1 Lecture #12 – Animal Immune Systems. 2 Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very.

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Lecture #12 – Animal Immune Systems

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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….

• 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

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Schematic of the human immune

system

The immune system is spread diffusely

throughout the body – a system of organs, nodes and lymph

vessels

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Diagram of the blood cells

Remember, the white blood cells are the defenders

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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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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

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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

Sweeping cilia in trachea

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Innate Immunity – internal defenses

• Sometimes pathogens get past the barriers and into the tissues

• Non-specific WBC’s attackNeutrophilsMonocytes macrophagesDendritic cellsEosinophilsBasophils

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• 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

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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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• Eosinophils destroy multi-cellular parasites by releasing toxic enzymesAlso contribute to allergic

responses

• Basophils contribute to inflammatory and allergic responses

Schistosoma mansoni

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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 virusesDefensins are secreted by macrophages,

attack pathogens

• Natural killer cells attack virus-infected cells and cancer cells

• The inflammatory response

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Diagram showing complement protein function

Complement Protein Function:these proteins complement other

immune system processes

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attack pathogens



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Diagram of interferon activity

Interferons initiate production of proteins that inhibit viral reproduction

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attack pathogens



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attack pathogens



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A natural killer cell (yellow) attacking a cancer cell (red).

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attack pathogens



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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

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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

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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 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

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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 systemEvery 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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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

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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 antigensBecause 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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Diagram showing structure of the cell membrane

Membranes are complex, with many surface molecules

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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 antigensBecause 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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Diagram showing epitope structure

Epitopes are the specific binding sites found on all antigens

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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

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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

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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

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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

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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 sequencesThese variable ends are the antigen binding

sitesThey bind directly to the epitopesB cells recognize unaltered antigens!

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B Cell Receptor Structure

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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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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

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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

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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

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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

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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

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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 ReceptorsB cell receptors bind directly to antigen on intact pathogen

T cell receptors bind to MHC+antigen complex on

self-cells

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Review: B and T Cell ReceptorsRemember – both B and T cells have multiple

receptors per cell (as many as 100,000), all identical

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Key Concepts:







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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)

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• 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

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• 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

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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

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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.

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The coding gene has 40 variable (V) segments and 5 joining (J) segments

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During differentiation of each B cell, one V segment is snipped out and attached to

one J segment.

Recombinase enzymes randomly snip and join!

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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.

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The V+J segment is attached via an intron to the C segment that codes for the constant region of the light chain.

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This “new” gene is processed and translated into the protein that makes up the light chain

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The DNA coding for the heavy chain goes through the same kind of random

rearrangement process, but there are more V regions

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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!!!

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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

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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

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Critical Thinking

• Why would testing be so important???

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Critical Thinking

• Why would testing be so important???

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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

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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

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Critical Thinking

• How are incoming pathogens exposed to these myriad B and T cells???

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Critical Thinking

• How are incoming pathogens exposed to these myriad B and T cells???

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Diagram showing clonal expansion of selected B cell


• When a lymphocyte receptor encounters a matching epitope, the lymphocyte is activated

• Activation = stimulation of the lymphocyte to begin mitotic cloning

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• 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

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Diagram showing clonal expansion of selected B cell

Clones divide into

two populations: effector and

memory

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• 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

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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

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Critical thinking

• If the immune system response is so rapidly initiated, why do we ever get sick???

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Critical thinking

• If the immune system response is so rapidly initiated, why do we ever get sick???

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Key Concepts:







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Diagram showing how B cell and T cell functions are integrated

Integrated B and T Cell Function

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Simultaneous

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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

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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

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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

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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

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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

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Some B cells are activated directly by exposure to the antigen

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B Cell Function





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Diagram showing an activated helper T activating a B cell

Most B cells are activated by proteins secreted from active helper T cells

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B Cell Function





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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

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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

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Antibodies

• Five classes of antibodies are secreted

• Each recognizes and attacks specific pathogens

• Read through this table for understanding; don’t memorize

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Antibodies

• Only one antibody per type of B cellBut remember,

most pathogens have multiple antigens with multiple epitopes

Many B cells are activated

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Diagram showing how antibodies work

Antibody Mediated Pathogen Disposal

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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

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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

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Critical Thinking

• What would be the advantage of passive immunity???

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Critical Thinking

• What would be the advantage of passive immunity???

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Key Concepts:







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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

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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…..

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Rheumatoid Arthritis

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Diabetes

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Multiple Sclerosis

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Lupus

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T Cell HIV

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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

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REVIEW – Key Concepts:







1 Lecture #12 – Animal Immune Systems. 2 Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very.

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