the immune system: innate and adaptive:body defenses: part a

PowerPoint® Lecture Slides prepared by Janice Meeking, Mount Royal College

C H A P T E R

Copyright © 2010 Pearson Education, Inc.

21The Immune System: Innate and Adaptive:Body Defenses: Part A


Immunity

• Resistance to disease

• Immune system has two intrinsic systems• Innate (nonspecific) defense system

• Adaptive (specific) defense system


Immunity

1. Innate defense system has two lines of defense• First line of defense is external body

membranes (skin and mucosae)• Second line of defense is antimicrobial

proteins, phagocytes, and other cells • Inhibit spread of invaders • Inflammation is its most important

mechanism


Immunity

2. Adaptive defense system • Third line of defense attacks particular

foreign substances

• Takes longer to react than the innate system

• Innate and adaptive defenses are deeply intertwined

Copyright © 2010 Pearson Education, Inc. Figure 21.1

Innatedefenses

Surface barriers• Skin• Mucous membranes

Internal defenses• Phagocytes• NK cells• Inflammation• Antimicrobial proteins• Fever

Humoral immunity• B cells

Cellular immunity• T cells

Adaptivedefenses


Innate Defenses

• Surface barriers• Skin, mucous membranes, and their

secretions

• Physical barrier to most microorganisms

• Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins

• Mucosae provide similar mechanical barriers


Surface Barriers

• Protective chemicals inhibit or destroy microorganisms• Skin acidity (pH of 3 – 5)

• Lipids in sebum and Dermcidin in eccrine sweat glands

• HCl and protein-digesting enzymes of stomach mucosae

• Lysozyme of saliva and lacrimal fluid

• Mucus


Surface Barriers

• Respiratory system modifications• Mucus-coated hairs in the nose

• Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus from lower respiratory passages


Internal Defenses: Cells and Chemicals

• Necessary if microorganisms invade deeper tissues• Phagocytes

• Natural killer (NK) cells

• Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)

• Antimicrobial proteins (interferons and complement proteins)

• Fever


Phagocytes: Macrophages

• Macrophages develop from monocytes to become the chief phagocytic cells

• Free macrophages wander through tissue spaces• E.g., alveolar macrophages

• Fixed macrophages are permanent residents of some organs• E.g., Kupffer cells (liver) and microglia

(brain)


Phagocytes: Neutrophils

• Neutrophils• Become phagocytic on encountering infectious

material in tissues


Mechanism of Phagocytosis

Step 1: Adherence of phagocyte to pathogen • Facilitated by opsonization—coating of

pathogen by complement proteins or antibodies

• In order to adhere the phagocytic cell must recognize and be able to bind to something on the outside of the organism-generally the carbohydrate. Some organisms cannot be bound to like the pneumococcus unless it is already coated – opsonization.

Copyright © 2010 Pearson Education, Inc. Figure 21.2a

(a) A macrophage (purple) uses its cytoplasmicextensions to pull spherical bacteria (green) toward it. Scanning electron micrograph (1750x).

Innate defenses Internal defenses

Copyright © 2010 Pearson Education, Inc. Figure 21.2b

Lysosome

Phagosome(phagocyticvesicle)

Acidhydrolaseenzymes

(b) Events of phagocytosis.

1 Phagocyteadheres to pathogens or debris.

2 Phagocyte formspseudopods that eventually engulf the particles forming a phagosome.

3 Lysosome fuseswith the phagocytic vesicle, forming a phagolysosome.

4 Lysosomal enzymes digest the particles, leaving a residual body.

5 Exocytosis of thevesicle removes indigestible andresidual material.


Mechanism of Phagocytosis • Destruction of pathogens

• Acidification and digestion by lysosomal enzymes – Some organisms cannot be destroyed by the lysosome enzymes – like TB – so a granuloma formed.

• Respiratory burst• Release of cell-killing free radicals• Activation of additional enzymes – generally by

changes in pH (becomes more basic) and osmolarity in the lysosome

• Oxidizing chemicals (e.g. H2O2) • Defensins (in neutrophils) – pierce membrane


Respiratory Burst• Respiratory burst (is sometimes called oxidative burst) is

the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from different types of cells.

• Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi.

• To maximally activate the respiratory burst – T-helper cells stimulate phagocytes

• The respiratory burst also increases the pH and osmolarity in the phagolysosome – thus activating other protein-digesting enzymes that digest the invader.

http://en.wikipedia.org/wiki/Reactive_oxygen_species

http://en.wikipedia.org/wiki/Superoxide

http://en.wikipedia.org/wiki/Hydrogen_peroxide

http://en.wikipedia.org/wiki/Cell_(biology)


Chronic granulomatous disease• a diverse group of hereditary diseases in which certain cells of

the immune system have difficulty forming the reactive oxygen compounds (most importantly, the superoxide radical) used to kill certain ingested pathogens. This leads to the formation of granulomata in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year

• There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease

• There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment children often die in the first decade of life.


Granuloma

Granuloma is a medical term for a roughly spherical mass of immune cells that forms when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as and bacteria and fungi as well as other materials such as keratin and suture fragments. A granuloma is therefore a special type of inflammation that can occur in a wide variety of diseases.


Natural Killer (NK) Cells (CD 16 & CD 56)• Large granular lymphocytes - larger lymphocytes with

small granules (stained vesicles)

• Target cells that lack “self” cell-surface receptors or cells that display wrong MHCI or MICA

• NK cell will not attack if a cell’s LY49 receptor is displayed and can be recognized by the NK cell’s MHCI

• Secrete perforans and granzyme

• Induce apoptosis in cancer cells and virus-infected cells

• Secrete potent chemicals that enhance the inflammatory response


Inflammatory Response

• Triggered whenever body tissues are injured or infected

1. Prevents the spread of damaging agents

2. Disposes of cell debris and pathogens

3. Sets the stage for repair



• Cardinal signs of acute inflammation:

1. Redness

2. Heat

3. Swelling

4. Pain

(And sometimes 5. Impairment of function)



• Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs)

• Eleven recognized TLR

• TLRs recognize specific classes of infecting microbes – like Salmonella and TB

• Activated TLRs trigger the release of cytokines that promote inflammation and attract WBCs



• Inflammatory mediators• Histamine (from mast cells and Basophils)

• Blood proteins

• Kinins, prostaglandins (PGs), leukotrienes, and complement

• Singulair is a leukotriene inhibitor

• Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells


Vasodilation and Increased Vascular Permeability• Inflammatory chemicals cause

• Dilation of arterioles, resulting in hyperemia

• Increased permeability of local capillaries and edema (leakage of exudate) – edema helps with sweep of organisms and chemicals into capillaries of the lymphatics

• Exudate contains proteins, clotting factors, and antibodies


Inflammatory Response: Edema• Functions of the surge of exudate

• Moves foreign material into lymphatic vessels

• Delivers clotting proteins to form a scaffold for repair and to isolate the area – by walling off the infected area

• Streptococcus can produce Streptokinase to break down clot and open the walled off area


Anti-inflammatory agents• NSAID – Non-steroidal antiinflammatory drugs

– which are anti-prostaglandins

• SAID – Steroidal anti-inflammatory drugs – which are natural and synthetic glucocorticoids


NSAID• drugs with analgesic and antipyretic (fever-

reducing) effects and which have, in higher doses, anti-inflammatory effects (reducing inflammation).

• There are two main types of NSAIDs, nonselective and selective. The terms nonselective and selective refer to different NSAIDs ability to inhibit specific types of cyclooxygenase (COX) enzymes.

• Nonselective NSAIDs — Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a similar degree.

• Selective NSAIDs — Selective NSAIDs inhibit COX enzymes found at sites of inflammation (COX-2) more than the type that is normally found in the stomach, blood platelets, and blood vessels (COX-1).

• Nonselective NSAIDs — Nonselective NSAIDs include commonly available drugs such as aspirin, ibuprofen (Advil®, Motrin®, Nuprin®), and naproxen (Aleve®), as well as some prescription-strength NSAIDs (table 1).

• Selective NSAIDs — Selective NSAIDs (also called COX-2 inhibitors) are as effective in relieving pain and inflammation as nonselective NSAIDs and are less likely to cause gastrointestinal injury. Celecoxib (Celebrex®) is the only selective NSAID currently available in the United States.

• Selective NSAIDs are sometimes recommended for people who have had a peptic ulcer, gastrointestinal bleeding, or gastrointestinal upset when taking nonselective NSAIDs. Selective NSAIDs have less potential to cause ulcers or gastrointestinal bleeding, but they do not prevent ulcers that develop for other reasons

http://www.uptodate.com/patients/content/image.do?imageKey=RHEUM/26364


• Nonselective NSAIDs — Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a similar degree.

• Selective NSAIDs — Selective NSAIDs inhibit COX enzymes found at sites of inflammation (COX-2) more than the type that is normally found in the stomach, blood platelets, and blood vessels (COX-1).


• Nonselective NSAIDs — Nonselective NSAIDs include commonly available drugs such as aspirin, ibuprofen (Advil®, Motrin®, Nuprin®), and naproxen (Aleve®), as well as some prescription-strength NSAIDs

• Selective NSAIDs — Selective NSAIDs (also called COX-2 inhibitors) are as effective in relieving pain and inflammation as nonselective NSAIDs and are less likely to cause gastrointestinal injury. Celecoxib (Celebrex®) is the only selective NSAID currently available in the United States.


SAID (Glucocorticoids) • Glucocorticoids influence all types of inflammatory

events, no matter their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.

• Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.


Beta Defensins• Beta defensins are a family of mammalian

defensins. The beta defensins are antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonization.

• Present in epithelial mucosal cells – and released when the epithelial cells are damaged

• Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.

• Alpha defensins are produced by neutrophils


Tissue injury

Release of chemical mediators(histamine, complement,kinins, prostaglandins, etc.)

Vasodilationof arterioles

Increased capillarypermeability

Local hyperemia(increased blood

flow to area)

Locally increasedtemperature increasesmetabolic rate of cells

Leaked protein-richfluid in tissue spaces

Leaked clottingproteins form interstitialclots that wall off area

to prevent injury tosurrounding tissue

Temporary fibrinpatch forms

scaffolding for repair

Healing

Capillariesleak fluid

(exudate formation)

Attract neutrophils,monocytes, andlymphocytes to

area (chemotaxis)

Release of leukocytosis-inducing factor

Leukocytosis (increased numbers of whiteblood cells in bloodstream)

Leukocytes migrate toinjured area

Margination (leukocytes cling to

capillary walls)

Diapedesis (leukocytes pass through

capillary walls)

Phagocytosis of pathogensand dead tissue cells

(by neutrophils, short-term;by macrophages, long-term)

Area cleared of debris

Pus may form

Signs of inflammation

Initial stimulusPhysiological response

Result


Possible temporarylimitation of

joint movement

Heat Redness Pain Swelling


Phagocyte Mobilization

• Neutrophils, then phagocytes flood to inflamed sites


Phagocyte Mobilization

• Steps for phagocyte mobilization

1. Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells

2. Margination: neutrophils cling to the walls of capillaries in the inflamed area (selectins)

3. Diapedesis of neutrophils

4. Chemotaxis: inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils


Innatedefenses

Internaldefenses

Leukocytosis.Neutrophils enter bloodfrom bone marrow.

Margination.Neutrophils clingto capillary wall.

Diapedesis.Neutrophils flatten andsqueeze out of capillaries.

Chemotaxis.Neutrophilsfollow chemicaltrail.Capillary wallBasementmembraneEndothelium

Inflammatorychemicalsdiffusingfrom theinflamed siteact as chemotacticagents.

1 2 3

4

Copyright © 2010 Pearson Education, Inc. Figure 21.4, step 1

Innatedefenses

Internaldefenses


Capillary wallBasementmembraneEndothelium


1


Innatedefenses

Internaldefenses





1 2


Innatedefenses

Internaldefenses






1 2 3


Innatedefenses

Internaldefenses




Chemotaxis.Neutrophilsfollow chemicaltrail.Capillary wallBasementmembraneEndothelium


1 2 3

4


Antimicrobial Proteins

• Interferons (IFNs) and complement proteins• Attack microorganisms directly

• Hinder microorganisms’ ability to reproduce


Interferons

• Viral-infected cells are activated to secrete IFNs

• IFNs enter neighboring cells

• Neighboring cells produce antiviral proteins that block viral reproduction


VirusNew viruses

Viral nucleic acid

DNA

mRNANucleus

Interferon

Virusenters cell.

Interferongenes switch on.

Cell producesinterferonmolecules.

Interferonbindingstimulates cell toturn on genes forantiviral proteins.

Antiviralproteins blockviralreproduction.

Host cell 1Infected by virus;makes interferon;is killed by virus


Host cell 2Binds interferon from cell 1; interferon induces synthesis ofprotective proteins

1

2

34

5


VirusViral nucleic acid

Virusenters cell.




1

Nucleus



DNA

Nucleus

Virusenters cell.





1

2



DNA

mRNANucleus

Interferon

Virusenters cell.






1

2

3



DNA

mRNANucleus

Interferon

Virusenters cell.







1

2

34


VirusNew viruses

Viral nucleic acid

DNA

mRNANucleus

Interferon

Virusenters cell.




Antiviralproteins blockviralreproduction.




1

2

34

5


Interferons• Produced by a variety of body cells

• Lymphocytes produce gamma (), or immune, interferon – stimulates macrophages to killer status

• Most other WBCs produce alpha () interferon – reduce inflammation

• Fibroblasts produce beta () interferon – reduce inflammation

• Interferons also activate macrophages and mobilize NKs


Interferons• Functions

• Anti-viral – in the cell being defended the cell produces PKR ( Protein Kinase RNA) – this blocks the virus from making new proteins in the host cell – blocks at the ribosome

• Reduce inflammation• Activate macrophages and mobilize NK cells

• Genetically engineered IFNs for• Antiviral agents against hepatitis and genital

warts virus – alpha and Beta Interferons• Multiple sclerosis treatment – Beta Interferon


Complement

• ~20 blood proteins that circulate in an inactive form

• Include C1–C9, factors B, D, and P, and regulatory proteins

• Major mechanism for destroying foreign substances


Complement

• Amplifies all aspects of the inflammatory response

• Kills bacteria and certain other cell types by cell lysis

• Enhances both nonspecific and specific defenses

• Opsonization – Inflammation and Lysis


Complement Activation• Two pathways

1. Classical pathway• Antibodies bind to invading organisms or

CRPNote: only two antibodies bind compliment

–IgG and IgM • C1 binds to the antigen-antibody

complexes (complement fixation)2. Alternative pathway

• Triggered when activated C3, B, D, and P interact on the surface of microorganisms


Complement Activation

• Each pathway involves activation of proteins in an orderly sequence

• Each step catalyzes the next

• Both pathways converge on C3, which cleaves into C3a and C3b


Complement Activation

• Activated complement• Enhances inflammation• Promotes phagocytosis• Causes cell lysis

• C3b initiates formation of a membrane attack complex (MAC)

• MAC causes cell lysis by inducing a massive influx of water

• C3b also causes opsonization, and C3a causes inflammation


Spontaneous activation

Stabilizing factors (B, D, and P)

No inhibitors on pathogensurface

Alternative pathway

Enhances inflammation:

Insertion of MAC and cell lysis(holes in target cell’s membrane)

Complementproteins(C5b–C9)

Pore

Membraneof target cell

++

stimulates histamine release,increases blood vessel permeability, attracts phagocytes by chemotaxis, etc.

complex

Opsonization:

+

coats pathogensurfaces, which enhances phagocytosis

Antigen-antibody complexClassical pathway

Two IgG or CRP or 1 IgM Surface not protected by sialic acid


C-Reactive Protein (CRP)• C-reactive protein (CRP) is a protein found

in the blood, the levels of which rise in response to inflammation (an acute-phase protein). Its physiological role is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex.

• CRP is synthesized by the liver in response to factors released by fat cells.


C-Reactive Protein (CRP)• CRP was originally discovered by Tillett and

Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C polysaccharide of pneumococcus.

• CRP is a member of the class of acute-phase reactants, as its levels rise dramatically during inflammation processes occurring in the body.

• CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and therefore its level is mainly determined by the rate of production


CRP versus ESR• The erythrocyte sedimentation rate (ESR is

the rate at which red blood cells precipitate in a period of 1 hour. It is a common hematology test which is a non-specific measure of inflammation. To perform the test, anticoagulated blood is placed in an upright tube, known as a Westergren tube, and the rate at which the red blood cells fall is measured and reported in mm/h.

• ESR – slower and more prolonged sign of inflammation than the CRP


Fever• Systemic response to invading

microorganisms

• Leukocytes and macrophages exposed to foreign substances secrete pyrogens

• Pyrogens reset the body’s thermostat upward


Fever• Pyrogens generally microorganisms cause the

release of fever inducing cytokines from cells such as WBC , smooth muscle cells, glial cells and some others

• The cytokines are IL1, TNF, Interferon alpha, and IL6

• These travel in the circulation causing certain blood vessel endothelial cells in the thermal control center (Pre-optic nucleus) in the hypothalamus to produce PGE2 – which causes cyclic AMP to produced subsequently causing the cells of the pre-optic nucleus to raise the body temperature


Fever• High fevers are dangerous because heat

denatures enzymes

• Benefits of moderate fever• Causes the liver and spleen to sequester iron

and zinc (needed by microorganisms)

• Increases metabolic rate, which speeds up repair

• Kills certain organisms like syphilis


Fever versus Hyperthermia• A fever is when the temperature set point in

the hypothalamus is changed

• Hyperthermia is a condition when normal metabolic heat cannot be dissipated – thus raising the body temperature


Adaptive Defenses

• The adaptive immune (specific defense) system• Protects against infectious agents and

abnormal body cells

• Amplifies the inflammatory response

• Activates complement


Adaptive Defenses

• Adaptive immune response• Is specific

• Is systemic

• Has memory

• Two separate overlapping arms

1. Humoral (antibody-mediated) immunity

2. Cellular (cell-mediated) immunity


Antigens (Antibody Generating) • Antigen – substance that be recognized by the

adaptive immune system (can be partial or complete)

• Isoantigens (self MHC 1) and hetero-antigens

• Immunogen – special type of antigen that can stimulate the 3rd line (adaptive immune system) by itself (complete antigen)

• Substances that can mobilize the adaptive defenses and provoke an immune response

• Most are large, complex organic molecules not normally found in the body (nonself) –proteins are generally the most antigenic


Complete Antigens (Immunogenicity) • Important functional properties

• Immunogenicity: ability to stimulate proliferation of specific lymphocytes and antibodies (complete antigen)

• Reactivity: ability to react with products of activated lymphocytes and antibodies released (partial antigen if only can do reactivity and not immunogenicity)

Examples: foreign protein, polysaccharides, lipids, and nucleic acids


Haptens (Incomplete Antigens)Antigenicity• Small molecules (peptides, nucleotides, and

hormones) – less than 1,000 AMU (Daltons) • Not immunogenic by themselves• Are immunogenic when attached to body

proteins• Cause the immune system to mount a harmful

attack • Examples: poison ivy, animal dander,

detergents, and cosmetics


Antigenic Determinants (Epitopes)

• Certain parts of an entire antigen that are immunogenic

• Antibodies and lymphocyte receptors bind to them


Antigenic Determinants

• Most naturally occurring antigens have numerous antigenic determinants that• Mobilize several different lymphocyte

populations

• Form different kinds of antibodies against it

• Large, chemically simple molecules (e.g., plastics or metals – like a prosthesis) have little or no immunogenicity


Multiple antigenic determinants on surface of the bacteriaIf each antigenic determinant is different – then a different antibody and/or T cell can attach to it. cell will attach


Antigenic determinantsAntigen-bindingsitesAntibody A

Antibody BAntibody C

Antigen


Self-Antigens (Isoantigens) : MHC Proteins

• Protein molecules (self-antigens) on the surface of cells

• Antigenic to others in transfusions or grafts

• Example: MHC proteins• Coded for by genes of the major

histocompatibility complex (MHC) and are unique to an individual


MHC Proteins• In humans, the 3.6-Mb (3,600,000 base pairs) MHC

region on chromosome 6 contains 140 genes• Classes of MHC proteins

• Class I MHC proteins, found on virtually all body cells

• Class II MHC proteins, found on certain cells in the immune response

• Class MHC III – code for immune components such as complement, and some cytokines like TNF

• MHC proteins display peptides (usually self-antigens)

• In infected cells, MHC proteins display fragments of foreign antigens- MICA, which help mobilize

• MICA – MHC Class I Chain – related Gene A


MHC I and II• The MHC surface markers are proteins that have

a groove in their surfaces exposed to the outside of the cell

• The groove is filled with some substance – if the MHC I – it is filled with a piece of a protein formed from the inside of the cells (endogenous antigens) – proteins formed on the inside of the cell could be normal or abnormal (virus or tumor)

• If MHC II – it is filled with some coming from the outside of the cell (exogenous antigens)


Cells of the Adaptive Immune System

• Two types of lymphocytes• B lymphocytes (B cells)—humoral immunity

• T lymphocytes (T cells)—cell-mediated immunity

• Antigen-presenting cells (APCs)• Do not respond to specific antigens

• Play essential auxiliary roles in immunity


Lymphocytes

• Originate in red bone marrow• B cells mature in the red bone marrow (B

originally came from the studies done in the Bursa of Fabricius of the chicken)

• T cells mature in the thymus


Proportions of Lymphocytes

• Natural Killer - 7% (2-13%)

• T helper – T4 – 46% (28 – 59%)

• T cytotoxic T8 – 19% (13-32%)

• T gamma –delta – no number

• B – cells - 23% (18 – 47%)


• When Lymphocytes are mature, they have

• Immunocompetence; they are able to recognize and bind to a specific antigen (recognize where to look for an antigen and bind tight if foreign)

• Self-tolerance – unresponsive to self antigens

• Naive (unexposed) B and T cells are exported from the primary lymphoid organs (Thymus and Bone marrow) to lymph nodes, spleen, and other lymphoid organs

• Terminology - before immunocompetence – immature – after immunocompetence but have not met an antigen – naïve – after meeting antigen but no costimulation- active idling – after costimulation – fully active


1

2

3

Red bone marrow: site of lymphocyte origin

Secondary lymphoid organs: site ofantigen encounter, and activation to becomeeffector and memory B or T cells

Primary lymphoid organs: site ofdevelopment of immunocompetence as B orT cells

Lymphocytes destined to become T cellsmigrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow.

Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen.

Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body.

Redbone marrow

Bone marrowThymus

Lymph nodes,spleen, and otherlymphoid tissues

Immaturelymphocytes

Adaptive defenses Humoral immunityCellular immunity


T Cells (Have TCR – T cell receptor –CD3)• In the thymus under the influence of thymic hormones

(Thymosins) get educated and get CDs (CD3 and other specific CD like 4, 8, 10 or gamma delta) on cell surface have 104 to 105

• Thymic education process involves two processes – positive and negative selection (no outsiders – Blood-Thymic barrier)• Positive selection

• Selects T cells capable of loosely binding to the self-MHC proteins themselves (MHC restriction) –– This is a recognition and restriction process

• Negative selection• Prompts apoptosis of T cells that bind too tightly to self-

the self antigens displayed by self-MHC proteins• Ensures self-tolerance


MHC restriction further clarified• 1. Good T-lymphocytes should be restricted to only view

antigens associated with an MHC I or MHC II

• 2. If the cell is a T helper cell it should be restricted to only view antigens (foreign) on an MHC II

• 3. If the T cell is any other variety like the T-cytotoxic – then it should only be restricted to view antigens (endogenously produced) on MHC I – and only view it if the antigen presented is endogenous. Some endogenous antigens (proteins) are cut up proteins displaying trouble (virus, intracellular parasite or tumor)


T-cells• When a cell enters the thymus gland it receives many

T cell receptors (CD 3) – the T cell receptors are of different varieties (variety determines whether it can view only MHC I or MHC II) – but each cell has one variety with somewhere between 100,000 – 1,000,000 copies of the receptors on the cell membrane

• During positive selection – only the variety of T-cells having a T cell receptor that recognizes our own MHC isoantigen proteins (only the MHC itself – not anything bound to it) displayed on the epithelial cells in the Thymus outer cortex are retained – those that do not undergo apoptosis – MHC restriction – T cells should only view MHC receptors

• During positive selection T helper cells should be directed to only view MHC II and all the others MHC I (like the T cytotoxic)


Negative Selection• Occurs in inner thymic cortex as cells move

downward from the outer cortical area where positive selection occurred.

• In negative selection – non T helper –cells that bind to (especially too tightly) MHC I receptors with one of our own proteins in its groove are eliminated (apoptosis) – this is how we develop tolerance


Types of T cells• While positive and negative selection is occurring in the

thymus the immature T cells are also expressing CD4 or CD8 antigens on their surface. Initially the pre-T cell that enters the thymus is CD4-CD8-. In the thymus it becomes CD4+CD8+ and as positive and negative selection proceeds a cell becomes either a CD4+ or CD8+ cell.

• The commitment to become either a CD4+ or CD8+ cells depends on which class of MHC molecule the cell encounters. If a CD4+CD8+ cell is presented with a class I molecule it will down regulate CD4 and become a CD8+ cell. If a cell is presented with a class II MHC molecule it will down regulate CD8 and become a CD4+ cell


Thymic education occurs in cortex• Outer cortex – Positive Selection

• Inner cortex – Negative Selection

Thymic education is a 2 -3 day process.

Only 2% graduate – 98% undergoapoptosis


Adaptive defensesPositive selection: T cells must recognize self major histocompatibility proteins (self-MHC).

Antigen-presentingthymic cell

Failure to recognize self-MHC results in apoptosis (death by cell suicide).

Recognizing self-MHC results inMHC restriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceedto negative selection.

Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases.

Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation.

MHCSelf-antigen

T cell receptor

DevelopingT cell

Cellular immunity

Negative selection: T cells must not recognize self-antigens.


B Cells (B-cell receptors are surface antibodies – CD 19 and 21) • B cells mature in red bone marrow

• Self-reactive B cells• Are eliminated by apoptosis (clonal deletion) or

• Undergo receptor editing – rearrangement of their receptors

• Are inactivated (anergy) if they escape from the bone marrow


B cells should only recognize foreign substances – not self at all!


Antigen Receptor Diversity• Lymphocytes make up to a billion different types of antigen

receptors

• Coded for by only ~20,000 - 25,000 genes (Domain genes)

• The haploid human genome contains 23,000 protein-coding genes, far fewer than had been expected before its sequencing. In fact, only about 1.5% of the genome codes for proteins, while the rest consists of non-coding RNA genes, regulatory sequences, introns, and (controversially named) "junk" DNA

• Gene segments are shuffled by somatic recombination

• Genes determine which foreign substances the immune system will recognize and resist


Karyotype


Introns act as spacers for genetic recombination of domains (exons)


Antigen-Presenting Cells (APCs)• Have MHC II on their cell surfaces

• Engulf antigens

• Present fragments of antigens to be recognized by T cells

• Major types• Dendritic cells in connective tissues and epidermis

• Macrophages in connective tissues and lymphoid organs

• Some B cells


Macrophages and Dendritic Cells

• Present antigens and activate T cells• Macrophages mostly remain fixed in the lymphoid

organs

• Dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs

• Activated T cells release chemicals that• Prod macrophages to become insatiable phagocytes

and to secrete bactericidal chemicals


Adaptive Immunity: Summary

• Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances

• Depends upon the ability of its cells to• Recognize antigens by binding to them

• Communicate with one another so that the whole system mounts a specific response


Humoral Immunity Response

• Antigen challenge• First encounter between an antigen and a

naive immunocompetent lymphocyte

• Usually occurs in the spleen or a lymph node

• If the lymphocyte is a B cell• The antigen provokes a humoral immune

response

• Antibodies are produced


Clonal Selection

1. B cell is activated when antigens bind to its surface receptors and cross-link them

2. Receptor-mediated endocytosis of cross-linked antigen-receptor complexes occurs

3. Stimulated B cell grows to form a clone of identical cells bearing the same antigen-specific receptors(T cells are usually required to help B cells achieve full activation)


Fate of the Clones

• Most clone cells become plasma cells• secrete specific antibodies at the rate of 2000

molecules per second for four to five days


Fate of the Clones

• Secreted antibodies• Circulate in blood or lymph

• Bind to free antigens

• Mark the antigens for destruction


Fate of the Clones

• Clone cells that do not become plasma cells become memory cells• Provide immunological memory

• Mount an immediate response to future exposures of the same antigen

Copyright © 2010 Pearson Education, Inc. Figure 21.11 (1 of 2)

Primary response(initial encounterwith antigen)

Antigen bindingto a receptor on aspecific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive)

Proliferation toform a cloneActivated B cells

Plasma cells(effector B cells)Secretedantibodymolecules

Memory B cell—primed to respond to same antigen

Adaptive defenses Humoral immunity

Antigen


Immunological Memory• Primary immune response

• Occurs on the first exposure to a specific antigen

• Lag period: three to six days • Note – the lag period is the time it takes for the

selected B cells to proliferate to approximately 12 generations and to differentiate into plasma cells

• Peak levels of plasma antibody are reached in 10 days

• Antibody levels then decline quickly


Immunological Memory

• Secondary immune response• Occurs on re-exposure to the same antigen

• Sensitized memory cells respond within hours

• Antibody levels peak in two to three days at much higher levels

• Antibodies bind with greater affinity

• Antibody level can remain high for weeks to months


Primary response(initial encounterwith antigen)

Antigen bindingto a receptor on aspecific B lymphocyte(B lymphocytes withnon-complementaryreceptors remaininactive)

Proliferation toform a cloneActivated B cells

Plasma cells(effector B cells)

Secretedantibodymolecules

Memory B cell—primed to respondto same antigen

Clone of cellsidentical toancestral cells

Subsequentchallenge by same antigenresults in more rapid response

Secondary response(can be years later)

MemoryB cells

Plasmacells

Secretedantibodymolecules

Adaptive defenses Humoral immunity

Antigen


Time (days)

Anti-bodiesto A

First exposureto antigen A

Second exposure to antigen A;first exposure to antigen B

Anti-bodiesto B

Primary immuneresponse to antigenA occurs after a delay.

Secondary immune response toantigen A is faster and larger; primaryimmune response to antigen B issimilar to that for antigen A.


Active Humoral Immunity

• Occurs when B cells encounter antigens and produce specific antibodies against them• Two types

• Naturally acquired—response to a bacterial or viral infection

• Artificially acquired—response to a vaccine of dead or attenuated pathogens


Active Immunity (Artificially Acquired) - Vaccines

See Vaccine PowerPoint


Passive Humoral Immunity• B cells are not challenged by antigens

• Immunological memory does not occur

• Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases


Passive Humoral Immunity

• Two types

1. Naturally acquired—antibodies delivered to a fetus via the placenta or to infant through milk

2. Artificially acquired—injection of serum, such as gamma globulin

• Protection is immediate but ends when antibodies naturally degrade in the body


• Artificially acquired passive immunity (termed Gamma Globulin injection) is a short-term immunization achieved by the transfer of antibodies, which can be administered in several forms; as 1. human or animal blood plasma or serum, as 2. pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, as 3. high-titer human IVIG or IG from immunized or from donors recovering from the disease, and as 4. monoclonal antibodies (MAb).


PassiveActive

Humoralimmunity

ArtificiallyacquiredInjection ofimmune serum (gamma globulin)

Naturallyacquired

Antibodiespass from mother tofetus via placenta; or to infant in her milk

ArtificiallyacquiredVaccine;dead or attenuated pathogens

Naturallyacquired

Infection;contact with pathogen

the immune system: innate and adaptive:body defenses: part a

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