Download Lecture #12 – Animal Defense and Immune Systems

Lecture #12 – Animal Immune Systems
1
Key Concepts:
• Innate immunity provides broad-spectrum
defense against many pathogens
• Acquired immunity is very specific, develops
over time, and relies on B and T cells
• Antigen recognition properties of B and T
cells
• B and T cell binding sites develop randomly!
• Integrated B and T cell function
• When the immune system goes wrong…
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Some definitions….
Generate
s
Patholog
y
• Pathogen = anything that causes disease
Microbes (bacteria, protozoans), viruses, fungal
spores, pollen, dust mites, etc
Secretions (venoms, animal saliva)
Non-self tissue cells (transplant rejections)
Generate
Some cancer cells
s
Antibodie
s
• Antigens = cell surface proteins and other
molecules that the body recognizes as nonself
Pathogens have Antigens
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The immune system is
spread diffusely
throughout the body –
a system of organs,
nodes and lymph
vessels
Schematic of the
human immune
system
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Remember, the white blood cells are
the defenders
Diagram of the blood cells
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Some WBC’s circulate
though the lymph, the
blood and the
interstitial fluid
Some are permanently
housed in lymph
nodes, thymus gland,
spleen, appendix and
a few other glands
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Defense is step-wise
• 90% of pathogens are neutralized by
innate immunity
Multiple strategies to destroy pathogens
• Any remaining pathogens are normally
attacked by the acquired immune system
Table showing the stages of defense
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Innate Immunity – you are born with it
• Pathogens are ubiquitous
• Innate immunity includes
both external and internal
systems to eliminate
pathogens
• Any and all pathogens are
targeted
• This system does not
recognize specific
pathogens – it goes after
any non-self cell
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Innate Immunity – external
defenses
• Skin – important barrier, acids
• Mucous membranes – trap, cilia evacuate
• Secretions – both skin and mucous secrete
anti-microbial proteins; stomach secretes
acids
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Sweeping cilia in trachea
Innate Immunity – internal
defenses
• Sometimes pathogens get past the barriers
and into the tissues
• Non-specific WBC’s attack
Neutrophils
Monocytes  macrophages
Dendritic cells
Eosinophils
Basophils
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Innate Immunity – internal
defenses
• Phagocytic WBC’s cells
ingest and destroy microbes
in the tissues
Neutrophils – the most
abundant, but short-lived
Macrophages develop from
monocytes – large and longlived
Dendritic cells – mostly
function to stimulate the
acquired immune system
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Model of a macrophage ingesting a
fungal spore
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Micrograph of macrophage ingesting bacteria
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Innate Immunity – internal
defenses
• Eosinophils destroy multicellular parasites by
releasing toxic enzymes
Also contribute to allergic
responses
• Basophils contribute to
inflammatory and allergic
responses
14
Schistosoma mansoni
Additional Internal Defenses
• Antimicrobial proteins
Lysosymes work in macrophages; also found in
saliva, tears and mucous
Complement proteins result in lysis; also help
trigger inflammation and activate acquired
immunity
Interferons limit intra-cellular spread of viruses
Defensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells
and cancer cells
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• The inflammatory response
Complement Protein Function:
these proteins complement other
immune system processes
Diagram showing complement protein function
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Additional Internal Defenses
• Antimicrobial proteins
Lysosymes work in macrophages; also found in
saliva, tears and mucous
Complement proteins result in lysis; also help
trigger inflammation and activate acquired
immunity
Interferons limit intra-cellular spread of viruses
Defensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells
and cancer cells
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• The inflammatory response
Interferons initiate production of proteins that
inhibit viral reproduction
Diagram of interferon activity
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Additional Internal Defenses
• Antimicrobial proteins
Lysosymes work in macrophages; also found in
saliva, tears and mucous
Complement proteins result in lysis; also help
trigger inflammation and activate acquired
immunity
Interferons limit intra-cellular spread of viruses
Defensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells
and cancer cells
19
• The inflammatory response
Additional Internal Defenses
• Antimicrobial proteins
Lysosymes work in macrophages; also found in
saliva, tears and mucous
Complement proteins result in lysis; also help
trigger inflammation and activate acquired
immunity
Interferons limit intra-cellular spread of viruses
Defensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells
and cancer cells
20
• The inflammatory response
A natural killer cell (yellow) attacking a
cancer cell (red).
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Additional Internal Defenses
• Antimicrobial proteins
Lysosymes work in macrophages; also found in
saliva, tears and mucous
Complement proteins result in lysis; also help
trigger inflammation and activate acquired
immunity
Interferons limit intra-cellular spread of viruses
Defensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells
and cancer cells
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• The inflammatory response
The Inflammatory Response
• Usually localized, in response to tissue injury
• Cascade of events
• May also be systemic – increased WBC
release from bone marrow; fever
Diagram of the inflammatory response
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Invertebrates Also Have Innate
Defense Systems
• Amoeboid cells ingest by phagocytosis in
echinoderms
• Insect exoskeleton acts as a barrier similar
to skin
• Hemocytes in insect hemolymph function
similarly to vertebrate innate internal
defenses
• Research indicates little immune system
memory
Little capacity for acquired immunity as seen in
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vertebrates
Defense is step-wise
• 90% of pathogens are neutralized by innate
immunity – both external and internal
• Any remaining pathogens are normally
attacked by the acquired immune system
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Acquired Immunity
• Develops over time, in response to exposure
to pathogens
• Highly specific – lymphocytes develop that
match each incoming pathogen
B cells and T cells
Circulate in tissues; some are also permanently
located in lymph nodes, the spleen and other
lymph system structures
• Pathogen contact with lymphocytes,
phagocytes, and other triggers initiates rapid
immune responses
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Remember – the lymph system is
closely tied to the circulatory system
• Lymph vessels absorb excess fluids in
capillary beds
• Pathogens in the blood are rapidly exposed
to the phagocytes and lymphocytes in the
lymph system
Every heart beat pushes blood, and any
pathogens it carries, past the immune system
structures
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The next 3 slides show the
relationship between the capillary
beds and the lymph vessels
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29
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Remember – the lymph system is
closely tied to the circulatory system
• Lymph vessels absorb excess fluids in
capillary beds
• Pathogens in the blood are rapidly exposed
to the phagocytes and lymphocytes in the
lymph system
Every heart beat pushes blood, and any
pathogens it carries, past the immune system
structures
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Antigen Recognition
• Remember, antigens are the non-self molecules
that initiate the immune response
• Mostly cell surface proteins, other cell surface
molecules, or toxins dissolved in fluid (venoms
and other secretions)
• Most pathogens have several different kinds of
antigens
 Because of this, there are usually several different
lymphocytes that recognize and respond to the
pathogen
• Antigens have specific binding sites = epitopes
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Membranes are complex, with many surface molecules
Diagram showing structure of the cell membrane
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Antigen Recognition
• Remember, antigens are the non-self molecules
that initiate the immune response
• Mostly cell surface proteins, other cell surface
molecules, or toxins dissolved in fluid (venoms
and other secretions)
• Most pathogens have several different kinds of
antigens
 Because of this, there are usually several different
lymphocytes that recognize and respond to the
pathogen
• Antigens have specific binding sites = epitopes
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Epitopes are the specific binding
sites found on all antigens
Diagram showing epitope structure
35
Lymphocytes – B and T Cells
• Remember, lymphocytes are one of the
categories of white blood cells
• Each B or T cell has ~100,000 antigen
receptors – all of the exact same type
Each B or T cell recognizes a single epitope
• The receptor molecules and recognition
process are different for B cells vs. T cells
Both types of receptors are protein-based
Both have both constant and variable regions
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37
Lymphocytes – B and T Cells
• Remember, lymphocytes are one of the
categories of white blood cells
• Each B or T cell has ~100,000 antigen
receptors – all of the exact same type
Each B or T cell recognizes a single epitope
• The receptor molecules and recognition
process are different for B cells vs. T cells
Both types of receptors are protein-based
Both have both constant and variable regions
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Constant regions have stable amino acid
sequences from cell to cell;
Variable regions have different amino acid
sequences from cell to cell
Diagram showing the receptor molecules in B cells and T cells.
This diagram is used several times in the next sequence of slides.
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Antigen Recognition – B Cells
• B cell receptors are Y-shaped
• Each branch of the “Y” has 2 parts, called
chains
Inner, heavy chain makes the full “Y”
Outer, light chain is located on the branches of
the “Y”
Both chains are proteins
Chains are linked by chemical bonds
• The bottom of the “Y” is anchored in the B
cell membrane
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B Cell Receptor Structure
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The protein structure of a
B cell receptor
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Antigen Recognition – B Cells
• The bottom regions of both chains have
constant amino acid sequences
• The outer branches of both chains, have
variable amino acid sequences
These variable ends are the antigen binding
sites
They bind directly to the epitopes
B cells recognize unaltered antigens!
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B Cell Receptor Structure
44
Antigen Recognition – T Cells
•
•
•
•
T cell receptors are unbranched
α chain and β chain are chemically linked
Both are anchored in the membrane
Both have basal constant regions and
terminal variable regions
• A single antigen binding site is at the
terminus
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46
T Cells DO NOT recognize intact
antigens on intact pathogens
• T cells recognize antigen fragments that
have been bound to a self-cell protein
called an MHC molecule
MHC  major histocompatibility complex of
genes codes for these molecules
• MHC molecules bind to antigen fragments
inside a self-cell, and present the fragments
at the surface of the cell
• T cells detect the presented antigen+MHC
complex
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MHC – self-cell proteins
Diagram showing the production of MHC
molecules, how they become attached to
antigen fragments, and how the complex is
presented at the cell surface.
This diagram is used repeatedly in the next
sequence of slides.
48
T Cells DO NOT recognize intact
antigens on intact pathogens
• T cells recognize antigen fragments that
have been bound to a self-cell protein
called an MHC molecule
MHC  major histocompatibility complex of
genes codes for these molecules
• MHC molecules bind to antigen fragments
inside a self-cell, and present the fragments
at the surface of the cell
• T cells detect the presented antigen+MHC
complex
49
Development of MHC Variation
• MHC alleles are numerous
Many more than just the 2 alleles common for
most genes (ie: not just dominant vs. recessive)
As a result, MHC molecules are the most
polymorphic proteins known
Almost all antigens are recognized
• Also, because of the high degree of variation,
it is very rare for any two individuals to have
the exact same set of MHC molecules
MHC molecules are unique to the “self”
Help to distinguish “self” from “non-self” cells
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Development of MHC Variation
• MHC alleles are numerous
Many more than just the 2 alleles common for
most genes (ie: not just dominant vs. recessive)
As a result, MHC molecules are the most
polymorphic proteins known
Almost all antigens are recognized
• Also, because of the high degree of variation,
it is very rare for any two individuals to have
the exact same set of MHC molecules
MHC molecules are unique to the “self”
Help to distinguish “self” from “non-self” cells
51
T Cells DO NOT recognize intact
antigens on intact pathogens
• T cells recognize antigen fragments that
have been bound to a self-cell protein
called an MHC molecule
MHC  major histocompatibility complex of
genes codes for these molecules
• MHC molecules bind to antigen fragments
inside a self-cell, and present the fragments
at the surface of the cell
• T cells detect the presented antigen+MHC
complex
52
Two classes of MHC molecules:
each found in a different type of
antigen presenting cell
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Class I MHC
• Found in most nucleated cells
• They bind antigen fragments if the cell has
been infected, or is cancerous
• Class I MHC+antigen complexes are
recognized by cytotoxic T cells
• Cytotoxic T cells then destroy the infected
or cancerous cell
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Antigen
Presentation –
Class I MHC
molecules are
presented on
infected or
cancerous cells
55
Class II MHC
• Found in dendritic cells, macrophages and
B cells
• Present antigens from pathogens that
have been engulfed by phagocytosis
• Class II MHC+antigen complexes are
recognized by helper T cells
• Activated helper T cells begin a cascade of
events that control the infection
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Antigen
Presentation –
Class II MHC
molecules are
presented on
phagocytic cells
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In both cases, the T cell recognizes ONLY
THE COMBINATION of antigen + self-protein
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Review: B and T Cell Receptors
B cell receptors bind directly
to antigen on intact
pathogen
T cell receptors bind to
MHC+antigen complex on
self-cells
59
Review: B and T Cell Receptors
Remember – both B and T cells have multiple
receptors per cell (as many as 100,000), all identical
60
Key Concepts:
• Innate immunity provides broad-spectrum
defense against many pathogens
• Acquired immunity is very specific, develops
over time, and relies on B and T cells
• Antigen recognition properties of B and T
cells
• B and T cell binding sites develop randomly!
• Integrated B and T cell function
• When the immune system goes wrong…
61
Lymphocyte (B & T cell) Development
• Lymphocytes
are all produced
from stem cells
in the bone
marrow
• Some mature in
the bone marrow
(B cells)
• The rest mature
in the thymus
gland (T cells)
62
Lymphocyte (B & T cell) Development
• Maturation = development of
the B and T cell receptors
• Once the cells are fully
differentiated, they migrate
into the rest of the body
Some stay permanently in the
organs of the lymph system
Some circulate constantly
through blood, lymph and
interstitial fluids
63
Lymphocyte (B & T cell) Development
• Step 1 – generation of diversity
• Step 2 – testing and removal
• Step 3 – clonal selection
• Steps 1 and 2 occur during the development
of the B and T cells
• Step 3 occurs after exposure of the fully
developed B and T cells to antigens
64
Lymphocyte (B & T cell) Development
Step 1 – generation of diversity
• The genes that code for the antigen receptors
are randomly rearranged by enzymes during
lymphocyte maturation
These are the genes that code for the variable
regions of the light and heavy chains of B cells
• Ditto for the variable regions of the α and β
chains of T cells
These chains are then linked together to form the
T cell receptor molecule
65
Example: gene re-alignment for the
light chain of a B cell receptor.
Diagram showing the development of diversity in the
receptors of a B cell. This diagram is used repeatedly
in the next sequence of slides.
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67
The coding gene has 40 variable (V)
segments and 5 joining (J) segments
68
During differentiation of each B cell, one V
segment is snipped out and attached to
one J segment.
Recombinase enzymes randomly snip
and join!
69
40 V regions x 5 J regions = 200 possible
combinations of V and J in the functional gene.
Each cell ends up with only one of these
possible combinations for the light chain.
70
The V+J segment is attached via an
intron to the C segment that codes for
the constant region of the light chain.
71
This “new” gene is processed and translated
into the protein that makes up the light chain
72
The DNA coding for the heavy chain goes
through the same kind of random
rearrangement process, but there are more V
regions
73
The light and heavy chains form independently
and are then linked – thus the enormous
number of possible receptors
Up to 1 million different receptors are produced
in B cells!!!
74
75
Lymphocyte (B & T cell) Development
Step 1 – generation of diversity
• The genes that code for the antigen receptors
are randomly rearranged by enzymes during
lymphocyte maturation
These are the genes that code for the variable
regions of the light and heavy chains of B cells
• Ditto for the variable regions of the α and β
chains of T cells
These chains are then linked together to form the
T cell receptor molecule
76
Lymphocyte (B & T cell) Development
Step 2 – testing and removal
• The rearrangement process is entirely
random
• Each new receptor is “tested” against selfcells – both during development and during
migration into lymph system organs
• Receptors that bind to self-cells or self-MHC
molecules are eliminated or deactivated
77
Critical Thinking
• Why would testing be so important???
78
Critical Thinking
• Why would testing be so important???
• Testing process ensures that the immune
system can distinguish self from non-self
79
Differentiation and testing result in an
enormous variety of B and T cells – each
capable of recognizing a single epitope
• ~ 1 million different B cells
• ~ 10 million different T cells
• Usually no duplication – you start out with
a single cell of each type
• Clonal selection (the next step) builds a
population of duplicate lymphocytes
80
Lymphocyte (B & T cell) Development
Step 3 – clonal selection
• Each B and T cell has receptors that are
specific to a single epitope
• Incoming pathogens typically display several
epitopes
• Virtually always, there is a B or T cell
receptor to match at least one of the
pathogen epitopes
81
Critical Thinking
• How are incoming pathogens exposed to
these myriad B and T cells???
82
Critical Thinking
• How are incoming pathogens exposed to
these myriad B and T cells???
• Remember the way blood and lymph
circulate
• Incoming pathogens are rapidly exposed
to the B and T cells because of the leaky
capillaries and the lymph “vacuum system”
83
Lymphocyte (B & T cell) Development
Step 3 – clonal selection
• When a lymphocyte
receptor encounters
a matching epitope,
the lymphocyte is
activated
• Activation =
stimulation of the
lymphocyte to begin
mitotic cloning
Diagram showing clonal expansion
of selected B cell
84
Lymphocyte (B & T cell) Development
Step 3 – clonal selection
• Duplicate lymphocytes are rapidly produced
• Two clonal populations form
• Effector cells are short-lived and carry out
the immune system response (varies based
on type of lymphocyte – more later)
• Memory cells are long-lived and “remember”
the epitope
Memory cells allow for rapid response to that
same pathogen the next time it enters the body
85
Memory cells confer active immunity
Clones
divide into
two
populations:
effector and
memory
Diagram showing clonal expansion
of selected B cell
86
Lymphocyte (B & T cell) Development
Step 3 – clonal selection
• Duplicate lymphocytes are rapidly produced
• Two clonal populations form
• Effector cells are short-lived and carry out
the immune system response (varies based
on type of lymphocyte – more later)
• Memory cells are long-lived and “remember”
the epitope
Memory cells allow for rapid response to that
same pathogen the next time it enters the body
87
Memory cells confer active immunity
Step 3 – clonal selection
Memory cells accumulate over repeated
exposure to the same pathogen
EX is for B cells;
T cells also accumulate
Graph showing accumulation of memory cells after repeated exposures.
88
Critical thinking
• If the immune system response is so rapidly
initiated, why do we ever get sick???
89
Critical thinking
• If the immune system response is so rapidly
initiated, why do we ever get sick???
• Note that the initial response takes about 2
weeks to peak
• This is about how long we usually stay sick
after first exposure to a new pathogen!
• Future exposures are more rapidly attacked
90
Key Concepts:
• Innate immunity provides broad-spectrum
defense against many pathogens
• Acquired immunity is very specific, develops
over time, and relies on B and T cells
• Antigen recognition properties of B and T
cells
• B and T cell binding sites develop randomly!
• Integrated B and T cell function
• When the immune system goes wrong…
91
Integrated B and T Cell Function
Diagram showing how B cell and T
cell functions are integrated
92
Simultaneous
93
Helper T Cell Function
• Nearly all antigens
activate helper T cells
• Dendritic phagocytes
1o activate naïve
helper T cells
Diagram of helper T cell binding
to antigen presenting cell.
 Important in primary
immune response
• Macrophages 1o
activate memory
helper T cells
 Important in secondary
immune response
94
Helper T Cell Function
• Clones of active
and memory T cells
develop after
exposure
• Active helper T
cells secrete
proteins that
stimulate cytotoxic
T cells and B cells
95
Active helper T cells stimulate the
rest of the immune system:
both cytotoxic T cells and B cells
Diagram showing activated helper T cell functions.
96
Cytotoxic T Cell Function
• Activated cytotoxic T cells release proteins
that perforate target cells & initiate apoptosis
• The activated T cell releases, and moves on
to target additional infected or cancer cells
Diagram showing cytotoxic T cell function
97
B Cell Function
• Remember, B cells recognize and bind to
specific intact pathogens
• B cells also engulf some pathogens by
phagocytosis
Antigens are presented on the B cell surface
These antigens are recognized by helper T
cells
Helper T cells activate the B cell
• Only its one specific antigen can be
presented by each type of B cell
98
Some B cells are activated directly
by exposure to the antigen
99
B Cell Function
• Remember, B cells recognize and bind to
specific intact pathogens
• B cells also engulf some pathogens by
phagocytosis
Antigens are presented on the B cell surface
These antigens are recognized by helper T
cells
Helper T cells activate the B cell
• Only its one specific antigen can be
presented by each type of B cell
100
Most B cells are activated by proteins
secreted from active helper T cells
Diagram showing an activated helper T activating a B cell
101
B Cell Function
• Remember, B cells recognize and bind to
specific intact pathogens
• B cells also engulf some pathogens by
phagocytosis
Antigens are presented on the B cell surface
These antigens are recognized by helper T
cells
Helper T cells activate the B cell
• Only its one specific antigen can be
presented by each type of B cell
102
B Cell Function
• Activated B cells form 2 clones – plasma
cells and memory cells
• Plasma cells release antibodies
Diagram showing secretion of antibodies from activated B cell
103
Antibodies
• Each activated B
cells produces
thousands of
clones
• Each clonal B cell
releases nearly a
billion antibodies
Table of antibodies and their functions
2000 antibodies
per second
Each B cell has a
4 – 5 day life span
104
Antibodies
• Five classes of
antibodies are
secreted
• Each recognizes
and attacks specific
pathogens
• Read through this
table for
understanding; don’t
memorize
105
Antibodies
• Only one antibody
per type of B cell
But remember,
most pathogens
have multiple
antigens with
multiple epitopes
Many B cells are
activated
106
Antibody Mediated Pathogen Disposal
Diagram showing how antibodies work
107
Integrated B and T Cell Function
• Responses to
pathogens are
coordinated and
simultaneous, NOT
mutually exclusive
• All components of
the immune system
are activated
• Positive feedback
increases function
108
Active vs. Passive Immunity
• Active immunity is generated when the
acquired immune system is activated
Memory cells are generated
Exposure to pathogen OR vaccination with
inactivated pathogen that still retains antigens
Confers long-term protection (often, lifetime)
• Passive immunity is generated when
antibodies alone are transferred
Does not generate memory cells
Antibodies cross placenta; are injected
Short-term protection
109
Critical Thinking
• What would be the advantage of passive
immunity???
110
Critical Thinking
• What would be the advantage of passive
immunity???
• Rapid protection against very toxic
pathogens – rabies virus, snake venoms
111
Key Concepts:
• Innate immunity provides broad-spectrum
defense against many pathogens
• Acquired immunity is very specific, develops
over time, and relies on B and T cells
• Antigen recognition properties of B and T
cells
• B and T cell binding sites develop randomly!
• Integrated B and T cell function
• When the immune system goes wrong…
112
Immune System Failure
• Allergic responses
Hypersensitive response to allergenic antigens
Antibody tails bind to mast cells
Exposure causes massive histamine release
• Autoimmune diseases
Immune system fails to distinguish self-cells
• Immunodeficiency diseases
Immune system fails
Can be genetic, developmental, or acquired
113
AIDS; also some cancers, chemotherapy, stress
Allergic Responses
•
•
•
•
•
•
Most generated by IgE antibodies
Antibody tail binds to mast cells
IgE accumulates on mast cell surface
Eventually, allergen binds between 2 IgE
This triggers massive release of histamine
Histamine dilates blood vessels…..
114
Immune System Failure
• Allergic responses
Hypersensitive response to allergenic antigens
Antibody tails bind to mast cells
Exposure causes massive histamine release
• Autoimmune diseases
Immune system fails to distinguish self-cells
• Immunodeficiency diseases
Immune system fails
Can be genetic, developmental, or acquired
115
AIDS; also some cancers, chemotherapy, stress
Rheumatoid Arthritis
116
Diabetes
117
Multiple Sclerosis
118
Lupus
119
Immune System Failure
• Allergic responses
Hypersensitive response to allergenic antigens
Antibody tails bind to mast cells
Exposure causes massive histamine release
• Autoimmune diseases
Immune system fails to distinguish self-cells
• Immunodeficiency diseases
Immune system fails
Can be genetic, developmental, or acquired
120
AIDS; also some cancers, chemotherapy, stress
T Cell
HIV
121
2007 – 40 million people are infected by HIV; 15 million children have been orphaned by AIDS
Graph showing relationship between HIV concentration, antibody
concentration and T cell concentration over time.
122
REVIEW – Key Concepts:
• Innate immunity provides broad-spectrum
defense against many pathogens
• Acquired immunity is very specific, develops
over time, and relies on B and T cells
• Antigen recognition properties of B and T
cells
• B and T cell binding sites develop randomly!
• Integrated B and T cell function
• When the immune system goes wrong…
123