1 lecture #12 – animal immune systems. 2 key concepts: innate immunity provides broad-spectrum...
Post on 21-Dec-2015
213 views
TRANSCRIPT
1
Lecture #12 – Animal Immune Systems
2
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…
3
Some definitions….
• Pathogen = anything that causes diseaseMicrobes (bacteria, protozoans), viruses, fungal
spores, pollen, dust mites, etc Secretions (venoms, animal saliva)Non-self tissue cells (transplant rejections)Some cancer cells
• Antigens = cell surface proteins and other molecules that the body recognizes as non-self
Generates
Pathology
Generates
Antibodies
Pathogens have Antigens
4
Schematic of the human immune
system
The immune system is spread diffusely
throughout the body – a system of organs, nodes and lymph
vessels
5
Diagram of the blood cells
Remember, the white blood cells are the defenders
6
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
7
Table showing the stages of defense
Defense is step-wise• 90% of pathogens are neutralized by
innate immunityMultiple strategies to destroy pathogens
• Any remaining pathogens are normally attacked by the acquired immune system
8
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
9
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
Sweeping cilia in trachea
10
Innate Immunity – internal defenses
• Sometimes pathogens get past the barriers and into the tissues
• Non-specific WBC’s attackNeutrophilsMonocytes macrophagesDendritic cellsEosinophilsBasophils
11
Innate Immunity – internal defenses
• Phagocytic WBC’s cells ingest and destroy microbes in the tissuesNeutrophils – the most
abundant, but short-livedMacrophages develop from
monocytes – large and long-lived
Dendritic cells – mostly function to stimulate the acquired immune system
12
Model of a macrophage ingesting a fungal spore
13
Micrograph of macrophage ingesting bacteria
14
Innate Immunity – internal defenses
• Eosinophils destroy multi-cellular parasites by releasing toxic enzymesAlso contribute to allergic
responses
• Basophils contribute to inflammatory and allergic responses
Schistosoma mansoni
15
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 virusesDefensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells and cancer cells
• The inflammatory response
16
Diagram showing complement protein function
Complement Protein Function:these proteins complement other
immune system processes
17
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 virusesDefensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells and cancer cells
• The inflammatory response
18
Diagram of interferon activity
Interferons initiate production of proteins that inhibit viral reproduction
19
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 virusesDefensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells and cancer cells
• The inflammatory response
20
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 virusesDefensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells and cancer cells
• The inflammatory response
21
A natural killer cell (yellow) attacking a cancer cell (red).
22
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 virusesDefensins are secreted by macrophages,
attack pathogens
• Natural killer cells attack virus-infected cells and cancer cells
• The inflammatory response
23
Diagram of 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
24
Invertebrates Also Have InnateDefense 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 memoryLittle capacity for acquired immunity as seen in
vertebrates
25
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
26
Acquired Immunity
• Develops over time, in response to exposure to pathogens
• Highly specific – lymphocytes develop that match each incoming pathogenB cells and T cellsCirculate 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
27
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 systemEvery heart beat pushes blood, and any
pathogens it carries, past the immune system structures
28
The next 3 slides show the relationship between the capillary
beds and the lymph vessels
29
30
31
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 systemEvery heart beat pushes blood, and any
pathogens it carries, past the immune system structures
32
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 antigensBecause of this, there are usually several different
lymphocytes that recognize and respond to the pathogen
• Antigens have specific binding sites = epitopes
33
Diagram showing structure of the cell membrane
Membranes are complex, with many surface molecules
34
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 antigensBecause of this, there are usually several different
lymphocytes that recognize and respond to the pathogen
• Antigens have specific binding sites = epitopes
35
Diagram showing epitope structure
Epitopes are the specific binding sites found on all antigens
36
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 typeEach B or T cell recognizes a single epitope
• The receptor molecules and recognition process are different for B cells vs. T cellsBoth types of receptors are protein-basedBoth have both constant and variable regions
37
38
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 typeEach B or T cell recognizes a single epitope
• The receptor molecules and recognition process are different for B cells vs. T cellsBoth types of receptors are protein-basedBoth have both constant and variable regions
39
Diagram showing the receptor molecules in B cells and T cells.This diagram is used several times in the next sequence of slides.
Constant regions have stable amino acid sequences from cell to cell;
Variable regions have different amino acid sequences from cell to cell
40
Antigen Recognition – B Cells
• B cell receptors are Y-shaped• Each branch of the “Y” has 2 parts, called
chainsInner, heavy chain makes the full “Y”Outer, light chain is located on the branches of
the “Y”Both chains are proteinsChains are linked by chemical bonds
• The bottom of the “Y” is anchored in the B cell membrane
41
B Cell Receptor Structure
42
The protein structure of a B cell receptor
43
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 sequencesThese variable ends are the antigen binding
sitesThey bind directly to the epitopesB cells recognize unaltered antigens!
44
B Cell Receptor Structure
45
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
46
47
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 moleculeMHC 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
48
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.
MHC – self-cell proteins
49
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 moleculeMHC 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
50
Development of MHC Variation
• MHC alleles are numerousMany 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 knownAlmost 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 moleculesMHC molecules are unique to the “self”Help to distinguish “self” from “non-self” cells
51
Development of MHC Variation
• MHC alleles are numerousMany 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 knownAlmost 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 moleculesMHC molecules are unique to the “self”Help to distinguish “self” from “non-self” cells
52
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 moleculeMHC 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
53
Two classes of MHC molecules: each found in a different type of
antigen presenting cell
54
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
55
Antigen Presentation – Class I MHC
molecules are presented on
infected or cancerous cells
56
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
57
Antigen Presentation – Class II MHC molecules are presented on
phagocytic cells
58
In both cases, the T cell recognizes ONLY THE COMBINATION of antigen + self-protein
59
Review: B and T Cell ReceptorsB cell receptors bind directly to antigen on intact pathogen
T cell receptors bind to MHC+antigen complex on
self-cells
60
Review: B and T Cell ReceptorsRemember – both B and T cells have multiple
receptors per cell (as many as 100,000), all identical
61
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…
62
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)
63
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 systemSome circulate constantly
through blood, lymph and interstitial fluids
64
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
65
Lymphocyte (B & T cell) DevelopmentStep 1 – generation of diversity
• The genes that code for the antigen receptors are randomly rearranged by enzymes during lymphocyte maturationThese 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 cellsThese chains are then linked together to form the
T cell receptor molecule
66
Diagram showing the development of diversity in the receptors of a B cell. This diagram is used repeatedly
in the next sequence of slides.
Example: gene re-alignment for the light chain of a B cell receptor.
67
68
The coding gene has 40 variable (V) segments and 5 joining (J) segments
69
During differentiation of each B cell, one V segment is snipped out and attached to
one J segment.
Recombinase enzymes randomly snip and join!
70
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.
71
The V+J segment is attached via an intron to the C segment that codes for the constant region of the light chain.
72
This “new” gene is processed and translated into the protein that makes up the light chain
73
The DNA coding for the heavy chain goes through the same kind of random
rearrangement process, but there are more V regions
74
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!!!
75
76
Lymphocyte (B & T cell) DevelopmentStep 1 – generation of diversity
• The genes that code for the antigen receptors are randomly rearranged by enzymes during lymphocyte maturationThese 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 cellsThese chains are then linked together to form the
T cell receptor molecule
77
Lymphocyte (B & T cell) DevelopmentStep 2 – testing and removal
• The rearrangement process is entirely random
• Each new receptor is “tested” against self-cells – both during development and during migration into lymph system organs
• Receptors that bind to self-cells or self-MHC molecules are eliminated or deactivated
78
Critical Thinking
• Why would testing be so important???
79
Critical Thinking
• Why would testing be so important???
80
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
81
Lymphocyte (B & T cell) DevelopmentStep 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
82
Critical Thinking
• How are incoming pathogens exposed to these myriad B and T cells???
83
Critical Thinking
• How are incoming pathogens exposed to these myriad B and T cells???
84
Diagram showing clonal expansion of selected B cell
Lymphocyte (B & T cell) DevelopmentStep 3 – clonal selection
• When a lymphocyte receptor encounters a matching epitope, the lymphocyte is activated
• Activation = stimulation of the lymphocyte to begin mitotic cloning
85
Lymphocyte (B & T cell) DevelopmentStep 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 epitopeMemory cells allow for rapid response to that
same pathogen the next time it enters the bodyMemory cells confer active immunity
86
Diagram showing clonal expansion of selected B cell
Clones divide into
two populations: effector and
memory
87
Lymphocyte (B & T cell) DevelopmentStep 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 epitopeMemory cells allow for rapid response to that
same pathogen the next time it enters the bodyMemory cells confer active immunity
88
Graph showing accumulation of memory cells after repeated exposures.
Step 3 – clonal selectionMemory cells accumulate over repeated
exposure to the same pathogen
EX is for B cells;T cells also accumulate
89
Critical thinking
• If the immune system response is so rapidly initiated, why do we ever get sick???
90
Critical thinking
• If the immune system response is so rapidly initiated, why do we ever get sick???
91
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…
92
Diagram showing how B cell and T cell functions are integrated
Integrated B and T Cell Function
93
Simultaneous
94
Diagram of helper T cell binding to antigen presenting cell.
Helper T Cell Function
• Nearly all antigens activate helper T cells
• Dendritic phagocytes 1o activate naïve helper T cells Important in primary
immune response
• Macrophages 1o activate memory helper T cells Important in secondary
immune response
95
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
96
Diagram showing activated helper T cell functions.
Active helper T cells stimulate the rest of the immune system:
both cytotoxic T cells and B cells
97
Diagram showing cytotoxic T cell function
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
98
B Cell Function
• Remember, B cells recognize and bind to specific intact pathogens
• B cells also engulf some pathogens by phagocytosisAntigens are presented on the B cell surfaceThese antigens are recognized by helper T
cellsHelper T cells activate the B cell
• Only its one specific antigen can be presented by each type of B cell
99
Some B cells are activated directly by exposure to the antigen
100
B Cell Function
• Remember, B cells recognize and bind to specific intact pathogens
• B cells also engulf some pathogens by phagocytosisAntigens are presented on the B cell surfaceThese antigens are recognized by helper T
cellsHelper T cells activate the B cell
• Only its one specific antigen can be presented by each type of B cell
101
Diagram showing an activated helper T activating a B cell
Most B cells are activated by proteins secreted from active helper T cells
102
B Cell Function
• Remember, B cells recognize and bind to specific intact pathogens
• B cells also engulf some pathogens by phagocytosisAntigens are presented on the B cell surfaceThese antigens are recognized by helper T
cellsHelper T cells activate the B cell
• Only its one specific antigen can be presented by each type of B cell
103
Diagram showing secretion of antibodies from activated B cell
B Cell Function• Activated B cells form 2 clones – plasma
cells and memory cells• Plasma cells release antibodies
104
Table of antibodies and their functions
Antibodies
• Each activated B cells produces thousands of clones
• Each clonal B cell releases nearly a billion antibodies2000 antibodies
per secondEach B cell has a
4 – 5 day life span
105
Antibodies
• Five classes of antibodies are secreted
• Each recognizes and attacks specific pathogens
• Read through this table for understanding; don’t memorize
106
Antibodies
• Only one antibody per type of B cellBut remember,
most pathogens have multiple antigens with multiple epitopes
Many B cells are activated
107
Diagram showing how antibodies work
Antibody Mediated Pathogen Disposal
108
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
109
Active vs. Passive Immunity
• Active immunity is generated when the acquired immune system is activatedMemory cells are generatedExposure to pathogen OR vaccination with
inactivated pathogen that still retains antigensConfers long-term protection (often, lifetime)
• Passive immunity is generated when antibodies alone are transferredDoes not generate memory cellsAntibodies cross placenta; are injectedShort-term protection
110
Critical Thinking
• What would be the advantage of passive immunity???
111
Critical Thinking
• What would be the advantage of passive immunity???
112
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…
113
Immune System Failure
• Allergic responsesHypersensitive response to allergenic antigensAntibody tails bind to mast cellsExposure causes massive histamine release
• Autoimmune diseasesImmune system fails to distinguish self-cells
• Immunodeficiency diseasesImmune system failsCan be genetic, developmental, or acquiredAIDS; also some cancers, chemotherapy, stress
114
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…..
115
Immune System Failure
• Allergic responsesHypersensitive response to allergenic antigensAntibody tails bind to mast cellsExposure causes massive histamine release
• Autoimmune diseasesImmune system fails to distinguish self-cells
• Immunodeficiency diseasesImmune system failsCan be genetic, developmental, or acquiredAIDS; also some cancers, chemotherapy, stress
116
Rheumatoid Arthritis
117
Diabetes
118
Multiple Sclerosis
119
Lupus
120
Immune System Failure
• Allergic responsesHypersensitive response to allergenic antigensAntibody tails bind to mast cellsExposure causes massive histamine release
• Autoimmune diseasesImmune system fails to distinguish self-cells
• Immunodeficiency diseasesImmune system failsCan be genetic, developmental, or acquiredAIDS; also some cancers, chemotherapy, stress
121
T Cell HIV
122
Graph showing relationship between HIV concentration, antibody concentration and T cell concentration over time.
2007 – 40 million people are infected by HIV; 15 million children have been orphaned by AIDS
123
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…