Transcript Foundations in Microbiology

Specific Immunity
Talaro Chapter 15
Dendritic cell (blue) communicates
with four T lymphocytes (yellow).
Talaro (5th ed.) page 445
Elvis receives his polio vaccination during a
1956 March of Dimes campaign.
www.marchofdimes.com
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Specific Immune Reaction Overview
• Specific Immune Reaction Overview
– Characteristics of Specific Immunity
– Humoral & Cellular Immune Response
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Lymphocyte Development & Differentiation
Cytokines
Major Histocompatibility Groups
Presenting of Antigens
Antibodies
– Immunoglobins (Igs)
• Two Scenarios
– Humoral
– Cellular
• Immunological Memory
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Four Characteristics of the Immune System
• Specificity
– Antigens are organisms or molecules that are
specifically recognized as foreign by the immune
system
– 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
• T cells & Abs aid in the removal of the antigen
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Foreign molecules less
than 1,000 MW are
not antigenic unless
attached to a larger
carrier molecule
Epitope
Proteins produced by the immune system
that specifically binds to an epitope and
initiates its removal of the antigen from the
body
Ab recognize and
bind to a specific epitope
Proteins (enzymes, exotoxins, Abs, hormones)
Lipoproteins
Glycoproteins
Nucleoproteins (pure DNA isn’t antigenic)
Polysaccharides (bacterial capsules) & LPS
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Antigens
Whole cells, viruses
and complex
molecules elicit the
immune response.
Viruses present various
antigenic determinants.
Small molecules, simple molecules,
and large but repetitive molecules can
evade the immune system.
Each determinant will stimulate
a unique lymphocyte and Ab
response.
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Characteristics of the Immune System
• Diversity
– The human immune system can distinguish and
respond to  10 million different antigenic
determinants
• Distinguishing Self from Non-self
– Major Histocompatibility Complex
• Proteins on the surface of every cell
• Immunological Memory
– Once exposed to a pathogen, the immune system
“remembers” and mounts future responses more
rapidly
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The Immune System
• Humoral Immune Response
– Defense against extracellular pathogens
– Abs bind to antigens
– Makes antigens easy targets for phagocytes
• Cellular Immune Response
– Intracellular pathogens & cancer
– Bind & lyse abnormal cells
• The two responses operate in concert and share mechanisms
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Lymphocytes
WBC (leukocytes) involved in the immune response. Two types: B cells & T
cells. Lymphocytes secrete cytokines that regulate the activities of many other
types of cells and are often present at sites of inflammation.
B Lymphocytes (B-Cells)
- Lymphocytes that mature in bone marrow
- Responsible for the production of antibodies and humoral
(fluid) immunity
T Lymphocytes (T-Cells)
- Lymphocytes that mature in thymus gland
- Responsible for the cell-mediated immunity
- Directed against a factor, such as a virus or mutation, that
changes a normal cell into an abnormal cell
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Lymphocytes develop from the same stem cell but undergo a
sequential development that begins in the embryonic yolk sac
and shifts to the liver and bone marrow. Diverge into two
distinct types: B cells & T cells.
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Immature lymphocytes cannot react
with antigens.
Lymphocyte differentiation &
immunocompetence are completed by late
fetal or early neonatal period.
Mature B cells are found in the lymph nodes,
spleen, gut associated lymphoid tissue. Have
immunoglobin receptors & numerous
microvillus projections.
Mature T cells are found in the lymphoid
organs but pass between lymphatic &
general circulation. 7 clusters of
differentiation (CD) or receptors that
recognize antigens bound on cells, MHC
receptors, B cells, T cells and
macrophages.
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Brief Explanation of B Cells
Specificity between the
antigen & Ab
Each B cell makes a
unique Ab on its surface
B cell divides
Production of Clones
“clonal selection”
A few develop into memory
cells that divide at a low rate
Some develop into effector
or plasma cells
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Brief Explanation of T Cells
Helper T cells activate other T & B cells
(CD4 or TH)
Cytotoxic T cells destroy
foreign or abnormal cells
by secreting perforins that
lyse cells
(CD8 or TC)
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Cytokines
• Soluble proteins
• Regulate immune system activities
• Cytokine network
– A complex web of signals among all the cell types
of the immune system
• Cytokines have been named after their cells of
origin, their function, and / or the order in
which they were discovered
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Common Examples of Cytokines
• Interleukins (ILs)
– Signal among leukocytes
– 27 different ILs
• Interferons (IFNs)
– Antiviral proteins that may also acts as cytokines
– IFN-g secreted by TH cells
• Growth Factors
– Stimulate stem cells to divide
– Sufficient quantity of leukocytes
• Tumor Necrosis Factor (TNF)
– Kill tumor cells & regulate immune response to inflammation
– Macrophages & T cells
• Chemokines
– Signal leukocytes to migrate to site of inflammation or infection
– Activate other leukocytes
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Major Histocompatibility Complex
Cellular surface glycoproteins
Self identifying labels
Coordinate interactions among lymphocytes
& macrophages
These molecules are called human leukocyte antigens (HLA)
• Class I MHC proteins are present on the surface of
every nucleated animal cell
– Not present on RBC
• Class II MHC proteins are found mostly on the
surface of B cells, macrophages, and other antigenpresenting cells
– When an antigen is ingested by an antigen-presenting cell, it
is broken down and fragments are presented at the cell
surface by class II MHC proteins
• 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
– Not surface proteins
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Antigen Presenting Cell
Macrophage takes up
an antigen by phagocytosis
Macrophage processes the
antigen by breaking it into
fragments
A class II MCH protein binds
the processed antigen
The MHC “presents” the antigen
to a helper T cell
A closer
look at this
interaction
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Interleukin-2 is produced by
TH to activate B & T cells
IL-1
Interleukin-1 is secreted by APC to
activate TH cells
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Antibodies / Immunoglobins
Bivalent
Variable regions
differ in the a.a.
sequences at the
antigen-binding
site & are
responsible for the
diversity of
Ab specificity
Fc
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- Antibodies interact with the epitope of the antigen by
shape/shape recognition (lock and key mechanism)
- Recognition depends on multiple noncovalent bonds
between the antigen-binding site and epitope
- Antibodies work to eliminate antigens by either
enhancing phagocytosis or inducing the complement
protein cascade
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• The variable regions differ in the amino acid
sequences at the antigen-binding site and are
responsible for the diversity of antibody specificity
• The enormous range of antibody specificities is
made possible by the recombination of numerous
versions of coding regions for the variable regions
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The Genetic Basis of Antibody Diversity
• As B cells develop, their genomes become
modified until the cell can produce only 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
random process
• 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
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Another pool of segments
is used for the constant region
Variable region for heavy chain
Constant Region
Encoded by one V segment,
one D segment & one J
segment
Figure 18.18 Heavy-Chain Genes
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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
– 21 billion possibilities
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Immunoglobin
• There are five immunoglobulin classes are based on differences
in the constant regions of the heavy chain
– Table 15.2
• IgG
– Classic Y shape
– Compose 85% of the total immunoglobulin content of the bloodstream
• Complementation activation
• Neutralize toxins
• Opsonization
– FC binds to phagocytes
– Cross the placenta
– Leave blood vessels and enter tissues
• IgM
– Pentamer
– More efficient at complement activation, neutralization and
agglutination
– Produced as a first response by plasma cells
– FC binds to B cells
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Macrophage has receptors
for constant region of Ab
Binding of Ab to receptor
initiates phagocytosis
Opsonization
Covered by complement proteins or Ab
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Some Review Before Moving On…
Two General parts of Immune Response…
1) Cell mediated immunity – deals with
destruction of cells… infected or tumor or
injured cells
2) Humoral or Ab-mediated immunity –
deals with production of Ab
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Some Review Before Moving On…
Lymphoid Tissue…characterized by two types
Primary: Bone Marrow Thymus Gland
Secondary: Lymph Nodes, Spleen, Tonsils,
Appendix (?)
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Review of Cells of Immune System
Ag-Presenting Cells- APCs
Include macrophages and some other
lymphocytes
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T-Cells
5 Types
1) TD cells: D = Delayed-type hypersensitivity,
involved in allergic reactions and inflammation
2) Natural Killer Cells (NK Cells): Responsible
for cell killing (many consider these not T cells
and are sometimes called null cells)
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T-Cells
3) TC cells: Cytotoxic T cells – Responsible for cell
killing
4) TH cells: Helper T cells – two types
a) TH1 Cells: Stimulate TC cells and so part of
Cell-mediated immune response; Stimulate
macrophages, Involved in inflammation
b) TH2 Cells: Stimulate B cells – leading to Ab
production so part of humoral immune response
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T-Cells
5) TS Cells: Supressor (or regulatory) T cells –
Supresses immune response of other cells… very
important. Two types…
a) One with CD4 receptor
b) One with CD8 and CD25 receptors
Some are using these to combat autoimmune
diseases
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CD (Cell-Associated Differential) Receptors
Two main types (for us)
1) CD4: On TH cells and TD cells and some
TS cells
2) CD8: TC cells and some TS cells
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Major Histocompatibility Complex Proteins
Found in all vertebrate animals
Collectively called Human Leukocyte Antigens
(transplantation problems)
Two Types:
1) Class I MHC – found on surfaces of all
nucleated cells
2) Class II MHC – found on B lymphocytes
macrophages, and dendritic cells (all of which are
APCs)
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B Cells
B Cells Give rise to 2 to two types of cells…
1) Plasma Cells – cells that produce
antibodies
2) Memory cells - slow growing cells that
will produce antibodies when same Ag in
reintroduced to host
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Additional Information of Immunoglobulins
5 Classes:
1) IgG (80%): Found in extracellular fluid,
blood and lymph, crosses placenta
2) IgM (6%): First Ab to appear after
immunization, bind complement strongly;
found in blood and lymph, and on the
surfaces of B lymphocytes (as a monomer)
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Additional Information of Immunoglobulins
3) IgA (dimer) (13%): Known as major secretory Ab,
found in all kinds of secretions including saliva,
colostrum, serum; is a monomer in serum and
dimer in everything else
4) IgD (1%): Minor circulating Ab found in blood
and lymph and lymphocyte surfaces; very heat
labile; no known function but abundant of surface
of memory B cells…
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•Additional Information of Immunoglobulins
5) IgE (0.002%): Involved in allergic
reactions, binds to mast cells; found in
blood and lymph only
Know term valence… valence
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Opsonization
Definition: Enhancement of phagocytosis by
antibody or complement binding
When Ab binds to an Ag on surface of cell,
the cell is more likely to be phagocytized…
When complement binds this Ab-Ag complex,
it is even more likely to be phagocytized
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Superantigens –e.g., Staphylococcus aureus
Toxins (TSS toxins)
Proteins capable of eliciting a very strong
immune response because they activate
more T cells than that activated in a
“normal” immune response…
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Other Terms…
1) Natural Active Immunity2) Artificial Immunity –
3) Passive Immunitya) General passive immunity- advanatges and
disadvantages
b) Maternal Passive Immunity- good for about 6
months
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Two Scenarios
Phases of the Humoral Immune Responses (Part 1)
IL-1
TH cells bind to an antigen
presented to it by an antigenpresenting macrophage
The activated TH cell
produces and secretes IL-2
molecules, which attach to
their own specific cell
membrane receptor proteins
IL-2
The TH cell divides to produce
clones capable of interacting with
B cells
These steps, called the
activation phase, occur in
the lymphatic tissues
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Phases of the Humoral Immune Responses (Part 2)
IL-4
IgM
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 plasma cells secrete Abs
The TH cell releases
growth factor, which
activate B cell
proliferation and
differentiation into
plasma cells and
memory cells
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Phases of the Cellular Immune Responses (Part 1)
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
IL-2
drives T cell
division
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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Phases of the Cellular Immune Responses (Part 2)
In the effector stage, TC cells once again bind
to the cells bearing MHC I–antigen complex
and secrete perforin molecules create pores
within the cell
TC secrete granzymes that enter
the pores and induce apoptosis
Granzymes are stored in
cytoplasmic granules
This system helps rid the body of
virus-infected cells. It also helps to
destroy some cancer tumors
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Memory (Fig 15.13)
Each B cell makes a
unique Ab on its surface
Specificity between the
antigen & Ab
B cell divides
Production of Clones
clonal selection
A few develop into memory
cells that divide at a low rate
Some develop into effector
cells (plasma cells)
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First exposure to the antigen
Primary response: IgM & IgG
Secondary response: IgG & IgM
Augmented response related to a
prior stimulation of the immune
system by antigens.
Memory B cells
survive in
lymphoid tissue
Latent Period
Antigen concentrated in lymphoid tissue
Memory B cells
differentiate into plasma
cells and produce IgG
Persists
5 days
Body produces
memory B cells
Persists
23 days
Produced by
plasma cells
Memory cells will divide and
differentiate into plasma cells without
interaction with APC
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Can there be B cells that make antibodies
against host….?
Yes… this a is a big problem… but most are
eliminated…
“Clonal Deletion”
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Allergic (Hypersensitivity Reactions)
Anaphylaxis – can be local or systemic
4 Types:
Type I: Immediate Hypersensitivity…
occurs within minutes, IgE sensitization of
mast cells that become degranulated (they
release histamine and serotonin)… therby
causing anaphylaxis… examples- bee sting
reactions, hay fever
Treatment - antihistamines
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Allergic (Hypersensitivity Reactions)
Type II: Cytotoxic Hypersensitivity – Mechanism
involves IgG interaction with cell surface Ag
Occurs in hours… example is many drug allergies
including that for penicillin
Type III: Immune Complex Hypersensitivity –
Mechanism is IgG interaction with soluble or
circulating Ag – Reaction takes hours…
Example : Systemic Lupus erythematosis (Lupis)
Involves autoantibodies against soluble, circulating
self-Ag. Ab bind to proteins forming insoluble
complexes and then complement becomes
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involved resulting in infallmation
Allergic (Hypersensitivity Reactions)
Type IV: Delayed-type hypersensitivity – Takes days
to develop (maximum reaction is typically 24-48
hours)… Mechanism involves TH1 inflammatory
cells… Ab not involved
Tissue damage due to inflammations by TH1
inflammatory cells that release cytokines that
attract macrophages to go to affected area
Examples: Contact dermatitis (poison ivy) and the
tuberculin test… Type I (juvenile) diabetes
mellitus
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Allergic (Hypersensitivity Reactions)
Autoimmune Diseases…
Caused by Types II, III, and IV
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