HS 345: HUMAN PHYSIOLOGY

WILMINGTON COLLEGE

LISA REGULA MEYER

Cellular Immunity

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Properties of Immunity

1. Specificity

2. Versatility

3. Memory

4. Tolerance

Immunity

Response to threats on anindividualized basis

Adaptive Immunity

Active Immunity Passive Immunity

Adaptive immunity is not present at birth; youacquire immunity to a specific antigen only whenyou have been exposed to that antigen or receiveantibodies fromanother source.

Develops in responseto antigen exposure

Develops afterexposure toantigens inenvironment

Develops afteradministration ofan antigen toprevent disease

Conferred bytransfer of maternalantibodies across placenta or inbreast milk

Conferred byadministration ofantibodies tocombat infection

Naturally acquiredactive immunity

Artificially inducedactive immunity

Naturally acquiredpassive immunity

Artificially inducedpassive immunity

Geneticallydetermined−noprior exposure orantibodyproductioninvolved

Innate Immunity

Produced by transferof antibodies fromanother source

Adaptive Defenses

Cell-MediatedImmunity

Direct Physical andChemical Attack

Antibody-MediatedImmunity

Attack by CirculatingAntibodies

Destructionof antigens

Phagocytesactivated

T cellsactivated

Communicationand feedback

Antigen presentationtriggers specificdefenses, or animmune response.

Activated Bcells give riseto cells thatproduceantibodies.

Activated T cells findthe pathogens andattack them throughphagocytosis or therelease of chemicaltoxins.

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Major Components of Cellular Immunity

CytokinesMHC proteinsLymphocytes

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Cytokines

Chemical messengers released by tissue cells

To coordinate local activities

To act as hormones to affect whole body

Four Functions of Cytokines

1. Stimulate T cell divisions

Produce memory TH cells

Accelerate cytotoxic T cell maturation

1. Attract and stimulate macrophages

2. Attract and stimulate activity of cytotoxic T cells

3. Promote activation of B cells

Alpha (α)-interferons areproduced by cells infectedwith viruses. They attractand stimulate NK cells andenhance resistance to viralinfection.

Beta (β)-interferons,secreted by fibroblasts,slow inflammation in adamaged area.

Gamma (γ)-interferons,secreted by T cells and NKcells, stimulatemacrophage activity.

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MHC Proteins

The membrane glycoproteins that bind to antigens

Genetically coded in chromosome 6

The major histocompatibility complex (MHC)

Differs among individuals

Antigen PresentationT cells only recognize antigens that are bound to

glycoproteins in plasma membranes

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Two Classes of MHC Proteins

Class I Found in membranes of all nucleated cells

Class II Found in membranes of antigen-presenting cells (APCs)

Found in lymphocytes

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Class I MHC Proteins Pick up small peptides in cell and carry them to the surface

T cells ignore normal peptides

Abnormal peptides or viral proteins activate T cells to destroy cell

Antigen presentationby Class I MHCproteins is triggered byviral or bacterialinfection of a body cell.

The infection resultsin the appearance ofabnormal peptides inthe cytoplasm.

The abnormal peptidesare incorporated intoClass I MHC proteinsas they are synthesizedat the endoplasmicreticulum.

Plasma membrane

Viral or bacterialpathogen

Transportvesicle

Endoplasmicreticulum

Nucleus

The abnormalpeptides aredisplayed by Class IMHC proteins on theplasma membrane.

After export to theGolgi apparatus, theMHC proteins reachthe plasmamembrane withintransport vesicles.

Infected cell

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Class II MHC Proteins Antigenic Fragments

From antigenic processing of pathogens

Bind to Class II proteins

Inserted in plasma membrane to stimulate T cells

Antigen-Presenting Cells (APCs) Responsible for activating T cells against foreign cells and

proteins

Antigenic fragments aredisplayed by Class IIMHC proteins on theplasma membrane.

Antigenic fragments are bound to Class IIMHC proteins.

The endoplasmicreticulum producesClass II MHC proteins.

Plasmamembrane

Endoplasmicreticulum

NucleusLysosome

Phagocytic antigen-presenting cell

Lysosomal actionproduces antigenicfragments.

Phagocytic APCsengulf the extracellularpathogens.

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Lymphocytes

Lymphoid Stem Cells

Group 1

Remains in bone marrow and develop with help of stromal cells

Produces B cells and natural killer cells

Group 2

Migrates to thymus

Produces T cells in environment isolated by blood–thymus

barrier

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T Cells make up 80% of circulating lymphocytes

Cytotoxic Attack cells infected by viruses Produce cell-mediated immunity

Memory Formed in response to foreign substance Remain in body to give “immunity”

Helper* Stimulate function of T cells and B cells

Suppressor* Inhibit function of T cells and B cells

*Regulatory T Cells control sensitivity of immune response

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Overview

Antigen presentationAntigen recognitionT Cell activation

Antigen binding Co-stimulation

T Cell proliferationT Cell differentiation

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Cell-Mediated Immune Response

Antigen Presentation First step in immune response

Extracted antigens are “presented” to lymphocytes

Or attached to dendritic cells to stimulate lymphocytes

Can be phagocytic or non-phagocytic antigen-presenting

cells

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Antigen Recognition Inactive T cell receptors

Recognize Class I or Class II MHC proteins

Recognize a specific foreign antigen

Double recognition

Binding occurs when MHC protein matches antigen

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CD Markers Also called cluster of differentiation markers

In T cell membranes

Molecular mechanism of antigen recognition

More than 70 types

Designated by an identifying number

CD3 Receptor Complex Found in all T cells

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• Two Important CD Markers1. CD8 Markers Found on cytotoxic T cells and

suppressor T cells Respond to antigens on Class I MHC

proteins

1. CD4 Markers Found on helper T cells Respond to antigens on Class II MHC

proteins

CD8 or CD4 Markers Bind to CD3 receptor complex Prepare cell for activation

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Co-Stimulation

For T cell to be activated, it must be

costimulated

By binding to stimulating cell at

second site

Which confirms the first signal

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Proliferation and Differentiation

After activation, activated T cells enlarge and multiply

Newly expanded population of T cells differentiate into Cytotoxic T cells Memory T cells Regulatory T cells

Suppressor T cells Helper T cells

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Activation of CD8 T Cells

Activation of CD8 T Cells Activated by exposure to antigens on MHC proteins

One responds quickly

Producing cytotoxic T cells and memory T cells

The other responds slowly

Producing suppressor T cells

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Cytotoxic T Cells

Seek out and immediately destroy target cells

1. Release perforin

To destroy antigenic plasma membrane

1. Secrete poisonous lymphotoxin

To destroy target cell

1. Activate genes in target cell

That cause cell to die

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Memory T Cells

Produced along with cytotoxic T cells

Stay in circulation

Immediately form cytotoxic T cells if same antigen

appears again

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Suppressor T Cells

Secrete suppression factors

Inhibit responses of T and B cells

Act after initial immune response

Limit immune reaction to single stimulus

Antigen Recognition Activation andCell Division

Infected cell

InactiveCD8

T cell

Viral orbacterial antigen

Antigen recognition occurswhen a CD8 T cell encountersan appropriate antigen on thesurface of another cell, boundto a Class I MHC protein.

Antigen recognition resultsin T cell activation and celldivision, producing active TC

cells and memory TC cells.

Active TC cell

Memory TC cells(inactive)

Infectedcell

CD8protein

Class IMHC

T cellreceptor

CD8T cell

Antigen

CostimulationactivatesCD8 T cell

Before activationcan occur, aT cell must bechemically orphysicallystimulated bythe abnormaltarget cell.

Costimulation

Destruction of Target Cells

The active TC cell destroys theantigen-bearing cell. It may useseveral different mechanisms tokill the target cell.

Lysedcell

Perforin release Destruction ofplasma membrane

Stimulation ofapoptosis

Disruption of cellmetabolism

Cytokine release

Lymphotoxin release

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Activation of CD4 T Cells

Active helper T cells (TH cells)

Secrete cytokines

Memory helper (TH) cells

Remain in reserve

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Antigen Recognition by CD4 T Cell

Foreign antigen

Antigen-presentingcell (APC)

Class II MHCAPC

Antigen

T cell receptor

Costimulation

CD4 protein

TH cell

InactiveCD4 (TH)cell

CD4 T Cell Activation and Cell Division

Memory TH cells(inactive)

Active TH cells

Cytokines

Active helper T cells secretecytokines that stimulate bothcell-mediated andantibody-mediated immunity.

Cytokines

Cytokines

Activation by Class I MHC proteins

Antigen bound toClass I MHC protein

Indicates that the cell is infectedor otherwise abnormal

CD8 T Cells

Cytotoxic T Cells Memory TC Cells

Attack and destroyinfected and

abnormal cellsdisplaying antigen

Awaitreappearanceof the antigen

Control or moderateimmune response by

T cells and B cells

Suppressor T Cells

Activation by Class II MHC proteins

Helper T Cells

Stimulate immuneresponse by

T cells and B cells

Awaitreappearanceof the antigen

Memory TH Cells

CD4 T Cells

Indicates presence of pathogens,toxins, or foreign proteins

Antigen bound toClass II MHC protein

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B Cell Sensitization

Corresponding antigens in interstitial fluids bind to B cell receptors

B cell prepares for activation Preparation process is sensitization During sensitization, antigens are:

Taken into the B cell Processed Reappear on surface, bound to Class II MHC protein

Sensitization

SensitizedB cell

Antigenbinding

Antigens bound toantibody molecules

Antigens

Class II MHC

Antibodies

Inactive B cell

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Helper T Cells Sensitized B cell is prepared for activation but needs helper T

cell activated by same antigen

B Cell Activation Helper T cell binds to MHC complex

Secretes cytokines that promote B cell activation and division

Activation

Cytokinecostimulation

Helper T cell

T cell

SensitizedB cell

B cell

Class II MHC T cell receptor

Antigen

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B Cell Division

Activated B cell divides into:

Plasma cells

Memory B cells

Division and Differentiation

Plasma cells

ANTIBODYPRODUCTION

Activated B cells

Memory B cells(inactive)

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Plasma Cells Synthesize and secrete antibodies into interstitial fluid

Memory B Cells Like memory T cells, remain in reserve to respond to next

infection

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Pathologies of Cellular Immunity

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Antibody Structure

Two parallel pairs of polypeptide chains

One pair of heavy chains

One pair of light chains

Each chain contains:

Constant segments

Variable segments

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Heavy-Chain Constant Segments

Determine five types of antibodies

1. IgG

2. IgE

3. IgD

4. IgM

5. IgA

Are found in body fluids

Are determined by constant segments

Have no effect on antibody specificity

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Variable Segments of Light and Heavy Chains Determine specificity of antibody molecule

Binding Sites Free tips of two variable segments

Form antigen binding sites of antibody molecule Which bind to antigenic determinant sites of antigen

molecule

Antigen–Antibody Complex An antibody bound to an antigen

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Antigen-Antibody Complex

A Complete Antigen Has two antigenic determinant sites

Binds to both antigen-binding sites of variable segments of antibody

B Cell Sensitization Exposure to a complete antigen leads to:

B cell sensitization

Immune response

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Haptens

Partial Antigens Must attach to a carrier molecule to act as a complete antigen

Dangers of Haptens

Antibodies produced will attack both hapten and carrier molecule

If carrier is “normal”:

Antibody attacks normal cells

For example, penicillin allergy

Antigenbinding

site

Variablesegment

Constantsegments

of lightand heavy

chains

Heavy chain

Disulfidebond

Antigenbinding site

Light chain

Complementbinding site

Site of bindingto macrophages

A diagrammatic view of the structure of an antibody.

A computer-generated image of atypical antibody.

Lightchain

Heavychain

Antigenbinding site

Antigen

Antigenicdeterminant

sites

Antibodies

Antibodies bind to portions ofan antigen called antigenicdeterminant sites, or epitopes.

Antibody molecules can bind ahapten (partial antigen) once it hasbecome a complete antigen bycombining with a carrier molecule.

Completeantigen

HaptenCarrier

molecule

Immunoglobulin Classes

IgG is the largest and most diverse class of antibodies

80 percent of all antibodies IgG antibodies are responsible for resistance

against many viruses, bacteria, and bacterial toxins

Can cross the placenta, and maternal IgG provides passive immunity to fetus during embryological development

Anti-Rh antibodies produced by Rh-negative mothers are also IgG antibodies and produce hemolytic disease of the newborn

Immunoglobulin Classes

IgE attaches as an individual molecule to the exposed surfaces of basophils and mast cells

When an antigen is bound by IgE molecules: The cell is stimulated to release histamine and other

chemicals that accelerate inflammation in the immediate area

IgE is also important in the allergic response

Immunoglobulin Classes

IgD is an individual molecule on the surfaces of B cells, where it can bind antigens in the extracellular fluid

Binding can play a role in the sensitization of the B cell involved

Immunoglobulin Classes

IgM is the first class of antibody secreted after an antigen is encountered

IgM concentration declines as IgG production accelerates

Plasma cells secrete individual IgM molecules, but it polymerizes and circulates as a five-antibody starburst

The anti-A and anti-B antibodies responsible for the agglutination of incompatible blood types are IgM antibodies

IgM antibodies may also attack bacteria that are insensitive to IgG

Immunoglobulin Classes

IgA is found primarily in glandular secretions such as mucus, tears, saliva, and semen

Attack pathogens before they gain access to internal tissues

IgA antibodies circulate in blood as individual molecules or in pairs

Epithelial cells absorb them from blood and attach a secretory piece, which confers solubility, before secreting IgA molecules onto the epithelial surface

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Functions of Antigen-Antibody Complexes

1. Neutralization of antigen binding sites

2. Precipitation and agglutination - formation of immune complex

3. Activation of complement

4. Attraction of phagocytes

5. Opsonization increasing phagocyte efficiency

6. Stimulation of inflammation

7. Prevention of bacterial and viral adhesion

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Responses to Antigen Exposure

Occur in both cell-mediated and antibody-mediated immunity

First exposure Produces initial primary response

Next exposure Triggers secondary response More extensive and prolonged Memory cells already primed

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Primary Response

Takes time to develop

Antigens activate B cells

Plasma cells differentiate

Antibody titer (level) slowly rises

Peak response can take two weeks to develop Declines rapidly

IgM Is produced faster than IgG

Is less effective

Time (weeks)

IgGIgM

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Secondary Response

Activates memory B cells

At lower antigen concentrations than original B cells

Secrete antibodies in massive quantities

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Memory B Cell Activation

IgG Rises very high and very quickly Can remain elevated for extended time

IgM Production is also quicker Slightly extended

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Combined Responses to Bacterial Infection

Neutrophils and NK cells begin killing bacteria

Cytokines draw phagocytes to area

Antigen presentation activates:

Helper T cells

Cytotoxic T cells

B cells activate and differentiate

Plasma cells increase antibody levels

Neutrophils Macrophages Plasma cells

Antibodytiter

CytotoxicT cells

Naturalkiller cells

Time (weeks)

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Combines Responses to Viral Infection

Similar to bacterial infection

But cytotoxic T cells and NK cells are activated by contact

with virus-infected cells

BACTERIA

Phagocytosis bymacrophages and APCs

Antigenpresentation

Activation ofcytotoxic T cells

Activation ofhelper T cells

Activation of B cells

Antibodyproduction byplasma cells

Destruction ofbacteria bycell lysis or

phagocytosis

Opsonizationand phagocyte

attraction

Formation ofantigen−antibody

complexes

Defenses against bacteria involve phagocy-tosis and antigen presentation by APCs.

Release of interferons

Infection oftissue cells

Appearance of antigenin plasma membrane

Infection of or uptakeby APCs

VIRUSES

Antigenpresentation

Activation ofhelper T cells

Activation of B cells

Antibodyproduction byplasma cells

Destruction ofviruses or

prevention ofvirus entry into cells

Increasedresistance toviral infection

and spread

Stimulationof NK cells

Activation ofcytotoxic T cells

Destruction ofvirus-infected cells

Defenses against viruses involves direct contact with virus-infected cellsand antigen presentation by APCs.