Fig. 43-1 1.5 µm Chapter 43 The Immune System. Fig. 43-2 INNATE IMMUNITY Recognition of traits...

Fig. 43-1

1.5 µm

Chapter 43 The Immune System

Fig. 43-2

INNATE IMMUNITY

Recognition of traitsshared by broad rangesof pathogens, using asmall set of receptors

•

•Rapid response

•Recognition of traitsspecific to particularpathogens, using a vastarray of receptors

•Slower response

ACQUIRED IMMUNITY

Pathogens(microorganisms

and viruses)

Barrier defenses:SkinMucous membranesSecretions

Internal defenses:Phagocytic cellsAntimicrobial proteinsInflammatory responseNatural killer cells

Humoral response:Antibodies defend againstinfection in body fluids.

Cell-mediated response:Cytotoxic lymphocytes defendagainst infection in body cells.

Fig. 43-3

Microbes

PHAGOCYTIC CELL

Vacuole

Lysosomecontaining enzymes

Fig. 43-4Activates antimicrobial peptide by infecting with bacteria

Engineered to express the GFP gene upon activation of the innate immune response

• Can a single antimicrobial peptide protect fruit flies against infection?

• In 2002, Bruno Lematire et al., • To test the function of a single antimicrobial peptide.

– Drosomycin or defensin– A single antimicrobial peptide in the fly’s body

can provide an effective and specific immune defense against a particular pathogen.

Fig. 43-5RESULTS

% s

urv

ival

Wild type

Fruit fly survival after infection by N. crassa fungi

100

75

50

25

00 24 7248 96 120

100

75

50

25

00 24 7248 96 120

Hours post-infection

Fruit fly survival after infection by M. luteus bacteria

Hours post-infection

% s

urv

ival

Mutant + drosomycin

Mutant + defensinMutant

Wild type

Mutant +drosomycin

Mutant +defensin

Mutant

Innate Immunity of Vertebrates

• The immune system of mammals is the best understood of the vertebrates

• Innate defenses include barrier defenses, phagocytosis, antimicrobial peptides

• Additional defenses are unique to vertebrates: the inflammatory response and natural killer cells

Cellular Innate Defenses

• White blood cells (leukocytes) engulf pathogens in the body

• Groups of pathogens are recognized by TLR, Toll-like receptors

Fig. 43-6

EXTRACELLULARFLUID Lipopolysaccharide

FlagellinTLR4

TLR5

Helperprotein

TLR9

TLR3

WHITEBLOODCELL

VESICLE

CpG DNA

ds RNA

Inflammatoryresponses

Toll-like receptor or TLR

Toll-like receptorFrom Wikipedia,

The curved leucine-rich repeat region of Toll-like receptors, represented

here by TLR3

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs which activates immune cell responses.

They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard.[1]

http://en.wikipedia.org/wiki/File:TLR3_structure.png

http://en.wikipedia.org/wiki/Leucine-rich_repeat

http://en.wikipedia.org/wiki/Leucine-rich_repeat

Signaling pathway of Toll-like receptors.

Dashed grey lines represent unknown associations

• A white blood cell engulfs a microbe, then fuses with a lysosome to destroy the microbe

• There are different types of phagocytic cells:– Neutrophils engulf and destroy microbes– Macrophages are part of the lymphatic system and

are found throughout the body– Eosinophils discharge destructive enzymes– Dendritic cells stimulate development of acquired

immunity

Fig. 43-7

Adenoid

Tonsil

Lymphnodes

Spleen

Peyer’s patches(small intestine)

Appendix

Lymphaticvessels Lymph

nodeMasses ofdefensive cells

Bloodcapillary

Lymphaticvessel

Tissuecells

Interstitial fluid

Antimicrobial Peptides and Proteins

• Peptides and proteins function in innate defense by attacking microbes directly or impeding their reproduction

• Interferon proteins provide innate defense against viruses and help activate macrophages

• About 30 proteins make up the complement system, which causes lysis of invading cells and helps trigger inflammation

Inflammatory Responses

• Following an injury, mast cells release histamine, which promotes changes in blood vessels; this is part of the inflammatory response

• These changes increase local blood supply and allow more phagocytes and antimicrobial proteins to enter tissues

• Pus, a fluid rich in white blood cells, dead microbes, and cell debris, accumulates at the site of inflammation

Fig. 43-8-1

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary

Phagocytic cellRed blood cells

Fig. 43-8-2

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary


Fluid

Fig. 43-8-3

Pathogen Splinter

Macrophage

Mast cell

Chemicalsignals

Capillary


Fluid

Phagocytosis

Specific immunity

Fig. 43-9

Antigen-bindingsite

Antigen-binding site

Antigen-bindingsite

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

T cell

chain chain

Disulfide bridge

Cytoplasm of T cell

(b) T cell receptor

Cytoplasm of B cell

(a) B cell receptor

B cell

V

V

C C

V

V

C C C C

VV

Fig. 43-9a

Antigen-bindingsite

Antigen-binding site

Disulfidebridge

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

Lightchain

Heavy chains

Cytoplasm of B cell

(a) B cell receptor

B cell

V

V

C C

V

V

C C

Fig. 43-9b

Antigen-bindingsite

Variableregions

Constantregions

Transmembraneregion

Plasmamembrane

T cell

chain chain

Disulfide bridge

Cytoplasm of T cell

(b) T cell receptor

C C

VV

Fig. 43-10

Antigen-binding sites

Antigen-bindingsites

Epitopes(antigenicdeterminants)

Antigen

Antibody B

Antibody CAntibody A

CC

CV

V

V

V

C

• Class I MHC molecules are found on almost all nucleated cells of the body

• They display peptide antigens to cytotoxic T cells

• Class II MHC molecules are located mainly on dendritic cells, macrophages, and B cells

• Dendritic cells, macrophages, and B cells are antigen-presenting cells that display antigens to cytotoxic T cells and helper T cells

Fig. 43-11

Antigen

Top view: binding surfaceexposed to antigen receptors

Plasmamembrane ofinfected cell

AntigenClass I MHCmolecule

Fig. 43-12

Infected cell

Antigenfragment

Class I MHCmolecule

T cellreceptor

(a)

Antigenassociateswith MHCmolecule

T cellrecognizescombination

Cytotoxic T cell (b) Helper T cell

T cellreceptor

Class II MHCmolecule

Antigenfragment

Antigen-presentingcell

Microbe

1

11

2

22

Fig. 43-13

DNA of undifferentiated B cell

1

DNA of differentiated B cell

pre-mRNA

mRNA

Light-chain polypeptide

Variableregion

Constantregion

Translation

B cell

B cell receptor

RNA processing

Transcription

DNA deleted between randomly selected V and Jsegments

Functional gene

V37 V38 V39 V40 J1 J2 J3 J4 CJ5 Intron

V37 V38 V39 CJ5 Intron

V39 CJ5 Intron

V39 CJ5 Poly-A tailCap

CV

VV

V

V

C C

C C

2

3

4

Ig gene rearrangement

The mechanism of Ig diversity

1. DNA recombination

2. The joining V, D, and J domains is not always precise

3. The DNA coding for hypervariable region is hypermutation

CU

Origin of Self-Tolerance

• Antigen receptors are generated by random rearrangement of DNA

• As lymphocytes mature in bone marrow or the thymus, they are tested for self-reactivity

• Lymphocytes with receptors specific for the body’s own molecules are destroyed by apoptosis, or rendered nonfunctional

Fig. 43-14

B cells thatdiffer inantigen specificity

Antibodymolecules

Antigenreceptor

Antigen molecules

Clone of memory cells Clone of plasma cells

Conal selection of B calla

Amplifying Lymphocytes by Clonal Selection

Fig. 43-15

Antibodiesto A

Antibodiesto B

Secondary immune response toantigen A produces antibodies to A;primary immune response to antigenB produces antibodies to B.

Primary immune responseto antigen A producesantibodies to A.

An

tib

od

y co

nce

ntr

atio

n(a

rbit

rary

un

its)

Exposureto antigen A

Exposure toantigens A and B

Time (days)

104

103

102

101

100

0 7 14 21 28 35 42 49 56

The specifity of immunological memory

Fig. 43-16

Humoral (antibody-mediated) immune response

B cell

Plasma cells

Cell-mediated immune response

Key

Stimulates

Gives rise to

+

+

++

+

+

+Memory B cells

Antigen (1st exposure)

Engulfed by

Antigen-presenting cell

MemoryHelper T cells

Helper T cell Cytotoxic T cell

MemoryCytotoxic T cells

ActiveCytotoxic T cells

Antigen (2nd exposure)

Secretedantibodies

Defend against extracellular pathogens by binding to antigens,thereby neutralizing pathogens or making them better targetsfor phagocytes and complement proteins.

Defend against intracellular pathogensand cancer by binding to and lysing theinfected cells or cancer cells.

+

+ +

Fig. 43-16a

Key

Stimulates

Gives rise to

+



Helper T cell

Engulfed by


+

+

+

+ +

+

Defend against extracellular pathogens

MemoryB cells


Plasma cells

B cell

Secretedantibodies

Humoral (antibody-mediated) immune response

Fig. 43-17

Antigen-presentingcell

Peptide antigen

Cell-mediatedimmunity (attack on

infected cells)

Class II MHC moleculeCD4

TCR (T cell receptor)

Helper T cell

Humoralimmunity

(secretion ofantibodies byplasma cells) Cytotoxic T cell

Cytokines

B cell

Bacterium

+

+ +

+

The central role of helper T cells in humoral and cell-mediated immune response

Fig. 43-16bCell-mediated immune response

Defend against intracellular pathogens

ActiveCytotoxic T cells

MemoryCytotoxic T cells




Helper T cell

Engulfed by


Cytotoxic T cell

KeyStimulates

Gives rise to

+

+

+

+

+ +

+

Fig. 43-18-1

Cytotoxic T cell

Perforin

Granzymes

TCRCD8

Class I MHCmolecule

Targetcell

Peptideantigen

Fig. 43-18-2

Cytotoxic T cell

Perforin

Granzymes

TCRCD8

Class I MHCmolecule

Targetcell

Peptideantigen

Pore

Fig. 43-18-3

Cytotoxic T cell

Perforin

Granzymes

TCRCD8

Class I MHCmolecule

Targetcell

Peptideantigen

Pore

Released cytotoxic T cell

Dying target cell

The killing action of cytotoxic T cells

----A response to infected cells

Fig. 43-19


Endoplasmicreticulum ofplasma cell

Secretedantibodymolecules

Bacterium

B cellPeptideantigen


TCR CD4

Helper T cellActivatedhelper T cell

Cytokines

Clone of memoryB cells

Clone of plasma cells

2 µm

+

B cell activation in the humoral immune response

----A response to extracellular pathogens

Fig. 43-19-1

Antigen-presenting cell Bacterium

Peptideantigen


TCR CD4

Helper T cell

Fig. 43-19-2


Peptideantigen


TCR CD4

Helper T cell

B cell

Activatedhelper T cell

Cytokines

+

Fig. 43-19-3


Peptideantigen


TCR CD4

Helper T cell

B cell

Activatedhelper T cell

Cytokines

+ Secretedantibodymolecules

Clone of memoryB cells

Clone of plasma cells

Fig. 43-19a

Endoplasmicreticulum ofplasma cell

2 µm

Fig. 43-20Class of Immuno-

globulin (Antibody)

IgG(monomer)

IgM(pentamer)

J chain

IgA(dimer)

IgE(monomer)

IgD(monomer)

Trans-membraneregion

J chain

Secretorycomponent

Distribution Function

First Ig classproduced afterinitial exposure toantigen; then itsconcentration inthe blood declines

Promotes neutraliza-tion and cross-linking of antigens;very effective incomplement systemactivation

Present insecretions suchas tears, saliva,mucus, andbreast milk

Only Ig class thatcrosses placenta,thus conferringpassive immunityon fetus

Triggers release frommast cells andbasophils of hista-mine and otherchemicals that causeallergic reactions

Present primarilyon surface ofB cells that havenot been exposedto antigens

Acts as antigenreceptor in theantigen-stimulatedproliferation anddifferentiation ofB cells (clonalselection)

Most abundant Igclass in blood;also present intissue fluids

Promotes opsoniza-tion, neutralization,and cross-linking ofantigens; less effec-tive in activation ofcomplement systemthan IgM

Provides localizeddefense of mucousmembranes bycross-linking andneutralization of antigens

Presence in breastmilk conferspassive immunityon nursing infant

Present in bloodat low concen-trations

The five ab , or immunoglobulin (Ig) classes

Fig. 43-20a

DistributionClass of Immuno-

globulin (Antibody)

IgM(pentamer)

J chain

First Ig classproduced afterinitial exposure toantigen; then itsconcentration inthe blood declines

Promotes neutraliza-tion and cross-linking of antigens;very effective incomplement systemactivation

Function

Fig. 43-20b

Distribution FunctionClass of Immuno-

globulin (Antibody)

IgG(monomer)

Most abundant Igclass in blood;also present intissue fluids

Promotes opsoniza-tion, neutralization,and cross-linking ofantigens; less effec-tive in activation ofcomplement systemthan IgM

Only Ig class thatcrosses placenta,thus conferringpassive immunityon fetus

Fig. 43-20c


globulin (Antibody)

IgA(dimer)

J chain

Secretorycomponent

Present insecretions suchas tears, saliva,mucus, andbreast milk

Provides localizeddefense of mucousmembranes bycross-linking andneutralization ofantigens

Presence in breastmilk conferspassive immunityon nursing infant

Fig. 43-20d


globulin (Antibody)

IgE(monomer)

Present in bloodat low concen-trations

Triggers release frommast cells andbasophils of hista-mine and otherchemicals that causeallergic reactions

Fig. 43-20e


globulin (Antibody)

IgD(monomer)

Trans-membraneregion

Present primarilyon surface ofB cells that havenot been exposedto antigens

Acts as antigenreceptor in theantigen-stimulatedproliferation anddifferentiation ofB cells (clonalselection)

Fig. 43-21

Viral neutralization

Virus

Opsonization

Bacterium

Macrophage

Activation of complement system and pore formation

Complement proteins

Formation ofmembraneattack complex

Flow of waterand ions

Pore

Foreigncell

Ab-mediated mechanisms of antigen disposal

Fig. 43-21a

Viral neutralization

Virus

Fig. 43-21b

Opsonization

Bacterium

Macrophage

Fig. 43-21c

Activation of complement system and pore formation

Complement proteins

Formation ofmembraneattack complex

Flow of waterand ions

Pore

Foreigncell

Fig. 43-22

Allergen

IgE

Granule

Mast cell

Histamine

Impact on public health

Fig. 43-24

•include systemic lupus erythematosus,• rheumatoid arthritis,• insulin-dependent diabetes mellitus, and• multiple sclerosis

Autoimmune diseases

Acquired immune system evasion by pathogens

• Antigenic variation

• Latency

• Herpes simplex viruses: typeI and II– Sensory neurons express relatively few MHCI

molecules

• Attack on the immune system:HIV

Fig. 43-25

Weeks after infection

Mill

ion

s o

f p

aras

ites

per

mL

of

blo

od

Antibodies tovariant 1appear



Variant 3Variant 2Variant 1

25 26 27 280

0.5

1.0

1.5

A change in epitope expression, which are called antigenic variation

---- sleeping sickness (trypanosomiasis)

Fig. 43-26

Latency

Relative antibodyconcentration

AIDSH

elp

er T

cel

l co

nce

ntr

atio

nin

blo

od

(ce

lls/m

m3 )

Helper T cellconcentration

Relative HIVconcentration

Years after untreated infection0 1 2 3 4 5 6 7 8 9 10

0

200

400

600

800

Fig. 43-1 1.5 µm Chapter 43 The Immune System. Fig. 43-2 INNATE IMMUNITY Recognition of traits...

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