The Immune Wars Part I

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The Immune WarsPart I
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General types of immunity
Innate (aka non-specific)
inborn
pattern recognition
Adaptive (aka specific, acquired)
learned through exposure
exquisite specificity
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Chapter 15 Innate Immunity Preview

• First line of defense
• Cells
• Sensor system
• Phagocytosis
• Inflammation

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First-line Defenses
Physical barrier Antimicrobial chemicals Normal
flora
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Physical Barriers
Skin

• Sheets of tightly packed cells
• Outermost layers are embedded with keratin (dry)
• Cells continually slough off
• Perspiration (salty)
• Normal flora

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Physical Barriers
Mucous Membranes

• Single layer of cells
• Layer of mucus (traps particles, including
  microbes)
• Often a mechanism to propel the mucus toward exit
• (ex. mucociliary escalator, peristalsis)

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Antimicrobial Chemicals

• Lysozyme
• Transferrin, lactoferrin
• Gastric acid

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The Cells of the Immune System
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Cell Communication
Surface receptors - eyes, ears
Cytokines - chemical messengers proteins
released by cells that affect the behavior of
other cells voice
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Cell Communication
Surface receptors - eyes, ears Cytokines -
chemical messengers proteins released by cells
that effect the behavior of other cells voice
Adhesion molecules - hands
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Sensor Systems
Toll-like receptors - surface receptors that
allow cells to see molecules that signify the
presence of microorganisms or viruses
pattern recognition
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Sensor Systems
Toll-like receptors - surface receptors that
allow cells to see molecules that signify the
presence of microorganisms or viruses
pattern recognition
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Sensor Systems
The complement system - series of proteins that,
when activated, result in destruction/removal of
foreign material cascade reaction
C3 C5

• C3a C3b

? C5a C5b
prepare for eating
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Sensor Systems
The complement system - series of proteins that,
when activated, result in destruction/removal of
foreign material cascade reaction
C3 C5

• C3a C3b

? C5a C5b
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Alternative Complement Systems
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Sensor Systems
The complement system - series of proteins that,
when activated, result in destruction/removal of
foreign material cascade reaction
C3 C5

• C3a C3b
• ? C5a C5b

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Sensor Systems
Recognition of long double-stranded RNA
Signifies to a cell that it is infected with a
virus
infected cell produces interferon
Apoptosis programmed cell death
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Phagocytosis
Macrophages Neutrophils (polymorphonuclear
leukocytes, PMNs, polys)
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Process of phagocytosis
Chemotaxis
Recognition and attachment

• opsonins

Engulfment (ingestion)

• phagosome

Fusion of the phagosome with lysosomes (forms a
phagolysosome)
Destruction and digestion Exocytosis
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Specialized attributes of macrophages
Fixed in tissue or routinely wander
Clean up infection
Long-lived (months)
Can become activated

• Specialized attributes of neutrophils

First to migrate to site of infection
Short-lived (days)
Always have tremendous killing power
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Specialized attributes of macrophages
Fixed in tissue or routinely wander
Clean up infection
Long-lived (months)
Can become activated

• Specialized attributes of neutrophils

First to migrate to site of infection
Short-lived (days)
Always have tremendous killing power
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Inflammation
Redness, pain, swelling, heat
Purpose Contain a site of damage Localize the
response Restore tissue function Factors that
initiate the inflammatory response Microbial cell
products detected by toll-like receptors Microbial
surfaces (trigger the complement cascade) Tissue
damage
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The Inflammatory Process

• Pro-inflammatory cytokines released
• Dilation of small blood vessels
• ? increased blood flow to the area
• Leakage of fluids from vessels
• Adherence of phagocytic cells to endothelial
  cells
• Diapedesis

Apoptosis - programmed cell death does not
trigger inflammation
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Other responses
Interferon
Fever
? metabolic rate ? response to invaders
elevates temperature above optimum growth
temperature of invader
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Immune Wars

• Adaptive Immunity

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Chapter16 Adaptive Immunity Preview

• Characteristics of adaptive immunity
• Lymphatic system
• Humoral immunity
• Antibody structure, function, classification,
  production (B cell activation)
• Cellular immunity
• T cell activation, function

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Strategy of the Adaptive Immune Response
Characteristics of adaptive immunity

• Memory
• Specificity
• Self vs. non-self

..or harmless vs. danger
self vs. dangerous non-self
Antigen - Material to which an immune system
mounts a response
Development of the Response Effect step 1
? step 2 ? step 3 ? ? ? ? ? ? ? ? ? ? ? ? ? finale
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Strategy of the Adaptive Immune Response
lymphocytes
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Strategy of the Adaptive Immune Response

• Extracellular antigens
• Most bacteria
• Toxins
• Viral particles

aka cell-mediated immunity (CMI)

• Intracellular antigens
• Viruses (inside a cell)
• Intracellular bacteria
• (Cancer cells)

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Strategy of the Adaptive Immune Response
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Strategy of the Adaptive Immune Response
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Strategy of the Adaptive Immune Response
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Strategy of the Adaptive Immune Response
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Strategy of the Adaptive Immune Response
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Anatomy of the Lymphoid System
Lymphatic vessels
Secondary lymphoid organs
Collect fluids, WBCs from the tissues
Where lymphocytes hang out to encounter antigens

• Lymph nodes

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Anatomy of the Lymphoid System
Lymphatic vessels
Secondary lymphoid organs
Where lymphocytes hang out to encounter antigens

• Lymph nodes

• Spleen

• Mucosal-associated lymphoid tissue
• Peyers patches M cells sample material in the
  intestine

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Anatomy of the Lymphoid System
Lymphatic vessels
Secondary lymphoid organs
Where lymphocytes hang out to encounter antigens

• Lymph nodes

• Spleen

• Mucosal-associated lymphoid tissue
• Peyers patches M cells sample material in the
  intestine
• Skin-associated lymphoid tissue

Primary lymphoid organs
Where lymphocytes develop

• Bone marrow

• Thymus

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The Nature of Antigens

• Proteins
• Molecules w/ repeating identical subunits (ex.
  polysaccharides)

Epitopes/antigenic determinants
10-20 amino acids
antigenic
T helper cell dependent T helper cell independent
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The Nature of Antibodies
Magic bullet bind antigen with high specificity
Basic structure Y-shaped molecule

• Fab regions - antigen-binding regions

• Fc region - red flag region

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The Nature of Antibodies
Structure and properties of antibodies
Basic structure Y-shaped molecule
200 a.a.
450 a.a.

• Fab regions - antigen-binding regions

• Fc region - red flag region

• four protein chains - two heavy chains (H) two
  light chains (L)

• variable region
• constant region

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Immunoglobulin Classes (isotypes)
Immunoglobulins antibodies
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Protective outcomes of antigen-antibody binding
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Protective outcomes of antigen-antibody binding
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Protective outcomes of antigen-antibody binding
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Naïve lymphocytes - have a receptor, but have not
seen antigen
BCRs are membrane-bound antibodies
1/2 billion naïve B cells, recognizing 100
million different epitopes! Those that
recognize self are eliminated during lymphocyte
development
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Activated lymphocytes - able to proliferate have
received confirmatory signals
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Activated lymphocytes - able to proliferate have
received confirmatory signals
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Activated lymphocytes - able to proliferate have
received confirmatory signals
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Effector lymphocytes - endowed with specific
protective attributes (plasma cells effector B
cells)
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Effector lymphocytes - endowed with specific
protective attributes (plasma cells effector B
cells)
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells
Memory lymphocytes - long-lived ready to become
effector cells
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Clonal Selection and Expansion of Lymphocytes
Basic principles are true for both B and T cells

• Naïve
• Activated
• Effector
• Memory

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B Lymphocytes and the Antibody Response
(T-dependent antigens)

• Most common type of response primarily protein
  antigens
• Requires assistance of T-helper cells (TH cells)

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B Cell Activation

• B cell processes/presents antigen to TH cell for
  inspection in order to gain second opinion

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B Cell Activation

• B cell processes/presents antigen to TH cell for
  inspection in order to gain second opinion

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B Cell Activation

• B cell processes/presents antigen to TH cell for
  inspection in order to gain second opinion

• If a TH cell recognizes a fragment being
  presented, it delivers cytokines that activate
  the B cell

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B Cell Activation

• B cell processes/presents antigen to TH cell for
  inspection in order to gain second opinion

• If a TH cell recognizes a fragment being
  presented, it delivers cytokines that activate
  the B cell
• If no TH cell recognizes antigen, the B cell
  becomes unresponsive

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B Cell Activation

• B cell processes/presents antigen to TH cell for
  inspection in order to gain second opinion

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Characteristics of the Primary Response
Affinity maturation

• Naïve
• Activated
• Effector
• Memory

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Characteristics of the Primary Response
Affinity maturation - mutation fine tunes the fit
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Characteristics of the Primary Response
Affinity maturation - mutation fine tunes the
fit Class switching - IgM ? IgG (or IgA or IgE)
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Characteristics of the Primary Response
Affinity maturation - mutation fine tunes the
fit Class switching - IgM ? IgG (or IgA or IgE)
Formation of memory cells - cells have undergone
affinity maturation and class switching
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Characteristics of the Primary Response
Affinity maturation Class switching
Formation of memory cells
Secondary response
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Characteristics of the Secondary Response
Swifter response, primarily IgG in blood/tissues
(due to memory cells)
(mucosal response is IgA) More effective response
(due to affinity maturation) Continued fine-tuning
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Characteristics of the Secondary Response
Swifter response, primarily IgG in blood/tissues
(due to memory cells)
(mucosal response is IgA) More effective response
(due to affinity maturation) Continued fine-tuning
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General Characteristics of T Cells
(regulatory T cells)
Two general categories of T cells
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General Characteristics of T Cells
T-cell receptor - recognizes antigen presented
by another cell
Antigen is presented by major histocompatibility
complex (MHC) molecules
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General Characteristics of T Cells
T-cell receptor - recognizes antigen presented
by another cell
Antigen is presented by major histocompatibility
complex (MHC) molecules
Effector T cell delivers signals to the
presenting cell
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General Characteristics of T Cells
CD cluster of differentiation

• CD8 T cell

• CD4 T cell

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Activation of T Cells
The role of dendritic cells
scouts
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Activation of T Cells
In secondary lymphoid organs antigen-presenting
to naïve T cells antigen presented by BOTH MHC
Class I AND MHC Class II molecules
In the tissues antigen-capturing
Co-stimulatory molecules expressed when danger
is sensed
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Activation of T Cells
In secondary lymphoid organs antigen-presenting
to naïve T cells antigen presented by BOTH MHC
Class I AND MHC Class II molecules
The role of dendritic cells
In the tissues antigen-capturing
Co-stimulatory molecules expressed when danger
is sensed
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Activation of T Cells
In secondary lymphoid organs antigen-presenting
to naïve T cells antigen presented by BOTH MHC
Class I AND MHC Class II molecules
The role of dendritic cells
In the tissues antigen-capturing
Activates naïve T cell
Co-stimulatory molecules expressed when danger
is sensed
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Activation of T Cells
In secondary lymphoid organs antigen-presenting
to naïve T cells antigen presented by BOTH MHC
Class I AND MHC Class II molecules
The role of dendritic cells
In the tissues antigen-capturing
In the tissues antigen-capturing
Naïve T cell becomes unresponsive
Co-stimulatory molecules expressed when danger
is sensed
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Activation of T Cells
In secondary lymphoid organs antigen-presenting
to naïve T cells antigen presented by BOTH MHC
Class I AND MHC Class II molecules
The role of dendritic cells
In the tissues antigen-capturing
Activates naïve T cell
Co-stimulatory molecules expressed when danger
is sensed
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Functions of TC (CD8) Cells

• Recognizes antigen presented by Major
  Histocompatibility Complex (MHC) Class I

• Found on all nucleated cells

• Endogenous proteins (i.e. made by the cell) are
  presented

• Induces apoptosis in corrupt self cells (ex.
  virally-infected)
• Secretes cytokines some increase surveillance
  of neighboring cells (?MHC Class I expression)

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Functions of TH (CD4) Cells
Helps other cells (operations commander)
produces various cytokines that activate
presenting cell and direct other cells
Recognizes antigen presented by Major
Histocompatibility Complex (MHC) Class II
Exogenous proteins (i.e. those that have been
taken up by the cell) are presented Found on
antigen-presenting cells (macrophages, B
cells.and dendritic cells)
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Functions of TH (CD4) Cells
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Functions of TH (CD4) Cells
B cell activation (B cell as the APC)
Antigen represents material that the B cells
receptor has recognized
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Functions of TH (CD4) Cells
B cell activation (B cell as the APC)
Antigen represents material that the B cells
receptor has recognized

• TH cell directs cytokines to that B cell,
  activating it/enabling it to

• Multiply and differentiate to form
  antibody-secreting plasma cells
• Produce memory cells
• Undergo class switching

Note T-independent antigens (generally
polysaccharides) can activate B cells without T
cell help IgM only, no memory
Children lt 2 yo have weak response
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Functions of TH (CD4) Cells
B cell activation ( B cell as the APC)
Antigen represents material that the B cells
receptor has recognized

• TH cell directs cytokines to that B cell,
  activating it/enabling it to

• Multiply and differentiate to form
  antibody-secreting plasma cells
• Produce memory cells
• Undergo class switching

Note T-independent antigens (generally
polysaccharides) can activate B cells without T
cell help IgM only, no memory
Children lt 2 yo have weak response
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Functions of TH (CD4) Cells
Macrophage activation (macrophage as the APC)
Presented peptides are parts of material that the
phagocyte has engulfed

• TH cell
• directs cytokines to that macrophage (activating
  it)

• secretes cytokines that stimulate activated
  T-cytotoxic cells

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B Lymphocytes and the Antibody Response
(T-independent antigens)
Primarily polysaccharide antigens also LPS of
Gram-negatives Multiple evenly-spaced identical
epitopes
No memory cells formed No class switching
(therefore IgM only) Immature immune systems
(children lt2 years of age) respond
poorly capsular polysaccharides - ex.
Haemophilus influenzae
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The Big Picture

• Presented step-by-step

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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
Secondary lymphoid organs
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
Secondary lymphoid organs
Naive B cells
Naive-helper T cells (CD4)
Naive cytotoxic T cells (CD8)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
Secondary lymphoid organs
Naive B cells
Naive cytotoxic T cells (CD8)
Naive-helper T cells (CD4)
Dendritic cells (gather antigen for
presentation to naive T cells)
Virus
Infected "self" cell (harbors antigen within the
cell)
Macrophage (engulf and destroy invaders limited
killing powers)
Extracellular antigen
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Virus
Infected "self" cell (harbors antigen within the
cell)
Macrophage (engulf and destroy invaders limited
killing powers)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Activation, proliferation, differentiation
to form effector cells and memory cells
Virus
Infected "self" cell (harbors antigen within the
cell)
Macrophage (engulf and destroy invaders limited
killing powers)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Activation, proliferation, differentiation
to form effector cells and memory cells
Virus
Infected "self" cell (harbors antigen within the
cell)
Macrophage (engulf and destroy invaders limited
killing powers)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Activation, proliferation, differentiation
to form effector cells and memory cells
Virus
Infected "self" cell (harbors antigen within the
cell)
TH cells activate macrophages that present
antigen via MHC class II molecules also produce
cytokines that orchestrate other responses.
Macrophage (engulf and destroy invaders limited
killing powers)
Activated macrophage (engulf and destroy
invaders enhanced killing powers)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Activation, proliferation, differentiation
to form effector cells and memory cells
Virus
TC cells induce apoptosis in infected "self"
cells also produce cytokines that
cause neighboring cells to become more vigilant
against intracellular pathogens.
Infected "self" cell (harbors antigen within the
cell)
TH cells activate macrophages that present
antigen via MHC class II molecules also produce
cytokines that orchestrate other responses.
Macrophage (engulf and destroy invaders limited
killing powers)
Activated macrophage (engulf and destroy
invaders enhanced killing powers)
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Peripheral Tissues
Primary Lymphoid Organs
Immature B cells (bone marrow)
Immature T cells (thymus marrow)
After gathering antigen in periphery, dendritic
cells bring it to naive T cells in the secondary
lymphoid organs co-stimulatory molecules are
expressed if antigen represents microbial
invasion or tissue damage. Antigens are
presented by both MHC class I and MHC class
II molecules, activating both cytotoxic T cells
and helper T cells.
Secondary lymphoid organs
Naive B cells
Activation, proliferation, differentiation
to form effector cells and memory cells
Virus
TC cells induce apoptosis in infected "self"
cells also produce cytokines that
cause neighboring cells to become more vigilant
against intracellular pathogens.
Infected "self" cell (harbors antigen within the
cell)
TH cells activate macrophages that present
antigen via MHC class II molecules also produce
cytokines that orchestrate other responses.
Macrophage (engulf and destroy invaders limited
killing powers)
Activated macrophage (engulf and destroy
invaders enhanced killing powers)
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Table 1 Table 1
Non-specific Immunity Specific Immunity
Response is antigen-independent Response is antigen-dependent
There is immediate maximal response There is a lag time between exposure and maximal response
Not antigen-specific Antigen-specific
Exposure results in no immunologic memory Exposure results in immunologic memory