Immune system provides resistance to disease...Part 2 –Adaptive Defenses Adaptive immune system is a specific defensive system • eliminates almost any pathogen or abnormal cell

The Immune System

• Immune system provides resistance to disease

– Infectious agents

• Free in the 'humors' that circulate

• Within our 'infected' cells

– Our own abnormal and cancerous cells

• Made up of two systems

– Innate (nonspecific) defense system

– Adaptive (specific) defense system

video

The Immune System

• Immune system is a functional system rather than organ system

– Cells utilize blood, lymph and lymphoid tissue, loose fibrous tissues of skin and mucosa

– Cells circulate performing surveillance and carrying instructions to proliferation/activation centers

• Innate and adaptive defenses are intertwined

– Both release and recognize many of the same defensive molecules

– Innate responses release proteins that alert cells of adaptive system to foreign molecules

– Adaptive system enhances innate actions

Representative Groups of Infectious Agents

• Numerous Species and Forms within each Group• Evolutionary battle between our defenses and theirs• Virus is non-living• Infectious agents depicted not to scale

Figure 21.1 Simplified overview of innate and adaptive defenses.

Surface barriers• Skin• Mucous membranes

Internal defenses• Phagocytes• Natural killer cells• Inflammation• Antimicrobial proteins• Fever

Innatedefenses

Adaptivedefenses

Humoral immunity• B cells

Cellular immunity• T cells

First Line of Defense: Surface Barriers

• Surface barriers are skin and mucous membranes, along with their secretions

Second Line of Defense: Cells and Chemicals

• Innate system 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

• Many second-line cells have pattern recognition

receptors

Phagocytes

• Neutrophils

– abundant but killed during response

– no ‘memory’ of the agent maintained by these cells

• Macrophages (monocytes)

– Free

– Fixed

• Act using

– phagocytosis (obviously) either by acidification or

respiratory burst (strong oxidizers) in the phagolysosome

• Helper T cells stimulate respiratory burst

– Defensin antimicrobial peptides – create holes

– Toxic release into the extracellular fluid

Phagocytosis.

Innate defenses Internal defenses

A macrophage (purple) uses its cytoplasmicextensions to pull rod-shaped bacteria (green)toward it. Scanning electron micrograph (4800×).

Phagocytosis.

Lysosome

Acid

hydrolase

enzymes

Phagosome

(phagocytic

vesicle)

Events of phagocytosis.

Phagocyte forms

pseudopods that

eventually engulf the

particles, forming a

phagosome.

1

2

3

4

5

Phagocyte adheres

to pathogens or debris.

Lysosome fuses

with the phagocytic

vesicle, forming a

phagolysosome.

Toxic compounds

and lysosomal

enzymes destroy

pathogens.

Sometimes

exocytosis of the

vesicle removes

indigestible and

residual material.

Agents identified by • carbohydrate 'signature’, if

present• If not, agent may be coated with

opsonins• antibodies or complement

proteins• Opsonization

Opsonins act as “handles” for phagocytes to grab on to, enhancing phagocytosis

Example of cooperation between innate and adaptive immune systems

Natural Killer (NK) Cells

• Large granular lymphocytes circulating in blood and lymph

• Generalists:

– Attack cells that lack “self” cell-surface receptors called major histocompatibility complex (MHC) proteins

– kill before adaptive immune system is activated

• Kill by inducing apoptosis in cancer cells and virus-infected cells, not phagocytosis

• Stimulate inflammation (chemical release)

Inflammation: Tissue Response to Injury

• Inflammation is triggered whenever body

tissues are injured

– Injuries can be due to trauma, heat, irritating

chemicals, or infections by microorganisms

• Benefits of inflammation:

– Prevents spread of damaging agents

– Disposes of cell debris and pathogens

– Alerts adaptive immune system

– Sets the stage for repair

Inflammation: Tissue Response to Injury

• Inflammatory chemical release

– Chemicals are released into ECF by injured tissues,

immune cells, or blood proteins

– Macrophages and epithelial cells bear pattern recognition

receptors called “Toll-like receptors” (TLRs)

• 11 types of TLRs recognize specific classes of infecting microbes

• Activated TLRs trigger release of cytokines


Inflammatorychemicalsdiffusing fromthe inflamedsite act aschemotacticagents.

Capillary wall

Basementmembrane

Endothelium

4

321

Chemotaxis.

Neutrophils follow chemical trail.

Diapedesis.

Neutrophils flatten and squeeze out of capillaries.

Margination.

Neutrophils clingto capillary wall.

Leukocytosis.

Neutrophils enter blood from bone marrow.

Four cardinal signs of acute inflammation:

Redness

Heat

Swelling

Pain

Impairment of function (maybe a fifth)

Stages of inflammation:

1. Inflammatory chemical release

2. Vasodilation and increased vascular permeability

3. Phagocyte mobilization

Figure 21.3 Events of acute inflammation.


Tissue injury

Initial stimulus

Physiological response

Signs of inflammation

Result

Release of inflammatory chemicals

(histamine, complement,

kinins, prostaglandins, etc.)

Release of leukocytosis-

inducing factors

Leukocytosis

(increased numbers of white

blood cells in bloodstream)

Leukocytes migrate to

injured area

Margination

(leukocytes cling to

capillary walls)

Diapedesis

(leukocytes pass through

capillary walls)

Phagocytosis of pathogens

and dead tissue cells

(by neutrophils, short-term;

by macrophages, long-term)

Area cleared of debris

Pus may form

Healing

Locally increased

temperature increases

metabolic rate of cells

Possible temporary

impairment of

function

Temporary fibrin

patch forms

scaffolding

for repair

Leaked clotting

proteins form

interstitial clots

that wall off area

to prevent injury to

surrounding tissueHeat

Arterioles

dilate

Local hyperemia

(increased blood

flow to area)

Increased capillary

permeability

Attract neutrophils,

monocytes, and

lymphocytes to

area (chemotaxis)

Capillaries

leak fluid

(exudate formation)

Leaked protein-rich

fluid in tissue spaces

Redness Pain Swelling

Antimicrobial Proteins

• Antimicrobial proteins enhance innate defense

by:

– Attacking microorganisms directly, or

– Hindering microorganisms’ ability to reproduce

• Most important antimicrobial proteins

– Interferons• Virus infected cells may secrete IFNs that “warn” healthy

neighboring cells

– IFNs enter neighboring cells

» Block synthesis of virus, degrade viral RNA – nonspecific

– May also activate NK cells, macrophages

– Complement proteins

Figure 21.5 The interferon mechanism against viruses.


Virus

Viral nucleic acid

New

viruses

Antiviral

mRNADNA

Nucleus

mRNA for

interferon

Interferon

receptorInterferon

Virus

enters cell.

1

2

3

4

5

Interferon

genes

switch on.

Host cell 1 Host cell 2

Binds interferon

from cell 1; interferon

induces synthesis of

protective proteins

Infected by virus;

makes interferon;

is killed by virus

Antiviral

proteins block

viral reproduction.

Interferon

binding stimulates

cell to turn on genes

for antiviral proteins.

Cell

produces

interferon

molecules.

Antimicrobial Proteins (cont.)

• Complement

– Complement system consists of ~20 blood

proteins that circulate in blood in inactive form

– Provides major mechanism for destroying foreign

substances

– Activation enhances inflammation and also

directly destroys bacteria

• Enhances both innate and adaptive defenses

• Acts in an orderly fashion (similar to clotting)

Figure 21.6 Complement activation.

Activated by antibodies

coating target cell

Classical pathway Lectin pathway Alternative pathway

Activated by lectins

binding to specific sugars

on microorganism’s surface

Activated spontaneously. Lack of

inhibitors on microorganism’s

surface allows process to proceed

Together with other complement

proteins and factors

Pore

Complement

proteins

(C5b–C9)

Membrane

of target cell

MACs form from activated

complement components (C5b

and C6–C9) that insert into the

target cell membrane, creating

pores that can lyse the target cell.

Stimulates histamine

release, increases blood

vessel permeability,

attracts phagocytes by

chemotaxis, etc.

Coats pathogen

surfaces, which

enhances phagocytosis

Opsonization:

C3

C3bC3a

C3b

C5b

C6

C7

C8

C9

C5aEnhances inflammation:

MA

C

Antimicrobial Proteins (cont.)

• Fever

– Abnormally high body temperature that is systemic response to invading microorganisms

– Leukocytes and macrophages exposed to foreign substances secrete pyrogens

– Pyrogens act on body’s thermostat in hypothalamus, raising body temperature

– Benefits of moderate fever

• Causes liver and spleen to sequester iron and zinc (needed by microorganisms)

• Increases metabolic rate, which increases rate of repair

Part 2 – Adaptive Defenses

Adaptive immune system is a specific defensive system• eliminates almost any pathogen or abnormal cell in

body• Shortcoming: must be primed by initial exposure to

specific foreign substance• Priming takes time

Characteristics of adaptive immunity• It is specific: recognizes and targets specific antigens• It is systemic: not restricted to initial site• It has memory: mounts an even stronger attack to

“known” antigens (second and subsequent exposures)

Two Main Branches Of Adaptive System

Humoral (antibody-mediated) immunity

• Lymphocytic antibodies circulate freely in body fluids

– Bind temporarily to target cell

– Temporarily inactivate

– Mark for destruction by phagocytes or complement

• extracellular targets - B cells are activated by circulating antigens directly

Cellular (cell-mediated) immunity

• Lymphocytes act against target cell

– Directly—by killing infected cells

– Indirectly—by releasing chemicals that enhance inflammatory response; or

activating other lymphocytes or macrophages

• Cellular targets – T cells are activated by antigens presented by antigen

presenting cells via Major Histocompatibility Complex (MHC)

Antigens• Targets of all adaptive immune responses

• Most are large, complex molecules not normally found in body (nonself)

– foreign proteins

– Polysaccharides

– Lipids

– nucleic acids

– seen on many foreign invaders or a product of their activity

• Characteristics of antigens

– Can be a complete antigen or hapten (small molecule that may initiate

immune response if it attaches to one or our proteins; allergens)

– Contain antigenic determinants – portion of the molecule that fits into

antigenic receptors on immune cells or that is presented by antigenic

presenting cells

– Can be a self-antigen – presented by membrane proteins called MHC• MHCs and self antigens are genetically controlled

Figure 21.7 Most antigens have several different antigenic determinants.

Antigenic determinantsAntigen-bindingsites

Antibody A

Antibody B

Antibody C

Antigen

Lymphocytes

Lymphocyte development, maturation, and activation

• T and B lymphocytes share common development and steps in their life

cycles

• Five general steps:

1. Origin

2. Maturation

• Immunocompetence

• Self-tolerance

• Those that don’t pass the ‘tests’ are destroyed by apoptosis

3. Seeding secondary lymphoid organs and

circulation

4. Antigen encounter and activation

5. Proliferation and differentiation

Figure 21.8 Lymphocyte development, maturation, and activation.

1

2

3

4

5

Adaptive defensesHumoral immunity

Cellular immunity

Red bone

marrow

Lymphocyte

precursors

Thymus

Red bone marrow

Lymph node

Antigen

Primary lymphoid organs

(red bone marrow and thymus)

Secondary lymphoid organs

(lymph nodes, spleen, etc.)

Origin

Maturation

Seeding secondary lymphoid organs and

circulation

Antigen encounter and activation

Proliferation and differentiation

• Both B and T lymphocyte precursors originate in

red bone marrow.

• Lymphocyte precursors destined to become T cells

migrate (in blood) to the thymus and mature there.

• B cells mature in the bone marrow.

• During maturation lymphocytes develop

immunocompetence and self-tolerance.

• Immunocompetent but still naive lymphocytes leave

the thymus and bone marrow.

• They “seed” the secondary lymphoid organs and

circulate through blood and lymph.

• When a lymphocyte’s antigen receptors bind its

antigen, that lymphocyte can be activated.

• Activated lymphocytes proliferate (multiply) and then

differentiate into effector cells and memory cells.

• Memory cells and effector T cells circulate continuously

in the blood and lymph and throughout the secondary

lymphoid organs.

Slide 6

Lymphocytes (cont.)

• Antigen receptor diversity

– Genes, not antigens, determine which foreign substances the immune system will recognize

• Variety of immune cell receptors are result of acquired genetic knowledge of microbes

– ∼25,000 different genes codes for up to a billion different types of lymphocyte antigen receptors

• Huge variety of receptors: gene segments are shuffled around, resulting in many combinations

Antigen-Presenting Cells (APCs)

• Engulf antigens and present fragments of antigens to

T cells for recognition

• Major types

– Dendritic cells – cells of connective tissue and epidermis

that phagocytize infectious agents and present antigens to

T cells in the lymphatic system

– Macrophages - widely distributed in connective tissues

and lymphoid organs, they phagocytize infectious agents,

present antigens to T cell, causing T cell activation, and

receiving a dose of stimulating ‘super-macrophage’

inducing substances: cytokines

– B cells – present antigens to helper T cells but not to

activate them – stimulate cytokine release that stimulates

B cell division

Figure 21.10 Dendritic cell.

Figure 21.11-1 Clonal selection of a B cell.

Adaptive defenses Humoral immunity

Primary response

(initial encounter

with antigen)

Antigen

Antigen binding

to a receptor on a

specific B lymphocyte

(B lymphocytes with

noncomplementary

receptors remain

inactive)

Proliferation

to form a

clone

Activated B cells

Plasma cells

(effector B cells)

Secreted

antibody

molecules

Memory B cell—

primed to respond

to same antigen

Naïve cells

Figure 21.11-2 Clonal selection of a B cell.

Memory B cell—

primed to respond

to same antigen

Secondary response

(can be years later)Clone of cells

identical to

ancestral cells

Subsequent

challenge by same

antigen results in

more rapid response

Plasma

cells

Secreted

antibody

molecules

Memory

B cells

No longer naïve

Figure 21.12 Primary and secondary humoral responses.

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.

First exposure

to antigen A

Second exposure to antigen A;

first exposure to antigen B

Time (days)

An

tib

od

y t

ite

r (a

nti

bod

y c

on

ce

ntr

ati

on)

in p

lasm

a (

arb

itra

ry u

nit

s) 104

103

102

101

100

0 7 14 21 28 35 42 49 56

Anti-

bodies

to A

Anti-

bodies

to B

Figure 21.13 Active and passive humoral immunity.

Humoral

immunity

Active Passive

Naturally

acquiredArtificially

acquired

Naturally

acquiredArtificially

acquired

Infection;

contact with

pathogen

Vaccine;dead orattenuatedpathogens

Antibodies passed frommother tofetus viaplacenta; orto infant inher milk

Injection ofexogenousantibodies(gammaglobulin)

Antibodies

• Antibodies—also called

Immunoglobulins (Igs)—are proteins

secreted by plasma cells

– Make up gamma globulin portion of blood

• Capable of binding specifically with antigen

detected by B cells

• Grouped into one of five Ig classes

Figure 21.14a Antibody structure.


Antigen-binding site

Hinge region

Stem region

Heavy chain

variable region

Heavy chain

constant region

Light chain

variable region

Light chain

constant region

Disulfide bond

3-D Antibody structure.

Antibodies (cont.)

• Antibody targets and functions

– Antibodies do not destroy antigens; they inactivate and tag

them

• Form antigen-antibody (immune) complexes

– Defensive mechanisms used by antibodies

• Neutralization – antibodies attach to antigenic determinants

preventing antigens from binding to receptors on cells and marking

them for phagocytosis

• Agglutination – antibody attaches to two or more determinants

forming clumps

• Precipitation – soluble antigens are bound creating precipitates that

can be engulfed by phagocytes

• Complement fixation – opsonization – antibodies attach to antigens

on cell surface aligning complement proteins leading to open holes

which destroy cell

Figure 21.15 Mechanisms of antibody action.


AntigenAntigen-antibody

complexAntibody

Inactivates by Fixes and activates

Neutralization(masks dangerousparts of bacterial

exotoxins; viruses)

Agglutination(cell-bound antigens)

Precipitation(soluble antigens)

Complement

Enhances Enhances Leads to

Phagocytosis Inflammation Cell lysis

Chemotaxis

Histamine

release

Cellular Immune Response

• T cells are more complex than B cells both in

classification and function

• Two populations of T cells are based on which

cell differentiation glycoprotein receptors are

displayed on their surface

– CD4 cells usually become helper T cells (TH)

that can activate B cells, other T cells, and

macrophages; direct adaptive immune response

• Some become regulatory T cells, which moderate

immune response

– Can also become memory T cells

Cellular Immune Response

– CD8 cells become cytotoxic T cells (TC) that are

capable of destroying cells harboring foreign

antigens

• Also become memory T cells

• Helper, cytotoxic, and regulatory T cells are

activated T cells

• Naive T cells are simply termed CD4 or CD8

cells

Figure 21.16 Major types of T cells.

Lymphoid

tissues and

organs

Thymus

Adaptive defenses Cellular immunity

Immature

lymphocyte

Class II MHC

protein displaying

antigen

CD4

cell

T cell

receptorMaturation

T cell

receptor

CD8

cell

Class I MHC

protein displaying

antigen

APC

(dendritic cell) Memory

cells

Activation Activation

APC

(dendritic cell)

CD8 cells

becomecytotoxic

T cells

CD4 cells

become eitherhelper

T cells or

regulatory

T cells Effector

cells

Blood plasma

CD8CD4

Red bone marrow

Naïve cells

Table 21.6 Role of MHC Proteins in Cellular Immunity

Figure 21.17 Clonal selection of T cells involves simultaneous recognition of self and nonself.

Bacterial antigen

Dendritic

cell

Co-stimulatory

molecule receptor

CD4 T cell

T cell

receptor

(TCR)

CD4 protein

Co-stimulatory

molecule

Class lI MHC

protein

displaying

processed

bacterial antigen

Helper

T cells

Memory

CD4 T cell

Clone

formation


Dendritic cell engulfs

an exogenous

antigen, processes it,

and displays its

fragments on class II

MHC protein.

CD4 T cell

recognizes antigen-

MHC complex. Both

TCR and CD4 proteins

bind to antigen-MHC

complex.

1

2

2a

2b

3

Co-stimulatory

molecules bind their

receptors.

Clone formation

Activated CD4 T cells

proliferate (clone), and

become memory and

effector cells.

Double recognition

Antigen

presentation

Slide 4

Figure 21.18 The central role of helper T cells in mobilizing both humoral and cellular immunity.

Adaptive defensesHumoral immunity

Cellular immunity

Helper T cells help in humoral immunity Helper T cells help in cellular immunity

Helper T cell

T cell receptor (TCR)

Helper T cell

CD4 protein

MHC II protein

of B cell displaying

processed antigen

IL-4 and other

cytokines

B cell (being activated)CD8 T cell

(becomes TC cell

after activation)

Class I

MHC protein

CD8

protein

APC (dendritic

cell)

Class II MHC

protein

CD4 protein Helper T cell

IL-2

1

2

1

2

3

TH cell binds with the self-nonselfcomplexes of a B cell that has encountered

its antigen and is

displaying it on

MHC II on its surface.

TH cell releases

interleukins as co-

stimulatory signals to

complete B cell

activation.

TH cell binds

dendritic cell.

TH cell

stimulates dendritic

cell to express

co-stimulatory

molecules.

Dendritic cell

can now activate

CD8 cell with the

help of interleukin 2

secreted by TH cell.

Figure 21.19a Cytotoxic T cells attack infected and cancerous cells.


Cytotoxic

T cell (TC)

PerforinGranule

TC cell

membrane

Target

cell

membrane

Perforin

pore

Target

cell

Granzymes

A mechanism of target cell killing by TC cells.

1 2 3

5

4

TC identifies foreign antigens on MHC I proteins and binds tightly to target cell.

TC releases perforin and granzymemolecules from its granules by exocytosis.

Perforin molecules insert intothe target cell membrane,polymerize, and formtransmembrane pores (cylindricalholes) similar to those producedby complement activation.

The TC detaches

and searches for

another prey.

Granzymes enter the

target cell via the pores.

Once inside, granzymes

activate enzymes that

trigger apoptosis.

Figure 21.20 Simplified summary of the primary immune response.

Cellular

immunity

Humoral

immunityAntigen (Ag) intruder

InhibitsTriggers

Inhibits

Adaptive defenses Innate defenses

Surface

barriers

Internal

defenses

Free Ags

may directly

activate B cell

Antigen-

activated

B cells

Clone and

give rise to

Memory

B cells

Plasma cells

(effector B cells)

Nonspecific killers

(macrophages and

NK cells of innate

immunity)

Antibodies (Igs)

Helper

T cells

Memory

CD4 T cells

Cytotoxic

T cells

Memory

CD8 T cells

Naive

CD4

T cells

Naive

CD8

T cells

Ag-presenting cell

(APC) presents

self-Ag complex

Ag-infected

body cell engulfed

by dendritic cell

Secrete

Cytokines stimulate

Together the nonspecific killers

and cytotoxic T cells mount a

physical attack on the Ag

Circulating lgs along with complement

mount a chemical attack on the Ag

Induce

co-stimulation

Activated to clone

and give rise to

Activates

Activated to clone

and give rise to

Co-s

tim

ula

te a

nd r

ele

ase c

yto

kin

es

Pre

sent

Ag t

o h

elp

er

T c

ells

Becomes

Activates

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Immune system provides resistance to disease...Part 2 –Adaptive Defenses Adaptive immune system is a specific defensive system • eliminates almost any pathogen or abnormal cell