mechanism of phagocytosis figure 21.1a, b natural killer (nk) cells cells that can lyse and kill...

Mechanism of Mechanism of PhagocytosisPhagocytosis

Figure 21.1a, b

Natural Killer (NK) CellsNatural Killer (NK) Cells

Cells that can lyse and kill cancer cells Cells that can lyse and kill cancer cells and virus-infected cellsand virus-infected cells

Natural killer cells: Natural killer cells: Are a small, distinct group of large granular Are a small, distinct group of large granular

lymphocytes lymphocytes React nonspecifically and eliminate cancerous React nonspecifically and eliminate cancerous

and virus-infected cellsand virus-infected cells Kill their target cells by releasing perforins and Kill their target cells by releasing perforins and

other cytolytic chemicalsother cytolytic chemicals Secrete potent chemicals that enhance the Secrete potent chemicals that enhance the

inflammatory responseinflammatory response

Immunity: Two Intrinsic Immunity: Two Intrinsic Defense SystemsDefense Systems

Innate (nonspecific) system responds Innate (nonspecific) system responds quickly and consists of:quickly and consists of: First line of defense – intact skin and First line of defense – intact skin and

mucosae prevent entry of microorganismsmucosae prevent entry of microorganisms Second line of defense – antimicrobial Second line of defense – antimicrobial

proteins, phagocytes, and other cells proteins, phagocytes, and other cells Inhibit spread of invaders throughout the bodyInhibit spread of invaders throughout the body Inflammation is its hallmark and most Inflammation is its hallmark and most

important mechanism important mechanism

Immunity: Two Intrinsic Immunity: Two Intrinsic Defense SystemsDefense Systems

Adaptive (specific) defense systemAdaptive (specific) defense system Third line of defense – mounts attack Third line of defense – mounts attack

against particular foreign substancesagainst particular foreign substances Takes longer to react than the innate Takes longer to react than the innate

systemsystem Works in conjunction with the innate systemWorks in conjunction with the innate system

Types of ImmunityTypes of Immunity ActiveActive- uses the - uses the

immune systemimmune system PassivePassive - gives the - gives the

system immunity from system immunity from another sourceanother source

Anti-serumAnti-serum = = antibodyantibodyBlood protein that reacts Blood protein that reacts

with specific substanceswith specific substances

AntigenAntigen- substance that - substance that induces an immune induces an immune response to be response to be initiatedinitiated

UN 16.1 - Overview

Blood ProteinsBlood ProteinsSerum ElectrophoresisSerum Electrophoresis

Albumin - Albumin - most abundant, carries most abundant, carries hormones, metals etc.hormones, metals etc.

Globulins - Globulins - Gamma globulinsGamma globulins - immunity- antibodies. - immunity- antibodies. AntibodyAntibody - Ab half life about 3 weeks. - Ab half life about 3 weeks.

Antigens and AntibodiesAntigens and Antibodies

AntigensAntigens usually usually proteins or proteins or carbohydrates carbohydrates (lipids (lipids and nucleic acids poor and nucleic acids poor unless coupled with proteins unless coupled with proteins or carbohydtrates).or carbohydtrates).

Anitgenic Anitgenic determinants determinants - - region of antigen region of antigen molecule that the molecule that the antibody binds to.antibody binds to.


Haptens- small molecules that bind to large molecules and serve as antigenic determinants. Penicillin binding to serum albumen and be coming antigenic

Flowchart of Events in InflammationFlowchart of Events in Inflammation

The adaptive immune system is a The adaptive immune system is a functional system that:functional system that: Recognizes specific foreign substancesRecognizes specific foreign substances Acts to immobilize, neutralize, or Acts to immobilize, neutralize, or

destroy foreign substancesdestroy foreign substances Amplifies inflammatory response and Amplifies inflammatory response and

activates complementactivates complement

Adaptive (Specific) Adaptive (Specific) DefensesDefenses

The adaptive immune system is The adaptive immune system is antigen-specific, systemic, and has antigen-specific, systemic, and has memorymemory

It has two separate but overlapping It has two separate but overlapping armsarms Humoral, or antibody-mediated Humoral, or antibody-mediated

immunityimmunity Cellular, or cell-mediated immunity Cellular, or cell-mediated immunity

Adaptive Immune DefensesAdaptive Immune Defenses

Substances that can mobilize the Substances that can mobilize the immune system and provoke an immune system and provoke an immune responseimmune response

The ultimate targets of all immune The ultimate targets of all immune responses are mostly large, complex responses are mostly large, complex molecules not normally found in the molecules not normally found in the body (nonself)body (nonself)

AntigensAntigens

Important functional properties:Important functional properties: Immunogenicity – the ability to stimulate Immunogenicity – the ability to stimulate

proliferation of specific lymphocytes and proliferation of specific lymphocytes and antibody productionantibody production

Reactivity – the ability to react with the Reactivity – the ability to react with the products of the activated lymphocytes and products of the activated lymphocytes and the antibodies released in response to themthe antibodies released in response to them

Complete antigens include foreign Complete antigens include foreign protein, nucleic acid, some lipids, and protein, nucleic acid, some lipids, and large polysaccharideslarge polysaccharides

Complete AntigensComplete Antigens

Small molecules, such as peptides, Small molecules, such as peptides, nucleotides, and many hormones, that are nucleotides, and many hormones, that are not immunogenic but are reactive when not immunogenic but are reactive when attached to protein carriersattached to protein carriers

If they link up with the body’s proteins, the If they link up with the body’s proteins, the adaptive immune system may recognize adaptive immune system may recognize them as foreign and mount a harmful them as foreign and mount a harmful attack (allergy)attack (allergy)

Haptens are found in poison ivy, dander, Haptens are found in poison ivy, dander, some detergents, and cosmeticssome detergents, and cosmetics

Haptens (Incomplete Haptens (Incomplete Antigens)Antigens)

Only certain parts of an entire antigen are Only certain parts of an entire antigen are immunogenicimmunogenic

Antibodies and activated lymphocytes bind to Antibodies and activated lymphocytes bind to these antigenic determinantsthese antigenic determinants

Most naturally occurring antigens have Most naturally occurring antigens have numerous antigenic determinants that:numerous antigenic determinants that: Mobilize several different lymphocyte populationsMobilize several different lymphocyte populations Form different kinds of antibodies against itForm different kinds of antibodies against it

Large, chemically simple molecules (e.g., Large, chemically simple molecules (e.g., plastics) have little or no immunogenicityplastics) have little or no immunogenicity

Antigenic DeterminantsAntigenic Determinants

Antigenic DeterminantsAntigenic Determinants

Figure 21.6


Monomer - simplest Antibody with 4 protein chains and 2 binding sites.

2 Heavy and 2 light chains coupled by disulfide (-S-S-) bridges. Variable and Constant regions.

Classes of Antibodies orClasses of Antibodies orImmunoglobulinsImmunoglobulins

Humoral ImmunityHumoral Immunity

Stem cells ---> B - cellB - cell --->

(stimulation) --> Plasma cells

----> Abs (Immunity)

T-cellsT-cells ---> cell mediated immunity


When presented with a previous antigen, that subset (clone) of memory B-cells is stimulated to convert to plasma cells and make Abs.

Humoral ImmunityHumoral ImmunityMecanisms of Ab Protection

1. Agglutination

2. Opsonization

3. Neutralization

4. Activate Complement

5. Inflammation

6. Ab Dependent Cell- Mediated cytotoxicity


The Anamnestic Response

Primary exposure- short duration, moderate response.

Secondary exposure- long duration, larger response.


Monoclonal Antibodies

1. Inject mouse with antigen.

2. Sacrifice mouse remove spleen and mix with myeloma cells.


Monoclonal Antibodies

3. Some cells fuse to form hybridoma cells.

4. Hybridomas produce MAbs. Each clone’s Ab targets same antigenic determinant.

Cellular ImmunityCellular ImmunityTypes of T-Cells

1. TH Helper - CD 4 -antigen presenting cells.

Stimulated by IL-1, it produces IL-2

B-cells stimulated by IL-2, makes Antibodies.

2. TC Cytotoxic - CD8- kill tumor cells.

Stimulated by IL-2, attacks cellular invaders.

3. TD hypersensitivity -cause allergic responses.

4. TS Suppressor - CD 8 - turn off immune response.

5. Null Killer Cell = Rogue Cell finds aberrant and initiates apoptosis = Kervorkian Cell

Since antibodies are useless against Since antibodies are useless against intracellular antigens, cell-mediated intracellular antigens, cell-mediated immunity is neededimmunity is needed

Two major populations of T cells mediate Two major populations of T cells mediate cellular immunitycellular immunity CD4 cells (T4 cells) are primarily helper T cells CD4 cells (T4 cells) are primarily helper T cells

(T(THH) ) CD8 cells (T8 cells) are cytotoxic T cells (TCD8 cells (T8 cells) are cytotoxic T cells (TCC) that ) that

destroy cells harboring foreign antigensdestroy cells harboring foreign antigens Other types of T cells are:Other types of T cells are:

Suppressor T cells (TSuppressor T cells (TSS)) Memory T cells Memory T cells

Cell-Mediated Immune Cell-Mediated Immune ResponseResponse

Major Types of T CellsMajor Types of T Cells

Figure 21.14

T cells recognize and respond only to T cells recognize and respond only to processed fragments of antigen processed fragments of antigen displayed on the surface of body cellsdisplayed on the surface of body cells

T cells are best suited for cell-to-cell T cells are best suited for cell-to-cell interactions, and target:interactions, and target: Cells infected with viruses, bacteria, or Cells infected with viruses, bacteria, or

intracellular parasitesintracellular parasites Abnormal or cancerous cellsAbnormal or cancerous cells Cells of infused or transplanted foreign Cells of infused or transplanted foreign

tissuetissue

Importance of Cellular Importance of Cellular ResponseResponse

Immunocompetent T cells are Immunocompetent T cells are activated when the V regions of their activated when the V regions of their surface receptors bind to a surface receptors bind to a recognized antigenrecognized antigen

T cells must simultaneously T cells must simultaneously recognize:recognize: Nonself (the antigen)Nonself (the antigen) Self (a MHC protein of a body cell)Self (a MHC protein of a body cell)

Antigen Recognition and Antigen Recognition and MHC RestrictionMHC Restriction

Both types of MHC proteins are Both types of MHC proteins are important to T cell activationimportant to T cell activation

Class I MHC proteinsClass I MHC proteins Always recognized by CD8 T cellsAlways recognized by CD8 T cells Display peptides from endogenous Display peptides from endogenous

antigens antigens

MHC ProteinsMHC Proteins

Endogenous antigens are:Endogenous antigens are: Degraded by proteases and enter the Degraded by proteases and enter the

endoplasmic reticulumendoplasmic reticulum Transported via TAP (Transported via TAP (ttransporter ransporter

associated with associated with aantigen ntigen pprocessing)rocessing) Loaded onto class I MHC moleculesLoaded onto class I MHC molecules Displayed on the cell surface in Displayed on the cell surface in

association with a class I MHC moleculeassociation with a class I MHC molecule

Class I MHC ProteinsClass I MHC Proteins

Class I MHC ProteinsClass I MHC Proteins

Figure 21.15a

Class II MHC proteins are found only Class II MHC proteins are found only on mature B cells, some T cells, and on mature B cells, some T cells, and antigen-presenting cellsantigen-presenting cells

A phagosome containing pathogens A phagosome containing pathogens (with exogenous antigens) merges (with exogenous antigens) merges with a lysosomewith a lysosome

Invariant protein prevents class II Invariant protein prevents class II MHC proteins from binding to MHC proteins from binding to peptides in the endoplasmic reticulumpeptides in the endoplasmic reticulum

Class II MHC ProteinsClass II MHC Proteins

Class II MHC proteins migrate into Class II MHC proteins migrate into the phagosomes where the antigen the phagosomes where the antigen is degraded and the invariant chain is degraded and the invariant chain is removed for peptide loadingis removed for peptide loading

Loaded Class II MHC molecules then Loaded Class II MHC molecules then migrate to the cell membrane and migrate to the cell membrane and display antigenic peptide for display antigenic peptide for recognition by CD4 cellsrecognition by CD4 cells



Figure 21.15b

Provides the key for the immune Provides the key for the immune system to recognize the presence of system to recognize the presence of intracellular microorganismsintracellular microorganisms

MHC proteins are ignored by T cells MHC proteins are ignored by T cells if they are complexed with self if they are complexed with self protein fragments protein fragments

Antigen RecognitionAntigen Recognition

T cell antigen receptors (TCRs):T cell antigen receptors (TCRs): Bind to an antigen-MHC protein Bind to an antigen-MHC protein

complex complex Have variable and constant regions Have variable and constant regions

consisting of two chains (alpha and consisting of two chains (alpha and beta)beta)

T Cell Activation: Step One T Cell Activation: Step One – Antigen Binding– Antigen Binding

MHC restriction – TMHC restriction – THH and T and TCC bind to bind to different classes of MHC proteins different classes of MHC proteins

TTHH cells bind to antigen linked to class cells bind to antigen linked to class II MHC proteinsII MHC proteins

Mobile APCs (Langerhans’ cells) Mobile APCs (Langerhans’ cells) quickly alert the body to the presence quickly alert the body to the presence of antigen by migrating to the lymph of antigen by migrating to the lymph nodes and presenting antigennodes and presenting antigen


TTCC cells are activated by antigen fragments cells are activated by antigen fragments complexed with class I MHC proteinscomplexed with class I MHC proteins

APCs produce co-stimulatory molecules that APCs produce co-stimulatory molecules that are required for Tare required for TCC activation activation

TCR that acts to recognize the self-antiself TCR that acts to recognize the self-antiself complex is linked to multiple intracellular complex is linked to multiple intracellular signaling pathways signaling pathways

Other T cell surface proteins are involved in Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition)maintain coupling during antigen recognition)


T Cell Activation: Step One – Antigen T Cell Activation: Step One – Antigen BindingBinding

Figure 21.16

Before a T cell can undergo clonal Before a T cell can undergo clonal expansion, it must recognize one or more expansion, it must recognize one or more co-stimulatory signalsco-stimulatory signals

This recognition may require binding to This recognition may require binding to other surface receptors on an APCother surface receptors on an APC Macrophages produce surface B7 proteins when Macrophages produce surface B7 proteins when

nonspecific defenses are mobilizednonspecific defenses are mobilized B7 binding with the CDB7 binding with the CD2828 receptor on the receptor on the

surface of T cells is a crucial co-stimulatory surface of T cells is a crucial co-stimulatory signalsignal

Other co-stimulatory signals include Other co-stimulatory signals include cytokines and interleukin 1 and 2cytokines and interleukin 1 and 2

T Cell Activation: Step Two T Cell Activation: Step Two – Co-stimulation– Co-stimulation

Depending on receptor type, co-Depending on receptor type, co-stimulators can cause T cells to stimulators can cause T cells to complete their activation or abort complete their activation or abort activationactivation

Without co-stimulation, T cells:Without co-stimulation, T cells: Become tolerant to that antigenBecome tolerant to that antigen Are unable to divide Are unable to divide Do not secrete cytokines Do not secrete cytokines


T cells that are activated:T cells that are activated: Enlarge, proliferate, and form clonesEnlarge, proliferate, and form clones Differentiate and perform functions Differentiate and perform functions

according to their T cell classaccording to their T cell class


Primary T cell response peaks within a Primary T cell response peaks within a week after signal exposureweek after signal exposure

T cells then undergo apoptosis between T cells then undergo apoptosis between days 7 and 30days 7 and 30

Effector activity wanes as the amount of Effector activity wanes as the amount of antigen declinesantigen declines

The disposal of activated effector cells is The disposal of activated effector cells is a protective mechanism for the bodya protective mechanism for the body

Memory T cells remain and mediate Memory T cells remain and mediate secondary responses to the same antigensecondary responses to the same antigen


Mediators involved in cellular immunity, Mediators involved in cellular immunity, including hormonelike glycoproteins including hormonelike glycoproteins released by activated T cells and released by activated T cells and macrophagesmacrophages

Some are co-stimulators of T cells and T cell Some are co-stimulators of T cells and T cell proliferationproliferation

Interleukin 1 (IL-1) released by Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to:macrophages co-stimulates bound T cells to: Release interleukin 2 (IL-2) Release interleukin 2 (IL-2) Synthesize more IL-2 receptorsSynthesize more IL-2 receptors

CytokinesCytokines

IL-2 is a key growth factor, which IL-2 is a key growth factor, which sets up a positive feedback cycle sets up a positive feedback cycle that encourages activated T cells to that encourages activated T cells to dividedivide It is used therapeutically to enhance the It is used therapeutically to enhance the

body’s defenses against cancerbody’s defenses against cancer Other cytokines amplify and regulate Other cytokines amplify and regulate

immune and nonspecific responsesimmune and nonspecific responses

CytokinesCytokines

Examples include:Examples include: Perforin and lymphotoxin – cell toxinsPerforin and lymphotoxin – cell toxins Gamma interferon – enhances the Gamma interferon – enhances the

killing power of macrophageskilling power of macrophages Inflammatory factorsInflammatory factors

CytokinesCytokines

Regulatory cells that play a central role Regulatory cells that play a central role in the immune responsein the immune response

Once primed by APC presentation of Once primed by APC presentation of antigen, they:antigen, they: Chemically or directly stimulate proliferation Chemically or directly stimulate proliferation

of other T cellsof other T cells Stimulate B cells that have already become Stimulate B cells that have already become

bound to antigenbound to antigen Without TWithout THH, there is no immune response, there is no immune response

Helper T Cells (THelper T Cells (THH))

Helper T Cells (THelper T Cells (THH))

Figure 21.17a

TTHH cells interact directly with B cells that cells interact directly with B cells that have antigen fragments on their surfaces have antigen fragments on their surfaces bound to MHC II receptorsbound to MHC II receptors

TTHH cells stimulate B cells to divide more cells stimulate B cells to divide more rapidly and begin antibody formationrapidly and begin antibody formation

B cells may be activated without TB cells may be activated without THH cells by cells by binding to T cell–independent antigensbinding to T cell–independent antigens

Most antigens, however, require TMost antigens, however, require THH co- co-stimulation to activate B cellsstimulation to activate B cells

Cytokines released by TCytokines released by THH amplify nonspecific amplify nonspecific defensesdefenses

Helper T CellHelper T Cell

Helper T CellsHelper T Cells

Figure 21.17b

TTCC cells, or killer T cells, are the only T cells cells, or killer T cells, are the only T cells that can directly attack and kill other cellsthat can directly attack and kill other cells

They circulate throughout the body in They circulate throughout the body in search of body cells that display the antigen search of body cells that display the antigen to which they have been sensitizedto which they have been sensitized

Their targets include:Their targets include: Virus-infected cellsVirus-infected cells Cells with intracellular bacteria or parasitesCells with intracellular bacteria or parasites Cancer cellsCancer cells Foreign cells from blood transfusions or Foreign cells from blood transfusions or

transplantstransplants

Cytotoxic T Cell (TCytotoxic T Cell (Tcc))

Bind to self-antiself complexes on all body Bind to self-antiself complexes on all body cells cells

Infected or abnormal cells can be destroyed Infected or abnormal cells can be destroyed as long as appropriate antigen and co-as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are presentstimulatory stimuli (e.g., IL-2) are present

Natural killer cells activate their killing Natural killer cells activate their killing machinery when they bind to MICA receptormachinery when they bind to MICA receptor

MICA receptor – MHC-related cell surface MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, protein in cancer cells, virus-infected cells, and cells of transplanted organsand cells of transplanted organs

Cytotoxic T CellsCytotoxic T Cells

In some cases, TIn some cases, TCC cells: cells: Bind to the target cell and release Bind to the target cell and release

perforin into its membraneperforin into its membrane In the presence of CaIn the presence of Ca2+2+ perforin causes cell perforin causes cell

lysis by creating transmembrane poreslysis by creating transmembrane pores Other TOther TCC cells induce cell death by: cells induce cell death by:

Secreting lymphotoxin, which Secreting lymphotoxin, which fragments the target cell’s DNAfragments the target cell’s DNA

Secreting gamma interferon, which Secreting gamma interferon, which stimulates phagocytosis by stimulates phagocytosis by macrophagesmacrophages

Mechanisms of TMechanisms of Tcc Action Action

Mechanisms of TMechanisms of Tcc Action Action

Figure 21.18a, b

Suppressor T cells (TSuppressor T cells (TSS) – regulatory ) – regulatory cells that release cytokines, which cells that release cytokines, which suppress the activity of both T cells suppress the activity of both T cells and B cellsand B cells

Gamma delta T cells (TGamma delta T cells (Tgdgd) – 10% of ) – 10% of all T cells found in the intestines that all T cells found in the intestines that are triggered by binding to MICA are triggered by binding to MICA receptorsreceptors

Other T CellsOther T Cells

Summary of the Primary Summary of the Primary Immune ResponseImmune Response

Figure 21.19

Cellular ImmunityCellular Immunity

Relationship between APC, MHC and Immune ResponseRelationship between APC, MHC and Immune Response

Mac (APC) digests organisms, presents antigens to TH.

TH recruits TC and B-cells.

Cellular ImmunityCellular Immunity

Cell Mediated Cytotoxicity.Cell Mediated Cytotoxicity.

TC recognizes invader cell.

Makes and releases perforin. Cell lyses.

Immunity - Dual SystemsImmunity - Dual Systems

Types of Immune Types of Immune ResponsesResponses

Primarily Humoral, B-Cells

Most common bacteria, free viruses, soluble antigens (like toxins, proteins)

Primarily Cellular, T-Cells

Mycobacteria, tumor cells, virus-infected cells, protozoans, large parasites

mechanism of phagocytosis figure 21.1a, b natural killer (nk) cells cells that can lyse and kill...

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