antigen.
• Normally, the number of any given type of B cell
present is relatively low.
• When a B cell binds an antigen, the B cell divides
and differentiates into plasma cells (which
produce antibodies) and memory cells.
• Thus, the antigen “selects” and activates a
particular antibody-producing cell.
Figure 18.7 Clonal Selection in B Cells
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Specific Defenses: The Immune System
• An activated lymphocyte (B cell or T cell) produces
two types of daughter cells: effector and memory
cells.
• Effector B cells, called plasma cells, produce
antibodies.
• Effector T cells release cytokines.
• Memory cells live longer and retain the ability to
divide quickly to produce more effector and more
memory cells.
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Specific Defenses: The Immune System
• When the body encounters an antigen for the first
time, a primary immune response is activated.
• When the antigen appears again, a secondary
immune response occurs. This response is
much more rapid, because of immunological
memory.
Figure 18.8 Immunological Memory
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Specific Defenses: The Immune System
• Artificial immunity is acquired by the introduction
of antigenic determinants into the body.
• Vaccination is inoculation with whole pathogens
that have been modified so they cannot cause
disease.
• Immunization is inoculation with antigenic
proteins, pathogen fragments, or other molecular
antigens.
• Immunization and vaccination initiate a primary
immune response that generates memory cells
without making the person ill.
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Specific Defenses: The Immune System
• Antigens used for immunization or vaccination must
be processed so that they will provoke an immune
response but not cause disease. There are three
principle ways to do this:
 Attenuation involves reducing the toxicity of the
antigenic molecule or organism.
 Biotechnology can produce antigenic fragments
that activate lymphocytes but do not have the
harmful part of the protein toxin.
 DNA vaccines are being developed that will
introduce a gene encoding an antigen into the
body.
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Specific Defenses: The Immune System
• The body is tolerant of its own molecules, even
those that would cause an immune response in
other individuals of the same species.
• Failure to do so results in autoimmune disease.
• This self tolerance is based on two mechanisms:
clonal deletion and clonal anergy.
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Specific Defenses: The Immune System
• Clonal deletion eliminates B or T cells from the
immune system at some point during differentiation.
• About 90 percent of all B cells made in the bone
marrow are removed in this way.
• Any immature B cell in the marrow that could mount
an immune response against self antigens is
eliminated.
• The same is true for T cells, but the selection
occurs in the thymus.
• Elimination is accomplished by means of apoptosis.
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Specific Defenses: The Immune System
• Clonal anergy is the suppression of the immune
response.
• Before a mature T cell mounts an immune
response, it must recognize both an antigen on a
cell and another molecule, CD28 (co-stimulatory
signal), which is not present on most body cells.
• CD28 is present only on certain antigen-presenting
cells, including macrophages and the dendritic cells
in the linings of the respiratory and digestive tracts.
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Specific Defenses: The Immune System
• Immunological tolerance is a poorly understood
but clearly observable phenomenon.
• Exposing a fetus to an antigen before birth
provides later tolerance to the antigen.
• Continued exposure is necessary to maintain the
tolerance.
• Some individuals experience the opposite effect;
they lose tolerance to themselves, which results in
autoimmune disease.
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B Cells: The Humoral Immune Response
• B cells are the basic component of the humoral
immune system.
• For a B cell to differentiate into a plasma cell, it
must bind an antigenic determinant.
• A helper T cell (TH) must also bind the same
determinant as it is presented by an antigenpresenting cell.
• Cellular division and differentiation of the B cell is
stimulated by a signal from the activated TH cell.
• Activated B cells become plasma cells and
memory cells.
Figure 18.9 A Plasma Cell
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B Cells: The Humoral Immune Response
• Antibody molecules are proteins called
immunoglobulins.
• All are composed of one or more tetramers
consisting of four polypeptide chains.
• Two identical light chains and two identical heavy
chains make up the tetrameric units.
• Disulfide bonds hold the chains together.
• Both the light and heavy chains on each peptide
have variable and constant regions.
• The constant regions are similar among the
immunoglobulins and determine the class of the
antibody.
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B Cells: The Humoral Immune Response
• The variable regions differ in the amino acid
sequences at the antigen-binding site and are
responsible for the diversity of antibody specificity.
• The heavy and light chain variable regions align
and form the binding sites.
• Each tetramer has two identical antigen-binding
sites, making the antibody bivalent.
• The enormous range of antibody specificities is
made possible by the recombination of numerous
versions of coding regions for the variable regions.
Figure 18.10 Structure of Immunoglobulins (Part 1)
Figure 18.10 Structure of Immunoglobulins (Part 2)
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B Cells: The Humoral Immune Response
• The five immunoglobulin classes are based on
differences in the constant regions of the heavy
chain.
• IgG molecules make up 80 percent of the total
immunoglobulin content of the bloodstream.
• They are the primary product of a secondary
immune response.
• The constant regions of IgG antibodies are like
handles that make it easier for a macrophage to
grab and ingest antibody-coated antigens.
Figure 18.11 IgG Antibodies Promote Phagocytosis
Table 18.3 Antibody Classes (Part 1)
Table 18.3 Antibody Classes (Part 2)
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B Cells: The Humoral Immune Response
• The normal antibody response is polyclonal:
Because most antigens have more than one
antigenic determinant, animals injected with a
single antigen generally produce several different
antibodies.
• Polyclonal antibodies may have some crossreactivity with other molecules that have similar
regions within the molecule.
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B Cells: The Humoral Immune Response
• A monoclonal antibody is made by a single
clonal line of B cells and binds to only one
antigenic determinant.
• Monoclonal antibodies are very useful for
immunoassays to determine the concentrations
of other molecules that are present in minute
amounts.
• Monoclonal antibodies are also used in
immunotherapy and passive immunization.
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B Cells: The Humoral Immune Response
• B cells cannot be cultured. To overcome this
problem, a cancerous myeloma cell is fused to the
plasma cell artificially.
• These new cells, called hybridomas, live long
and produce monoclonal antibodies.
Figure 18.12 Creating Hybridomas for the Production of Monoclonal Antibodies (Part 1)
Figure 18.12 Creating Hybridomas for the Production of Monoclonal Antibodies (Part 2)
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T Cells: The Cellular Immune Response
• T cells, like B cells, possess specific surface
receptors.
• The genes that code for T cell receptors are
similar to those for immunoglobulins.
• T cell receptors also have constant and variable
regions.
• A major difference between antibodies and T cell
receptors is that T cell receptors bind only to an
antigenic determinant that is displayed on the
surface of an antigen-presenting cell.
Figure 18.13 A T Cell Receptor
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T Cells: The Cellular Immune Response
• Activated T cells give rise to two types of effector
cells.
• Cytotoxic cells, or TC, recognize virus-infected
cells and kill them by causing them to lyse.
• Helper T cells, or TH cells, assist both the cellular
and humoral immune systems.
• Activated helper T cells proliferate and stimulate
both B and TC cells to divide.
Figure 18.14 Cytotoxic T Cells in Action
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T Cells: The Cellular Immune Response
• The major histocompatibility complex (MHC)
gene products are plasma membrane
glycoproteins.
• These molecules are called human leukocyte
antigens (HLA) in humans and H-2 proteins in
mice.
• There are three classes of MHC proteins.
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T Cells: The Cellular Immune Response
• Class I MHC proteins are present on the surface
of every nucleated cell in animals.
• When cellular proteins are degraded in the
proteasome, an MHC I protein may bind a
fragment and travel to the plasma membrane to
present it outside on the cell’s plasma membrane
surface.
• TC cells have a surface protein called CD8 that
recognizes MHC I.
Figure 18.16 The Interaction between T Cells and Antigen-Presenting Cells (Part 1)
Figure 18.16 The Interaction between T Cells and Antigen-Presenting Cells (Part 2)
Figure 18.16 The Interaction between T Cells and Antigen-Presenting Cells (Part 3)
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T Cells: The Cellular Immune Response
• Class II MHC proteins are found mostly on the
surface of B cells, macrophages, and other
antigen-presenting cells.
• When an antigen is ingested by an antigenpresenting cell, it is broken down and fragments
are presented at the cell surface by class II MHC
proteins.
• TH cells have CD4 surface proteins that
recognize MHC II.
Figure 18.15 Macrophages Are Antigen-Presenting Cells
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T Cells: The Cellular Immune Response
• Class III MHC proteins include some of the
proteins of the complement system that interact
with antigen–antibody complexes to cause lysis of
foreign cells.
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T Cells: The Cellular Immune Response
• T cells recognize the MHC I or II and then inspect
the attached fragment.
• There are three different loci for each MHC I and
for each MHC II.
• The six loci have as many as 100 different alleles.
• This is why different individuals generally have
different MHC genotypes.
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T Cells: The Cellular Immune Response
• TH cells bind to an antigen presented to it by an
antigen-presenting macrophage.
• The then-activated TH cell produces and secretes
cytokine molecules, which attach to their own
specific cell membrane receptor proteins.
• The cell can then divide to produce clones
capable of interacting with B cells.
• These steps, called the activation phase, occur
in the lymphatic tissues.
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T Cells: The Cellular Immune Response
• In the effector stage, an antigen of the same sort
that was processed by the macrophage binds to a
specific IgM receptor on the surface of a B cell.
• The B cell degrades the antigen and presents a
piece of processed antigen in a class II MHC
protein on its cell surface.
• One of the TH cells created in the activation stage
recognizes the processed antigen and class II
MHC protein on the surface of the B cell.
• The TH cell releases cytokines, which activate B
cell proliferation and differentiation into plasma
cells and memory cells.
• The plasma cells secrete antibodies.
Figure 18.17 (a) Phases of the Humoral and Cellular Immune Responses (Part 1)
Figure 18.17 (a) Phases of the Humoral and Cellular Immune Responses (Part 2)
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T Cells: The Cellular Immune Response
• Like class II MHC molecules, class I MHC
molecules also present processed antigen to T
cells.
• Foreign protein fragments are bound by class I
MHC molecules and carried to the plasma
membrane, where TC cells can check them.
• If a cell has been infected by a virus, or has
mutated, it may present protein fragments that are
not normally found in the body.
• If a TC cell binds to the MHC I–antigen complex,
the TC cell is activated to proliferate and
differentiate.
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T Cells: The Cellular Immune Response
• In the effector stage, TC cells once again bind to
the cells bearing MHC I–antigen complex and
secrete molecules that lyse the cell.
• TC cells can also bind to a specific target cell
receptor (called Fas).
• This binding initiates apoptosis in the target (for
example, virus-infected) cell.
• This system helps rid the body of virus-infected
cells. It also helps to destroy some cancer tumors.
Figure 18.17 (b) Phases of the Humoral and Cellular Immune Responses (Part 1)
Figure 18.17 (b) Phases of the Humoral and Cellular Immune Responses (Part 2)
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T Cells: The Cellular Immune Response
• T cells developing in the thymus are tested to
ensure that they will be functional and will not
attack normal self antigens.
• Each new T cell must recognize the body’s MHC
proteins. If it fails to do so, it dies within about 3
days.
• If the developing T cell binds to self MHC proteins
and to one of the body’s own normal antigens, it
undergoes apoptosis.
• If these T cells were not destroyed they would be
harmful or lethal to the animal.
• If the T cell survives these tests, it becomes either
a TC or TH cell.
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T Cells: The Cellular Immune Response
• For organ transplants to be successful, MHC
molecules must match; otherwise, these same
molecules will act as antigens.
• The cellular immune system is responsible for
rejection.
• Rejection problems can be controlled somewhat
by treating patients with immunosuppressing
drugs such as cyclosporin.
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The Genetic Basis of Antibody Diversity
• As B cells develop, their genomes become
modified until the cell can produce one specific
type of antibody.
• If we had a different gene for each antibody our
immune systems are capable of producing, our
entire genome would be taken up by antibody
genes.
• Instead, just a small number of genes that can
recombine to generate multitudes of possibilities
are responsible for the vast diversity of antibodies.
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The Genetic Basis of Antibody Diversity
• Each gene encoding an immunoglobin is in reality
a “supergene” assembled from several clusters of
smaller genes located along part of a
chromosome.
• During B cell development, these variable regions
rearrange and join.
• Pieces of DNA are deleted, and DNA segments
formerly distant from one another are joined
together.
• Immunoglobulin genes are assembled from
randomly selected pieces of DNA.
Figure 18.18 Heavy-Chain Genes
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The Genetic Basis of Antibody Diversity
• Each B cell precursor assembles its own two
specific antibody genes, one for a heavy chain,
and the other for a light chain.
• In both humans and mice, the DNA segments
coding for immunoglobulin heavy chains are on
one chromosome and those for light chains are on
another.
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The Genetic Basis of Antibody Diversity
• There are multiple genes coding for each of the
four kinds of segments in the polypeptide chain
for the heavy chain in mice: 100 V, 30 D, 6 J, and
8 C regions.
• Each B cell randomly selects one gene for each of
the V, D, J, and C regions.
• A similar process occurs for the light chain.
• Theoretically, there are 144,000 x 144,000
possible combinations of light and heavy chains,
i.e, 21 billion possibilities.
Figure 18. Heavy-Chain Gene Rearrangement and Splicing (Part 1)
Figure 18. Heavy-Chain Gene Rearrangement and Splicing (Part 2)
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The Genetic Basis of Antibody Diversity
• Additional diversity is possible because the
recombinations do not occur at precise segments.
Imprecise recombinations can create new codons
at the junctions.
• After DNA fragments are cut out and before they
are joined, an enzyme, terminal transferase, adds
some nucleotides to the free end. This adds even
more variability by causing frame shifts and new
codons.
• Finally, the relatively high mutation rate in
immunoglobulin genes leads to even more
diversity.
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The Genetic Basis of Antibody Diversity
• B cells make only one class of antibody at a time,
but class switching can occur. For example, the
B cell can switch from IgM to IgG.
• The constant region for IgM is coded for by the m
segment.
• If the cell becomes a plasma cell, another DNA
splicing event positions the heavy-chain variable
region next to a constant segment farther down
the DNA strand, and the m segment is deleted.
• Class switching is triggered and controlled by a TH
cell via cytokine signals.
Figure 18.20 Class Switching
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Disorders of the Immune System
• The human immune system can overreact to a
dose of antigen and produce an inappropriate
immune response. Allergies are the most familiar
example.
• Immediate hypersensitivity occurs when too
much IgE is made.
 If the IgE binds with antigens, mast cells and
basophils are triggered to release histamine.
• Delayed hypersensitivity does not begin until
hours after exposure to an antigen and involves
antigen-presenting cells and T cells.
 The response can activate macrophages and
cause tissue damage.
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Disorders of the Immune System
• If clonal deletion fails, “forbidden clones” of B and
T cells directed against self-antigens are
sometimes made.
• Examples of autoimmune diseases include:
 Systemic lupus erythematosis
 Rheumatoid arthritis
 Multiple sclerosis
 Insulin-dependent (juvenile-onset) diabetes
mellitus
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Disorders of the Immune System
• HIV (human immunodeficiency virus), which leads
to AIDS (acquired immune deficiency syndrome),
causes a depletion of TH cells.
• It can be transmitted through blood or by
exposure of broken skin or an open wound to the
body fluids of an infected person.
Figure 18.21 The Course of an HIV Infection
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Disorders of the Immune System
• HIV uses RNA as its genetic molecule.
• The core of the virus contains two identical
molecules of RNA and the enzymes reverse
transcriptase, integrase, and a protease.
• The envelope is derived from the plasma
membrane of the cell in which the virus grew.
• The envelope has glycoproteins gp120 and gp41
protruding. These proteins are necessary for the
targeting of TH cells.
• The virus enters the cell via CD4 membrane
proteins on TH cells. The gp120 protein binds to
CD4.
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Disorders of the Immune System
• Once in the cell, reverse transcriptase makes a
DNA copy (cDNA) of the viral RNA, and cellular
DNA polymerase makes the complementary
strand.
• Reverse transcriptase is error prone; this elevates
the mutation rate and adds to the adaptability of
the virus.
• The cDNA integrates into the host DNA.
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Disorders of the Immune System
• Viruses are made when the TH cell is activated.
• Transcription of the viral DNA requires host
transcription factors and a viral protein, Tat.
• The RNA is either spliced and translated or
unspliced to become the genetic molecule of a
new virus.
• A viral protease is needed to cleave large viral
precursor proteins into smaller functional units.
• Viral membrane proteins are synthesized on
rough ER, and glycosylation occurs within the ER
and Golgi complex.
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Disorders of the Immune System
• Highly active antiretroviral therapy (HAART) was
developed in the late 1990s.
• A protease inhibitor obstructs the active site of the
HIV protease.
• Two reverse transcriptase inhibitors that terminate
the cDNA molecules prematurely are used.
• Unfortunately, 80 percent of patients taking
HAART develop mutant strains of HIV that are
resistant.
Figure 18.22 Relationship Between TH Cell Count and Opportunistic Infections